link-springer-com-443.webvpn.jmu.edu.cn · vii foreword it is perhaps surprising that a book on...

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Aryeh ShanderHoward L. Corwin Editors

Hematologic Challenges in the Critically Ill

Aryeh Shander • Howard L. CorwinEditors


ISBN 978-3-319-93571-3 ISBN 978-3-319-93572-0 (eBook)https://doi.org/10.1007/978-3-319-93572-0

Library of Congress Control Number: 2018957332

© Springer International Publishing AG, part of Springer Nature 2018This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AGThe registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

EditorsAryeh ShanderDepartment of AnesthesiologyCritical Care and Hyperbaric MedicineTeam Health Research InstituteEnglewood, NJ USA

Englewood HealthEnglewood, NJ USA

Howard L. CorwinDepartment of Critical Care MedicineGeisinger Health SystemDanville, PA USA

https://doi.org/10.1007/978-3-319-93572-0

To my parents and sister. To my children for their inspiration, Noah, Hannah, Nina, and Eytan, and the wind in my sails, one and only, Susan.

Aryeh Shander

To my wife Randi and children Julie and Greg with love.

Howard L. Corwin

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Foreword

It is perhaps surprising that a book on hematologic challenges in critical care medi-cine has not surfaced in the past. However, critical care medicine had its origins in pulmonary medicine with the development of positive pressure mechanical ventila-tion during the 1950’s polio epidemics. At the time, hematology was an adolescent speciality, and blood transfusion was increasingly regarded as the logical therapy for deficiencies of the blood.

The central importance of the blood to the healthy and diseased human body is not new as William Harvey (1578–1657) stated: “The life then inheres in the blood, because therein the life and the soul are manifest first and fail last.”

Sir William Osler, the father of integrated scientific and personalized medicine, a doyen of internal medicine, established clinical pathology and the medical school at Johns Hopkins Hospital in the 1890s placing the study of blood central to his teaching, research, and clinical practice (British Medical Journal 14 Jan 1899). Dr. Henry Hewes, a Harvard medical school physician, stated in 1899: “The utilisation of the examination of the blood as an aid to diagnosis in ordinary clinical work is far less common than its value in this regard warrants” (Boston Medical and Surgical Journal 13 July 1899).

During the twentieth century and as medical practice entered the new millen-nium, remarkable advances in science and technology have dramatically impacted on the management of critically ill patients, especially the hematological aspects. A patient’s hematological and immunological systems, whether normal or abnormal, are now accepted as having a central role in the pathophysiology and clinical man-agement of most diseases. The publication of this book is an acknowledgment of this reality and answers the need for a source of knowledge and clinical expertise in the complex world of critical care medicine. The broad range of clinical settings and the eclectic range of experienced contributing authors acknowledge and address the importance and relevance of the blood to the care of critically ill patients.

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A highlight of this book is a focus on patient blood management with allogeneic blood transfusion no longer a default therapy, but only indicated when there are no alternative safer and effective interventions.

James P. IsbisterClinical Professor of Medicine

University of Sydney Emeritus Consultant Physician in Hematology

and Transfusion Medicine Royal North Shore Hospital of Sydney

Camperdown Australia

Foreword

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Preface

The origins of hematology date back to Hippocrates and the ancient Greeks, a time when blood was believed to be one of four humors whose balance was responsible for health and disease. As such, phlebotomy or bloodletting, implemented to restore balance in the body, was for several thousand years the mainstay of medical therapy for the seriously ill. No therapy matches bloodletting for longevity, but not until the nineteenth century did the practice of phlebotomy finally begin to fall into disfavor. On the other hand, critical care medicine as we know it today dates back just 60 years. Today, the old and the new have merged, and hematologic issues are inte-gral to the care of the critically ill. Whether disease or therapy, hematologic condi-tions present significant challenges to clinicians in the ICU because of the range of afflictions, diagnostic difficulties, and paucity of available therapeutic interventions.

The most prominent intersection between hematology and critical care medicine over the last 25 years has centered on the role of red blood cell (RBC) transfusion. Historically, RBC transfusions have been viewed as a safe and effective means of improving oxygen delivery to tissues. Beginning in the early 1980s, transfusion practice began to come under systematic scrutiny. Initially, primary concerns related to the risks of transfusion-related infection. While advances in transfusion medicine have greatly decreased the risk of viral transmission during RBC transfusion, other risks have driven the debate over transfusion practice and have continued the reex-amination of the approach to RBC transfusion. At the same time, examination and debate over RBC transfusion risks over the last quarter century have led to a more critical examination of transfusion benefits. These issues are particularly important in the critically ill patient population, and much of the progress in our understanding of the risks and benefits of RBC transfusion has been a direct result of efforts to better define the risks and benefits of RBC transfusion in the critically ill. Today, it is becoming clear that the risks and benefits of transfusion are not the same for all critical care populations.

While RBC transfusion has dominated the conversation regarding the intersec-tion of hematology and critical care, over recent years, other aspects of hematology have become more prominent in the critically ill. Advances in hematologic therapies

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such as bone marrow transplant have introduced a new group of complicated criti-cally ill patients. Other advances such as therapeutic apheresis and novel hemato-logic testing are also playing more of a role in the ICU. Advances in coagulation have been important in increasing our understanding of both the etiology and com-plications of critical illness. Improvements in monitoring the coagulation process and the availability of coagulation factors have facilitated the care of bleeding trauma and surgical patients. The relationship of the vasculature interaction with coagulation represents a new challenge in identifying the causes of thrombotic microangiopathy, the impact of fluids we use on hematologic outcome, and the newly available interventions. Key to early intervention is recognition of severe clotting syndromes that originate in endothelium disruption and in turn further aggravate the disruption culminating in a vicious cycle leading significant morbidity or death. From sepsis to trauma, understanding the coagulation and other hemato-logic events is essential if we are to improve management of patient to achieve the desired outcomes.

Critical care medicine from its origins has relied upon collaboration between all members of the health-care team in a true multidisciplinary approach to best serve our patients. This book attempts to span current hematologic challenges of the criti-cally ill patient using this multidisciplinary approach, bringing together experts who are either directly providing care at the bedside or indirectly involved in the care of these patients facing hematologic challenges, whether primary hematologic or a result of an underlying condition.

The first section addresses general issues in the critically including anemia in the critically ill, coagulation abnormalities, and the hematologic impact of fluid resus-citation. Also discussed are advances in hematologic testing. This latter topic is of particular importance as the challenge when it comes to hematologic diseases and conditions is being able to render a quick and accurate diagnosis. Viewing the chal-lenges faced from the point of view of laboratory medicine may help the ICU clini-cian understand the pitfalls of the available tests, their intended use, and new advances that may improve our ability to both diagnose conditions and follow response to therapy.

The second section addresses hematologic challenges associated with specific clinical situations. It has become clear over recent years that both the hematologic challenges that arise and the approach to specific hematologic challenges are very much influenced by the underlying disease process and/or organ system involved. For example, the approach to anemia is very different in the patient with cardiac disease than the surgical or trauma patient. Similarly, massive transfusion and hemostasis in the trauma patient present a unique set of challenges. Specific clinical areas addressed include trauma, sepsis, cardiovascular disease, GI and liver disease, obstetrics, neurologic disease, solid organ transplant, malignancy, and ECMO.

In the final section, topics of more general interest, not specific to any organ system or condition, are addressed. Several topics discussed revolve around special issues around RBC transfusion including risk of transfusion, age of blood, and treat-ment modalities other than transfusion. Also included is the increasingly important topic of the use of anticoagulants in the critically ill and the approach to reversing

Preface

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anticoagulation. There is also a discussion of the appropriate role of therapeutic apheresis in the critically ill as well as the role of two important partners of the ICU, the blood bank and the pharmacy, in dealing with hematologic challenges. Finally, the growing role of patient blood management in applying evidence-based practice to the treatment of underlying hematologic diseases and the use of blood compo-nents is reviewed.

This book attempts to span current and future hematologic challenges of the critically ill patient by bringing together experts in their respective areas. While our goal is to be complete, we understand that some issues may have either been left out or not covered in sufficient depth for some. That aside, we feel that we have excel-lent representation across disciplines to render a complete and clear view of the challenges one faces with ICU patients with hematologic conditions, whether pri-mary, associated, or a result of an underlying condition.

Englewood, NJ, USA Aryeh ShanderDanville, PA, USA Howard L. Corwin

Preface

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Contents

1 Anemia in the Critically Ill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Jens Meier

2 Hemostatic Abnormalities in the Critically Ill . . . . . . . . . . . . . . . . . . . 17Michelle Sholzberg

3 Understanding Advanced Hematologic Testing . . . . . . . . . . . . . . . . . . 41Amy E. Schmidt and Marisa B. Marques

4 Current and Emerging Technologies in Hematologic Testing. . . . . . . 65James E. Littlejohn and Richard L. Applegate II

5 Hematologic Impact of Fluid Replacement . . . . . . . . . . . . . . . . . . . . . 89Christopher R. Barnes and Anthony M. Roche

6 Hematologic Advances in Trauma Resuscitation . . . . . . . . . . . . . . . . . 103Lena M. Napolitano

7 Hematologic Issues in Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Tulin Budak-Alpdogan, Jeffrey Levine, and Phil Dellinger

8 Hematologic Challenges in ICU Patients with Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145Annemarie Beth Docherty and Timothy Simon Walsh

9 Hematologic Challenges in ICU Patients with Liver Disease and Gastrointestinal Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Jeannie Callum, Harry L. A. Janssen, and Walter Dzik

10 Hematological Challenges in Intensive Care Unit Patients with Neurological Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Alejandro Vargas and Thomas P. Bleck

11 Hematologic Challenges in the Critically Ill: Obstetrics . . . . . . . . . . . 199Nadav Levy and Carolyn F. Weiniger

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12 Hematologic Challenges in ICU Patients with Malignancy . . . . . . . . 215Michael Gale, Vikram Dhawan, and Stephen M. Pastores

13 Hematologic Challenges in ICU Patients on ECMO . . . . . . . . . . . . . . 237Cara Agerstrand, Andrew Eisenberger, and Daniel Brodie

14 Hematologic Challenges in Intensive Care Unit Patients with Solid Organ Transplants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Gerardo Tamayo-Enríquez and Daniel Borja-Cacho

15 Current Risks of Transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279Amy E. Schmidt, Majed A. Refaai, and Neil Blumberg

16 Clinical Outcomes and Red Blood Cell Storage . . . . . . . . . . . . . . . . . . 305Shuoyan Ning and Nancy M. Heddle

17 Anticoagulants in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321Pablo Perez d’Empaire, Pulkit Bhuptani, Selina Ho, and C. David Mazer

18 Therapeutic Apheresis for Hematologic Emergencies . . . . . . . . . . . . . 341Jori E. May and Marisa B. Marques

19 Intravenous Oxygen Therapeutics: A Revolution in Medicine Yet to Be Realized? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363Bruce D. Spiess

20 Role of Blood Bank, Transfusion Services, and Pharmacy in ICU Patients with Hematologic Challenges . . . . . . . . . . . . . . . . . . . . . . . . . 391Joseph E. Cruz, Jeffrey Nemeth, and Ana Burga

21 Patient Blood Management in Critically Ill . . . . . . . . . . . . . . . . . . . . . 407Suma Choorapoikayil, Kai Zacharowski, Christoph Füllenbach, and Patrick Meybohm

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425

Contents

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Contributors

Cara Agerstrand, MD Division of Pulmonary, Allergy and Critical Care, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY, USA

Richard L. Applegate II, MD UC Davis Medical Center, Department of Anesthesiology and Pain Medicine, Sacramento, CA, USA

Christopher R. Barnes, MD Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

Pulkit Bhuptani, BHSc, PharmD Pharmacy Department, St. Michael’s Hospital, Toronto, ON, Canada

Thomas P. Bleck, MD Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

Neil Blumberg, MD Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA

Daniel Borja-Cacho Department of Surgery, Division of Transplant Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Daniel Brodie, MD Division of Pulmonary, Allergy and Critical Care, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY, USA

Tulin Budak-Alpdogan Division of Hematology and Oncology, Department of Medicine, Cooper University Hospital, Camden, NJ, USA

Ana Burga Englewood Hospital and Medical Center, Englewood, NJ, USA

Jeannie Callum Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

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Suma Choorapoikayil Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany

Joseph E. Cruz Englewood Hospital and Medical Center, Englewood, NJ, USA

Pablo Perez d’Empaire, MD, FRCPC, FCCM Department of Anesthesia, St. Michael’s Hospital and Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

Phil Dellinger Department of Medicine, Cooper University Hospital, Camden, NJ, USA

Vikram Dhawan, MD Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Annemarie Beth Docherty Anaesthesia, Critical Care and Pain Medicine, School of Clinical Sciences, University of Edinburgh, Edinburgh, UK

Walter Dzik Department of Pathology, Harvard University, Boston, MA, USA

Pathology, Massachusetts General Hospital, Boston, MA, USA

Andrew Eisenberger, MD Division of Hematology, Columbia University College of Physicians and Surgeons, New York, NY, USA

Christoph Füllenbach Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany

Michael Gale, MD Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Nancy M. Heddle Department of Medicine, McMaster University, Hamilton, ON, Canada

Selina Ho, MBChB, FRCA Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

Harry L. A. Janssen Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada

Hepatology, University Health Network, Toronto, ON, Canada

Jeffrey Levine Division of Hematology and Oncology, Department of Medicine, Cooper University Hospital, Camden, NJ, USA

Nadav Levy, MD Division of Anesthesia, Intensive Care and Pain Medicine, Tel- Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel

James E. Littlejohn, MD, PhD UC Davis Medical Center, Department of Anesthesiology and Pain Medicine, Sacramento, CA, USA

Marisa B. Marques, MD Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA

Jori E. May Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

C. David Mazer, MD, FRCPC Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

Contributors

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Li Ka Shing Knowledge Institute and Keenan Research Center of St. Michael’s Hospital, Toronto, ON, Canada

Jens Meier Kepler Universitätsklinikum GmBH, Klinik für Anästhesiologie und Intensivmedizin, Linz, Austria

Patrick Meybohm, MD Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany

Lena M. Napolitano, MD, FACS, FCCP, MCCM Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA

Jeffrey Nemeth Englewood Hospital and Medical Center, Englewood, NJ, USA

Shuoyan Ning Department of Medicine, McMaster University, Hamilton, ON, Canada

Stephen M. Pastores, MD Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Majed A. Refaai, MD Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA

Anthony M. Roche, MBChB, FRCA, MMed Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

Amy E. Schmidt, MD, PhD Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA

Michelle Sholzberg, MD CM, FRCPC, MSc Departments of Medicine and Laboratory Medicine and Pathobiology, St. Michael’s Hospital, Toronto, ON, Canada

University of Toronto, Toronto, ON, Canada

Bruce D. Spiess Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA

Gerardo Tamayo-Enríquez Department of Surgery, Division of Transplant Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Alejandro Vargas, MD Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

Timothy Simon Walsh Anaesthesia, Critical Care and Pain Medicine, School of Clinical Sciences, University of Edinburgh, Edinburgh, UK

Carolyn F. Weiniger, MB ChB Division of Anesthesia, Intensive Care and Pain Medicine, Tel-Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel

Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Kai Zacharowski Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany

Contributors

1© Springer International Publishing AG, part of Springer Nature 2018 A. Shander, H. L. Corwin (eds.), Hematologic Challenges in the Critically Ill, https://doi.org/10.1007/978-3-319-93572-0_1

Chapter 1Anemia in the Critically Ill

Jens Meier

Introduction

Anemia is a common, worldwide health-care problem, and as a consequence patients suffering from anemia are treated by physicians all over the world on a daily basis. Depending on the region examined, up to 50% of all humans are anemic [1]; thus anemia has become one of the most prevalent and burdensome diseases. Anemia is characterized by a decreased quantity of red blood cells, often accompa-nied by diminished hemoglobin levels or altered red blood cell morphology. According to the definition of the World Health Organization (WHO), anemia is a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiological needs, which vary by age, gender, altitude, smoking, and pregnancy status. Several years ago, the WHO has also published thresholds that define the limits of normal and abnormal hemoglobin concentra-tions. A hemoglobin concentration of 13 g/dL in men and a hemoglobin concentra-tion of 12 g/dL in women are the lower threshold for the definition of anemia [1].

Anemia is pathophysiologically diverse and often multifactorial. Iron deficiency is thought to be the most common cause of anemia globally, although other condi-tions, such as folate, vitamin B12 and vitamin A deficiencies, chronic inflammation, parasitic infections, and inherited disorders can all cause anemia.

Many physicians judge anemia as a symptom and not as a disease per se. However, since anemia has gained an increase of interest in the last few years, more and more investigations describe anemia not solely as a symptom but as a pathologi-cal entity, which is an independent risk of morbidity and mortality.

J. Meier Kepler Universitätsklinikum GmBH, Klinik für Anästhesiologie und Intensivmedizin, Linz, Austriae-mail: [email protected]

http://crossmark.crossref.org/dialog/?doi=10.1007/978-3-319-93572-0_1&domain=pdf

mailto:[email protected]

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What holds true for the common population is even more pronounced for patients admitted to an intensive care unit (ICU). It is a well-known fact that nearly all ICU patients are either anemic at the time point of admission or become so after a few days of ICU stay [2]. The reasons for anemia in this situation are manifold and range from underlying diseases being the reason for ICU admission to the problem of a high number and probably unnecessary blood draws. As a consequence, most of the patients that leave the ICU remain anemic according to the WHO definition and by that are endangered by the risks associated with anemia risks that persist beyond their time in the ICU [2]. These include, but are not limited to, hypoxia, infection, myocardial infarction, stroke, etc. This extended risk profile very often results in the transfusion of allogeneic red blood cells during and after the ICU stay [3, 4]. However, within the last 20–30 years, it has been clearly demonstrated that not only anemia but also the transfusion of allogeneic red blood cells is indepen-dently associated with important risks and adverse effects. Therefore, anemia in the ICU is not only a side issue but a very important driver of ICU morbidity and mor-tality that determines the outcome of critically ill patients.

Pathophysiology of Anemia of Critical Illness

There are three main categories of anemia: anemia due to blood loss, anemia due to decreased red blood cell production, and anemia due to increased red blood cell break-down [5]. Furthermore, anemias are often categorized by a different approach based on RBC morphology and further parameters like, e.g., mean cellular volume (MCV).

Blood Loss-Induced Anemia

In contrast to the other types of anemia, anemia of blood loss is characterized by a reduced hemoglobin concentration with initial normal RBC indices, whereas ane-mias associated with normocytic and normochromic red cells and an inappropri-ately low reticulocyte response (reticulocyte index <2–2.5) are called hypoproliferative anemias.

Blood losses are very common in patients that have been admitted to an ICU: either severe, massive bleeding is the reason for admission to the ICU or less severe bleeding will occur during the duration of the stay due to several reasons, including occult bleeding, diagnostic blood tests, etc.

Massive Bleeding

Massive bleeding of many different etiologies still endangers patients in different clinical settings. It is currently defined by (a) indices of its rate and extent and (b) the magnitude of the consequent blood components transfused [6]. Depending on

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the clinical situation, these definitions might differ. At the onset of massive bleed-ing, the organism is endangered by severe hypovolemia and in the end by hypoper-fusion and a syndrome of hemorrhagic shock. Hemorrhagic shock is defined as a condition in which tissue perfusion is not capable of sustaining aerobic metabo-lism due to a loss of circulation blood [7]. Significant loss of intravascular volume may lead sequentially to hemodynamic instability, decreased tissue perfusion, cel-lular hypoxia, organ damage, and death. However, it is important to note that hem-orrhagic shock is not defined by the presentation of anemia, or defined as a low hemoglobin concentration, but is a result of severe bleeding-induced hypovolemia and hypoperfusion. As a consequence, in the early phase of hemorrhagic shock, the hemoglobin concentration may remain constant (since red blood cells and flu-ids are lost in a balanced manner), masking the occurrence of blood loss in situa-tion of occult bleeding. As events progress the course of hemorrhagic shock compensatory mechanisms (e.g., diffusion of interstitial and intracellular fluids into the blood vessels) will finally result in a decline of the hemoglobin concentra-tion by dilution of the remaining circulating red blood cells. Furthermore, the stan-dard treatment of hemorrhagic shock (i.e., the application of crystalloids and colloids) pronounces development of acute anemia by the same dilutional mechanism.

Although anemia due to massive bleeding is often described by the decline of the hemoglobin concentration, it has to be noted that all other components of blood are diluted as well by the mechanisms described above. Therefore, hemorrhagic shock does not only result in a decline of the hemoglobin concentration but also in a decline of proteins, coagulation factors, and other cellular elements of blood, resulting in hypoalbuminemia, coagulopathy, and thrombocytopenia. Furthermore, activation of an extensive network of proinflammatory mediator pathways by the innate immune system plays a significant role in the progression of hemorrhagic shock and contributes importantly to the development of multiple organ injury, multiple organ dysfunction (MOD), and multiorgan failure (MOF) and the highest risks of mortality [8].

There are a multitude of humoral mediators that are activated during shock and tissue injury. The complement cascade, activated through both the classic and alter-nate pathways, generates the anaphylatoxins C3a and C5a. Activation of the coagu-lation cascade causes microvascular thrombosis, with subsequent fibrinolysis leading to repeated episodes of ischemia and reperfusion. Components of the coag-ulation system (e.g., thrombin) are potent proinflammatory mediators that cause expression of adhesion molecules on endothelial cells and activation of neutrophils, leading to microvascular injury. Coagulation also activates the kallikrein-kininogen cascade, contributing and aggravating the presence of hypotension.

Therefore, massive bleeding-induced anemia is not only characterized by the decline of the hemoglobin concentration but has to be understood predominantly as a multifactorial, complicated pathophysiological event influencing oxygen, transport, tissue oxygenation, coagulation, and inflammation. Therefore, proper treatment is not limited to restoration of the circulating red cell mass but has also to include all the other side effects that are adjunctive to the sole hemoglobin loss.

1 Anemia in the Critically Ill

4

Protracted and Low-Volume Bleeding During the ICU Stay

The reasons for mild to moderate blood losses during an ICU stay are manifold. First of all, nearly half of the patients that are admitted to a general ICU suffer from some level of a coagulopathy [9] and by that are prone to bleeding complications of many different kinds. Some of these coagulopathies have their sources in the under-lying diseases, whereas a relevant number of patients suffer from iatrogenic coagu-lopathies since nowadays many patients are under oral antithrombotic therapy due to several reasons. Irrespective of the underlying pathophysiology, these coagulopa-thies result from overt and diffuse bleeding that might be responsible for significant and ongoing blood loss.

A second reason for moderate blood losses during the ICU stay is ICU-induced ulcers of the upper gastrointestinal tract. Stress ulcers typically occur in the gastric body, esophagus, or duodenum, sometimes resulting in severe gastrointestinal (GI) bleeding. Earlier studies reported overt GI bleeding in 5–25% of critically ill patients. In contrast, the incidence of clinically important GI bleeding is much lower, estimated between 1% and 4% [10]; however, it is found to be associated with increased ICU mortality and increased length of stay. As a consequence, recent guidelines strongly encourage perioperative GI ulcer prophylaxis at the ICU for the prevention of GI stress ulcers and the resultant bleeding.

The most frequent and probably most important reason for mild to moderate blood loss in the ICU is the “standard” blood tests that are usually drawn on a regu-lar basis every morning while in the ICU. Most physicians are accustomed to the routine of checking the most recent laboratory values on morning rounds, and there-fore frequent mutational blood sampling is one of the physicians’ rituals that has become an integral part of our daily work.

It has been demonstrated by several investigators that after 2 weeks in the ICU, more than 1 L of blood will be drawn depending on the underlying disease and the policy of the hospital [11, 12]. Therefore, even if other blood losses are absent, regu-larly drawing blood samples is a common risk factor for ICU-associated anemia, since typically 50 mL or more are drawn for one specific determination of a set of laboratory parameters [11, 12]. Although several guidelines urge physicians not to perform unnecessary laboratory tests, the approach described above is very com-mon, and it seems as if it is very difficult to deter physicians from this deep cultural event.

Decreased Red Blood Cell Production

Nutritional Deficiency Anemia

Although nutritional deficiency anemia is the most important type of anemia worldwide [1], its prevalence in modern ICUs is lower than for many people out-side the ICU [2]. It has been demonstrated by Lasocki and coworkers that less than

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10% of ICU patients suffer from iron deficiency when they are discharged from the ICU, whereas 100% of them were anemic in this situation. However, 6 months later 25% of them developed severe iron deficiency due to the high iron demand during recovery [2].

Erythropoiesis consists of two distinct steps, one of them is iron dependent, whereas the other is erythropoietin dependent. Erythropoietin is a hormone that is produced in adulthood by the kidneys. It is upregulated when oxygen delivery to the tissues and when regional oxygen tension fall below a specific value. As long as body iron storages are sufficient to produce enough erythrocytes in the bone marrow from erythroid progenitor cells, the hematocrit will reach physiological levels. However, as soon as iron depletion occurs, erythropoiesis will be insufficient, and this condition will result in the production of smaller and fewer RBCs that contain a reduced amount of hemoglobin, resulting in hypochromic anemia. Hypochromic anemia may be caused by low iron intake, diminished iron absorption, or excessive iron loss. It can also be caused by infections (e.g., hookworms) or other diseases, therapeutic medications, copper toxicity, and lead poisoning. Sources of blood loss can include heavy menstrual periods (HMP), childbirth, uterine fibroids, stomach ulcers, colon cancer, and urinary tract bleeding. A poor ability to absorb iron may occur as a result of Crohn’s disease or a gastric bypass. In the developing world, parasitic worms, malaria, and HIV/AIDS increase the risk of decreased iron absorp-tion. In the developed world, dietary restrictions are becoming more and more important. Especially the cutoff values for iron deficiency anemia might differ in this situation, since ferritin is an acute-phase protein [13].

Anemia of Chronic Disease

Most of the iron that is stored in the body is incorporated into hemoglobin in devel-oping erythroid precursor cells and mature RBCs. In contrast to patients with nutri-tional deficiency anemia, patients with anemia of chronic disease do not have depleted iron stores but lack the ability to utilize the iron which is theoretically available in the body. The key player of iron hemostasis in this situation is the hor-mone hepcidin. It is encoded by the HAMP gene and is the key regulator of iron metabolism in mammalian cells. Hepcidin inhibits iron absorption and transport by binding to the iron export channel ferroportin that is located on the basolateral sur-face of gut enterocytes and the plasma membrane of reticuloendothelial cells. Furthermore, hepcidin breaks down the transporter protein in the lysosome [14]. As long as ferroportin is inhibited, iron export from the cells is impossible, resulting in a situation which prevents iron from being released to the blood stream and results in sequestration of iron in the cells [15]. During sepsis proinflammatory cytokines like IFN-γ, TNFα, IL-1β, and IL-6 induce the release of hepcidin, and as a conse-quence erythropoiesis is reduced due to lack of available serum iron, although theo-retically enough iron is stored in the cells [16]. Beyond that the inflammatory cytokines also inhibit erythropoietin release from the kidneys and erythroid prolif-eration in the bone marrow further reducing erythropoiesis.


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Additionally, the release of inflammatory cytokines leads to activation of RBC destruction by macrophages, which not only decreases the absolute number of RBCs but also reduces RBC life span. Several studies were able to demonstrate that iron status as well as erythropoiesis are altered in non-bleeding ICU patients who are post-surgery, trauma, or are septic [17]. However, one has to be aware of the fact that anemia of chronic disease might be accompanied by other forms of anemia and that can be complicated making the diagnosis of complex anemia challenging.

Anemia Due to Increased Red Blood Cell Breakdown

There is a huge amount of hematological diseases that might result in increased red blood cell breakdown; however, the most important reasons for hemolytic anemia at the ICU are immune hemolytic anemias. Two different mechanisms are responsible for immune hemolytic anemias: [1] there is a true autoantibody directed against a red cell antigen, i.e., a molecule present on the surface of red cells, or [2] there is an antibody directed against a certain molecule (e.g., a drug). If that antibody reacts with that molecule, red cells may get caught in the reaction, whereby they are dam-aged and/or destroyed.

While the first pathophysiology is mainly treated by hematologists and is sel-domly an acute problem at the ICU, the second one is quite often induced by differ-ent medications that can lead to anemia by causing hemolysis via this immunologic pathway. Although “drug-induced” hemolytic anemia is relatively rare, serious adverse effect of therapeutic medications might play a role in the ICU under specific circumstances. The three most often identified medications as causing “drug- induced” hemolytic anemia are piperacillin, cefotetan, and ceftriaxone [18]. The most important modality to treat “drug-induced” anemia is the immediate with-drawal of these agents. However, since ICU patients are treated with a multitude of different medications, it is sometimes quite challenging to discover which medica-tion should be omitted in order to stop or prevent hemolysis.

Anemia and Hemoglobinopathies in the Critically Ill

Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero. With approximately 7% of the worldwide population being carriers, hemoglobinopathies are the most common monogenic diseases and one of the world’s major health problems. They were origi-nally found mainly in the Mediterranean area and large parts of Asia and Africa. International migration has spread them from those areas all over the world, and therefore they can be found in many ICUs mainly in large cities. Today, in many parts of Europe and the USA, hemoglobin (Hb) defects are classified as endemic

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diseases [19]. The most clinically relevant variant hemoglobins polymerize abnor-mally, as in sickle cell disease or exhibit altered solubility or oxygen-binding affin-ity. There are five major classes of hemoglobinopathies: [1] structural hemoglobinopathies (i.e., hemoglobins with altered amino sequences like, e.g., sickle cell disease), [2] thalassemias, [3] thalassemic hemoglobin variants (structur-ally abnormal Hb associated with coinherited thalassemic phenotype), [4] structur-ally abnormal Hb associated with coinherited thalassemic phenotype, and [5] acquired hemoglobinopathies. Thalassemias are the most common genetic disor-ders in the world, affecting nearly 200 million people worldwide underlining the relevance of this type of anemia.

The most important diagnostic tool for the detection of hemoglobinopathies is electrophoretic techniques, although it is not always conclusive since some signifi-cant variants of hemoglobinopathies (such as some variants of thalassemia) are elec-trophoretically silent. In these cases, the mutant hemoglobins can usually be detected by mass spectroscopy, which is gaining more traction as the standard diagnostic test.

Since hemoglobinopathies are prevalent and complex in both diagnosis and man-agement, a detailed description is beyond this book chapter. Consultation with a hematologist should be always considered if microcytic hypochromic anemia is detected after iron deficiency has been ruled out, chronic hemolytic anemia has been diagnosed, vascular obliteration crises of unclear etiology in patients from areas in which HbS and/or HbC is widespread occur, “drug-induced” anemia is considered, and erythrocytosis and cyanosis caused by hematological factors are seen. Generalized hemoglobin electrophoresis for all cases of anemia cannot be justified on the basis of expediency or financial considerations, particularly in those with no background of migration [19].

Evaluation and Treatment

Evaluation

Anemia is easily diagnosed by the determination of the hemoglobin concentration (Hb) or the hematocrit (hct). However, the solely diagnosis of anemia yields no information about the causes of anemia or the underlying disease. Several algo-rithms have been developed for the differential diagnosis of different types of ane-mia. However, most of them aim at the diagnosis of anemia of ambulatory patients and are therefore are not very helpful for patients that have been admitted to the ICU.

In daily clinical practice, typically two different types of anemia may occur: [1] either a patient is suffering from significant blood loss after trauma or surgery or due to occult bleeding or [2] a patient is anemic in the ICU with signs of severe anemia but without any signs of overt or occult blood losses. While in the first case diagnosis and treatment of anemia are relatively straightforward, the latter case requires an extensive and thoughtful workup of acute anemia.


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Diagnosis of Anemia Due to Overt or Occult Bleeding

If the reason for anemia is overt or occult acute bleeding, the evaluation of anemia can be reduced to some very basic laboratory values. Acute blood loss is defined as a concurrent loss of plasma and red blood cells. Therefore, in the acute phase of bleeding and blood loss, the hemoglobin concentration will not necessarily decline; however, in all cases a decline of the hemoglobin concentration is seen either due to resorption from interstitial or intracellular fluid or due to the infusion of crystalloids or colloids in the further course of treatment. Taking this into account, it is an accepted practice that the hemoglobin concentration (Hb) or the hematocrit (hct), the parameters that are most often used for description and quantification of acute bleeding, is an inappropriate measure for the estimation of the severity of blood losses in the acute phase of bleeding but is very useful later on to determine the Hb deficit. It has been demonstrated that in many clinical scenarios, determination of lactate concentration, arterial base excess, pH, or lactate clearance is more useful for estimation of blood loss and prediction of mortality in this situation [20–22]. However, after termination of the acute phase of bleeding and subsequent restora-tion of the volume lost, the hemoglobin concentration is then used to determine the oxygen transport capacity of blood. Furthermore, in daily clinical practice, the hemoglobin concentration is the most common parameter for the indication of red blood cell (RBC) transfusions, although this single dimensional practice can result in substantial and unnecessary transfusions in many clinical situations [3, 4, 23].

Diagnosis of Anemia in Patients Without Overt or Occult Bleeding

Diagnosis of anemia in patients without overt or occult bleeding is much more dif-ficult than in the group of patients described above. In this situation, the hemoglobin concentration or the hematocrit is the key parameter to help in diagnosing the evolv-ing anemia. However, since the reason for anemia is unknown in this setting, further tests are needed for a proper workup of anemia in this situation. First, efforts should focus on ruling out any cause of bleeding not considered so far. Typically, patients in the ICU suffer from occult GI bleeding, a pathophysiology that should be diag-nosed by gastroscopy or colonoscopy. Furthermore, chest tubes and drains give a hint for occult bleeding, although even drainage of the operation site is not neces-sarily a useful parameter for the exclusion of occult bleeding. Sometimes computer tomography can help in identifying the source of bleeding.

In order to determine the type of anemia in patients without overt or occult bleed-ing, a set of laboratory determination is used to diagnose the type of anemia.

Since more than 80 years, MCV has been the most used parameter to distinguish microcytic, normocytic, and macrocytic anemia [24]. Although MCHC played a major role in earlier times for differentiation of hypochromic, normochromic, or hyperchromic anemia, nowadays anemias are very seldomly classified using this parameter [25]. In addition to MCV, the reticulocyte count should be determined, which enables a classification of anemia by a kinetic approach [25]. The reticulo-

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cyte count is clinically important both for the pathophysiological classification of anemia (due to an inadequate production of erythrocytes by the bone marrow, in which case there is a decreased number of reticulocytes, or to an excessive loss or the destruction of erythrocytes, in which there is an increase in reticulocyte count) and for the early identification of the normalization of erythropoiesis by the bone marrow after therapeutic intervention (iron, cobalamin, folic acid, ESAs, etc.), after spontaneous or pharmacologically induced aplasia of the marrow, or following bone marrow transplantation. However, it has to be stated that the reticulocyte count should be determined using a modern analyzer, since manual counts of reticulocytes are prone to severe inaccuracies. The latest generation of hematology analyzers provides some reticulocyte indices analogous to the equivalent RBC indices. Among these, the most promising from a clinical point of view are the hemoglobin content of reticulocyte and the mean reticulocyte volume [25].

If anemia is present despite a lack of overt or occult bleeding, one should con-sider the potential prevalence of the different kinds of hemoglobinopathies described above. However, it has to be stated that generalized hemoglobin electrophoresis for all cases of anemia cannot be justified particularly in those with no background of migration. Therefore, knowledge about the local population prevalence of specific hemoglobinopathies is essential for tailored screening and diagnosis in these patients.

While anemia can occur as an expression and a side effect of many diseases, it may also result from pharmacological treatment. Unfortunately, there is no easy, specific diagnostic test that is evidentiary for medications being the cause of anemia in a specific patient. As a consequence, only a treatment-free interval can be used for the diagnosis of “drug-induced” anemia. In daily clinical practice, this is often impossible, and many patients leave the ICU without a clear proof for the tentative diagnosis of “drug-induced” anemia.

Probably the most important kind of anemia prevalent in ICUs is a hybrid form of iron deficiency anemia and anemia of chronic disease. The diagnosis of iron deficiency anemia typically focuses on two different laboratory values, the transfer-rin saturation and the ferritin level in the blood. However, no specific test confirms the diagnosis of IDA in all patients because serum ferritin may be falsely normal-ized/elevated and transferrin saturation may be reduced in inflammatory states. If the ferritin level is low, then the iron stores of the organism are thought to be depleted, but there are many clinical situations, especially in the postoperative phase where iron stores are depleted and the ferritin level is high. Therefore, a mul-titude of different ferritin levels have been published as cutoff for iron deficiency anemia [13].

Newer markers, such as serum transferrin receptor and reticulocyte hemoglobin (Hb) content, have been advocated as additional tools for the discrimination of iron deficiency/chronic disease anemia for a while. Serum transferrin receptor levels as a diagnostic tool for IDA are still a test that is infrequently available. In contrast, reticulocyte hemoglobin content is becoming ubiquitous but requires the clinician awareness of the test and a separate order [26]. Furthermore, measurements of serum hepcidin appear to be promising and worth pursuing in larger diagnostic and


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therapeutic trials [27], but hepcidin levels have not attained the level of a standard clinical tool [15]. In daily clinical practice, many physicians use mainly the Hb, the transferrin saturation, and the ferritin level together with the C-reactive protein to determine the presence of IDA [13].

Treatment

Iron and/or Erythropoietin Therapy

Although the transfusion of red blood cells seems to be the most common treatment modality for anemia in ICU patients, there are effective treatment modalities espe-cially for patients with IDA or anemia of chronic disease that must be entertained. Since both types of anemia occur often in ICU patients, and the prevalence of both pathophysiologies overlaps often, iron and exogenous erythropoietin (EPO) as the standard treatment of this entity are administered regularly in this situation.

As described above the diagnosis of iron deficiency can be difficult in ICU patients, since the most important laboratory parameter for iron deficiency, the fer-ritin concentration, is elevated in inflammatory states. Despite this diagnostic obsta-cle, iron is regularly used in daily clinical practice in ICU patients. Although it has been demonstrated that per os (oral) iron can reduce the likelihood of RBC transfu-sion [28], it has to be stated that nowadays typically intravenous application of iron is the standard route of administration especially for the stressed ICU patient. However, the results for the efficacy of intravenous iron are mixed. In trauma patients it has been demonstrated that the application of intravenous iron reduced the number of RBC transfusions [29], whereas in a very similar study, this effect has not been confirmed [30]. However, taking a look at the most recent meta-analysis, it has to be stated that although not being significant all outcomes are in favor of the application of iron [31].

It has been argued that iron, especially intravenous preparation, might signifi-cantly increase the risk of postoperative infections. Although the underlying mecha-nisms are very plausible, in daily clinical practice, this phenomenon seems to play a minor role. Two large meta-analyses performed could not demonstrate an increase of postoperative infection rates [32, 33]. Furthermore, a transfusion of one pack RBCs results in an addition of heme iron (not present in commercial preparations) content of 200 mg, a different iron modality that may be associated with increased postoperative infectious risks [34].

Nowadays erythropoietin is used seldomly in the ICU. The first study that described EPO usage in the ICU with the aim to reduce perioperative transfusion needs has been published by Corwin in 2007 [35]. Although this study failed in terms of the main outcome parameter (transfusion), it could be clearly demonstrated that some secondary outcome parameters were significantly better in the treatment group. Especially, survival was significantly better in the EPO group. Since EPO is thought to increase the risk for perioperative thrombosis, the interest in this com-

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pound diminished over the years for this indication, although it has been demon-strated that EPO obviously has no negative short-term effects on survival [36, 37].

There are also some other deficiencies that might result in anemia, e.g., folate deficiency, or Vit-B12 deficiency, etc. Recently, Rodriguez and colleagues reported iron deficiency in 9% of ICU patients; 2% of the patients were deficient in vitamin B12, and another 2% suffered from folic acid deficiency [38]. However, whether proper treatment of these pathologies results in a reduction of the transfusion rate during the ICU stay remains unknown.

Transfusion of Red Blood Cells

It has been demonstrated by many different investigators that anemic patients in the ICU suffer from high morbidity and mortality [39]; nevertheless this problem is often severely under-recognized [40, 41]. Since the quality of blood component has reached a high level in the last few years, it seems obvious that a low hemoglobin concentration can be easily treated by the transfusion of red blood cells [42]. However, the risks of transfusion still remain despite the quality [43], and the desired effects of blood transfusions on oxygen transport and tissue oxygenation are less predictable than expected. It has been demonstrated by a meta-analysis that the transfusion of one pack of red blood cells increases the hemoglobin concentration and by that oxygen carrying capacity in all cases but regularly fails to increase oxy-gen delivery and oxygen consumption resulting in a disputable risk/benefit ratio for transfusion [44]. The reason for this phenomenon might be an increase of blood viscosity that is induced by the transfusion of a single and multiple packs of RBCs, resulting in a decrease blood flow and a decrease of regional oxygen delivery [45]. Taking into account the low efficacy of blood transfusion on the one hand and the risks of transfusion on the other, one has to concur that the trade-off of transfusion versus anemia is difficult to judge. As a consequence, many clinical studies have investigated the effects of a restrictive transfusion regime (accepting lower hemo-globin values and sparing RBC transfusions) versus a liberal transfusion regime (with higher hemoglobin values but more RBC transfusions). The first of these stud-ies has been published by Hebert and coworkers in 1999 [46]. In this landmark paper, they demonstrated that a restrictive transfusion regime is as safe as a liberal one, with the advantage that less resources are needed, and as a consequence, the costs for treatment were clearly lower. Similar experiments have been performed in the following years, with the focus set to more patient populations at the ICU.

The FOCUS trial demonstrated that a restrictive and a liberal transfusion regime are equivalent for patients with cardiac risk factors undergoing total hip replace-ment [47, 48]. The TRIS trial had a similar outcome in septic patients [49]. The TRACs and the TRICS-3 trial demonstrated that a restrictive transfusion regime is as safe as a liberal one in cardiac surgery patients [50, 51]. The first trial to demon-strate that a restrictive transfusion regime results in a lower mortality than a liberal transfusion regime has been published by Villanueva in patients with acute upper gastrointestinal bleeding [52].


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The studies demonstrating the opposite are rare: one trial in oncologic surgery patients demonstrated superiority of a liberal transfusion regime [53], and the same result has been obtained for patients with symptomatic coronary artery disease in an inconclusive pilot study [43, 54]. While in the second case the pathophysiological reasons are obvious, the mechanism for improved outcome in the first case remains incomprehensibly.

In patients with hemoglobinopathies, transfusion of red blood cells is often the only possible therapeutic modality [55], although the efficacy of this measure is questionable for some of the indications [56]. However, even if some of the symp-toms of many different hemoglobinopathies can be reduced by the transfusion of red blood cells, it has to be stated that these often recurring transfusions are associ-ated with significant adverse events [57].

A very recent Cochrane analysis sums up the evidence for the comparison of a restrictive and a liberal transfusion regime. Transfusing at a restrictive hemoglobin concentration of between 7 and 8 g/dL decreased the proportion of participants exposed to RBC transfusion, while there was no evidence that a restrictive transfu-sion strategy impacts 30-day mortality or morbidity (i.e., mortality at other points, cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infec-tion) compared with a liberal transfusion strategy [58].

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52. Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11–21.

53. Bergamin FS, Almeida JP, Landoni G, Galas FRBG, Fukushima JT, Fominskiy E, et al. Liberal versus restrictive transfusion strategy in critically ill oncologic patients. Crit Care Med. 2017;45(5):766–73.

54. Carson JL, Brooks MM, Abbott JD, Chaitman B, Kelsey SF, Triulzi DJ, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013 Jun;165(6):964–971.e1.

55. Wang WC, Dwan K. Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. In: The Cochrane Collaboration, editor. Cochrane data-base of systematic reviews. Chichester, UK: Wiley; 2013. Available from: http://doi.wiley.com/10.1002/14651858.CD003146.pub2.

56. Estcourt LJ, Fortin PM, Trivella M, Hopewell S. Preoperative blood transfusions for sickle cell disease. In: The Cochrane Collaboration, editor. Cochrane database of systematic reviews. Chichester, UK: Wiley; 2016. Available from: http://doi.wiley.com/10.1002/14651858.CD003149.pub3.

57. Vichinsky E, Neumayr L, Trimble S, Giardina PJ, Cohen AR, Coates T, et al. Transfusion complications in thalassemia patients: a report from the Centers for Disease Control and Prevention (CME): Transfusion Complications in Thalassemia. Transfusion (Paris). 2014 Apr;54(4):972–81.

58. Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi D, Doree C, et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2016 Oct;10(5):CD002042.







Chapter 2Hemostatic Abnormalities in the Critically Ill

Michelle Sholzberg

Pathophysiology of Hemostatic Abnormalities in the Critically Ill

Hemostasis involves a series of physiologic events that lead to the formation of a strong and appropriately designed blood clot to stop bleeding. Hemostasis is trig-gered by endothelial damage. The platelet plug forms with the help of von Willebrand factor and fibrinogen, and this phase is called primary hemostasis. Secondary hemo-stasis results in fibrin formation which occurs very delicately on the surface of acti-vated platelets; clot stabilizers then strengthen the clot both structurally and by sheltering the clot from early fibrinolytic degradation.

We are evolutionarily designed to boost the release of acute-phase reactants in the face of acute systemic stress, and many acute-phase reactants are involved in hemostasis. Therefore, an appropriate, regulated response to sympathetic nervous system activation is a balanced pro-hemostatic one which protects us from potential hemorrhagic death [1, 2]. When the response is inadequate, dysregulated, or disor-ganized, the pro-hemostatic compensation is lost, and the patient is at risk for bleed-ing and/or thromboembolism [3, 4].

The patients in the hospital at highest risk for hemostatic complications are those admitted to the intensive care unit (ICU), and ICU patients with hemostatic abnor-malities have a higher risk of death [5–7]. To understand hemostatic abnormalities associated with critical illness, we must first appreciate that nearly all coagulation factors involved in secondary hemostasis are made in the liver (with the notable exception of factor VIII which is also made by the endothelium), that platelets arise from megakaryocytes in the bone marrow, and that an increasing proportion of

M. Sholzberg, MDCM, FRCPC, MSc Departments of Medicine and Laboratory Medicine and Pathobiology, St. Michael’s Hospital, Toronto, ON, Canada

University of Toronto, Toronto, ON, Canadae-mail: [email protected]



18

patients admitted to the ICU will be on some antithrombotic medication given the increase in therapeutic indications and prevalence of age-related conditions requir-ing anticoagulation. Nearly all hemostatic abnormalities encountered in ICU patients are acquired and can be divided into the following categories: (1) deficien-cies of coagulation factors and platelets and (2) inhibition or dysfunction of coagu-lation factors and platelet function.

Deficiencies of Coagulation Factors and Platelets

Deficiencies in coagulation factors are mostly caused by diminished or altered hepatic synthesis, massive consumption, and/or loss. Impaired synthesis of clotting factors in the liver occur in the context of liver failure or vitamin K deficiency which interferes with the appropriate activation (gamma carboxylation) of vitamin K-dependent coagulation factors (II, VII, IX, X, protein C, and protein S). Vitamin K antagonists (e.g., warfarin) specifically interfere with the gamma carboxylation step, and when patients are on therapeutic doses of warfarin, their vitamin K-dependent clotting factor activity ranges between 20% and 40% of normal. Risk factors for vitamin K deficiency include chronic antibiotic use, malnutrition, and cholestasis – all of which can occur in patients admitted to the ICU.

Liver dysfunction is a relatively common occurrence in this patient population and can be due to acute infection, hypoperfusion, medication effect, or direct injury. Liver dysfunction can be differentiated from vitamin K deficiency by assessment of non-vitamin K-dependent clotting factor activity (e.g., factor V), and if normal then vitamin K deficiency is suggested [8]. One should expect to first detect diminished activity of the clotting factor with the shortest half-life (i.e., factor VII) in vitamin K deficiency since its activity and ability to accumulate will be affected earliest. Almost all coagulation factors are produced in the liver; therefore acute organ fail-ure commonly results in diminished production of many coagulation factors, with the exception of factor VIII since it is also made by the endothelium. Thrombocytopenia is also a feature of liver disease due to decreased thrombopoietin production and release.

Massive losses of coagulation factors and platelets can occur during and after massive hemorrhage in surgical patients or in those who have experienced major trauma. Cold temperature, acidosis, and rapid, dilutional intravascular volume replacement with crystalloids, colloids, and red blood cells will aggravate the bleed-ing tendency. Furthermore, surgical causes for bleeding and acute coagulopathy of trauma, a hypocoagulable and hyperfibrinolytic state thought to be triggered by systemic activation of protein C, may contribute. Consumption due to disseminated intravascular coagulation (DIC), the most common thrombotic microangiopathy, may also contribute to the bleeding tendency. DIC can be differentiated from liver disease by diminished or inappropriately normal factor VIII as factor VIII is expected to rise with acute illness (in the absence of DIC) since it is an acute-phase reactant. DIC will be discussed in detail later in this chapter.

M. Sholzberg

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Thrombocytopenia is a common occurrence in patients admitted to the ICU with a reported prevalence at the time of admission between 8.3% and 67.6% [9, 10]. The incidence of thrombocytopenia during the ICU admission is between 14% and 44% [9, 10]. Factors associated with thrombocytopenia in the ICU patient include illness severity, organ dysfunction, sepsis, vasopressor use, and acute kidney injury [9, 11]. Sustained, severe thrombocytopenia is associated with prolonged ICU stay and mortality [6, 7, 9, 12–20]. Thrombocytopenia of any severity also appears to associate with bleeding and transfusion risk [9, 11, 21, 22], while recovery of the platelet count in the critically ill is positively correlated with survival [7].

There are many contributing mechanisms to thrombocytopenia in the critically ill, and the exact mechanisms remain incompletely understood. Thrombocytopenia typically occurs on the basis of consumption from bleeding and/or platelet activa-tion/adhesion/aggregation, presumed diminished production from bone marrow suppression or insult (although never critically evaluated/proven), increased destruc-tion from directed clearance or toxicity, dilution in the context of resuscitation, or any combination thereof.

Thrombocytopenia from consumption in critically ill patients is by far the most common cause and therefore warrants additional discussion. Consumption was classically thought to be due solely to thrombin-medicated platelet activation, but novel mechanisms involving excessive platelet adhesion and aggregation from high von Willebrand factor (and diminished ADAMTS13), histone release, hemophago-cytosis, and complement activation have been described [23, 24]. In fact, the mech-anisms involved in thrombocytopenia associated with sepsis are multiple and probably interactive, but the relative contribution of each mechanism may vary per patient and even within a given patient over time. Moreover, in patients with septic shock with thrombocytopenia, platelet count recovery typically occurs several days after vasopressor independence [25].

Thrombocytopenia commonly accompanies deficiencies of coagulation factors, and therefore their co-occurrence may not be particularly helpful in narrowing the differential diagnosis; thus thrombocytopenia must always be analyzed in the clini-cal context to clarify the underlying pathophysiologic mechanism. There are certain clues however that may help identify a cause of thrombocytopenia in the critically ill, and these are described in Fig. 2.1. See Table 2.1 for the approach to the differ-ential diagnosis of thrombocytopenia in the ICU.

It is worthy of mention that platelets and coagulation factors have roles beyond hemostasis and thrombosis, and this is particularly relevant in the patient with sepsis and/or compromised tissue integrity. In fact, platelets are now recognized as critical players of the innate immune response; they contribute to inflammation, microor-ganism attack, and tissue repair [28–33]. Coagulation factors and platelets often contribute to both vascular and tissue injury via inflammation while also contribut-ing to resolution of inflammation and repair (see Fig. 2.2). These opposing (and sometime concurrent) actions of the hemostatic systems in relation to the endothe-lium have been extensively described and are thought to be related to complications of sepsis in particular [30, 34, 35].

2 Hemostatic Abnormalities in the Critically Ill

20

Platelet count less than 100 x 109/I Exclude laboratory artefacts

Drug-induced ITP, HIT, PTP

Postoperative drop

Sepsis, DIC, Liver disease

Thrombotic microangiopathy

Haemodilution

Clot related consumption

Post-transfusion purpura

Sepsis-associatedthrombocytopenia

Dialysis, Cardiac assist deviceor ECMO-related

Acute drop (more than 50% in 24–48 h)

Surgery less than three days ago

Clear evidence of sepsis (e.g., culture +ve)

Abnormal coagulation profile (PT/APTT)

Blood contact with devices

Blood film shows microangiopathy

Large amount of fluids given

Recent extensive thrombosis

Recent blood transfusion

Fig. 2.1 Clues for the diagnosis of thrombocytopenia in critically ill patients. ITP immune throm-bocytopenia, HIT heparin-induced thrombocytopenia, PTP posttransfusion purpura. PT prothrom-bin time. aPTT activated partial thromboplastin time. DIC disseminated intravascular coagulation [27]. (Used with permission)

Table 2.1 Mechanisms of thrombocytopenia in the critically ill [27]

Increased platelet consumption – with or without overt disseminated intravascular coagulationIncreased platelet consumption with clinically overt thrombosis (e.g., pulmonary embolism, heparin-induced thrombocytopenia)Platelet aggregation due to high von Willebrand factor multimers in sepsis or inflammatory disordersIncreased destruction – by autoantibodies in immune thrombocytopenia (ITP) or drug-dependent antibodies (D-ITP) or alloantibodies in posttransfusion purpuraPlatelet adherence to other cells including vascular endothelial cells or leucocytes in sepsis or inflammatory disordersComplement-mediated platelet destruction in sepsis or inflammatory disordersHemolysis-induced platelet aggregation in hemolytic disordersHistone-induced thrombocytopenia in any condition which causes extensive cell damageArtificial membrane capture of platelets in medical devices (e.g., hemofiltration, extracorporeal membrane oxygenation, and cardiac assist devices)Hemodilution from administration of large amount of fluids or blood componentsSplenic sequestration – portal hypertension, hypersplenism, or splenomegaly of any causeDecreased production of platelets – chemotherapy or radiotherapy, bone marrow disorders, drug- or virus-induced marrow failure, hemophagocytosis, hematinic deficiency (B12 or folate)Pseudothrombocytopenia (laboratory artifacts)In many cases, more than one mechanism is causing or contributing to the thrombocytopenia

Used with permission

M. Sholzberg

21

Pharmacologic Inhibition of Coagulation Factors and Platelet Function

Coagulation factors can be inhibited either directly or indirectly by anticoagulants. Heparins (unfractionated and low molecular weight heparins) are indirect antico-agulants as they exert their function by enhancing the natural inhibitory activity of endogenous antithrombin. Antithrombin is an inhibitor of serine proteases which account for nearly all coagulation factors. Antithrombin, however, preferentially inhibits activated factor X and II, and in doing so it disables the rate-limiting and final effector enzymes of secondary hemostasis (i.e., formation of the insoluble fibrin clot). Heparins convert antithrombin from a slow to a rapid inhibitor; there-fore, they make antithrombin more efficient at what it does naturally.

Infection/wound/tissueinjury

Platelet activationVascular/tissue repair

and regeneration

Haemostasis

Inflammation/pathogenclearance

Matrix reconstitution; recruitment,proliferation and activation of

tissue progenitor cells;angiogenesis

Inflammation; immune cell recruitmentand activation; trapping of bacteria,

thrombocidin release ...Platelet plug; blood clotting...

Quiescent platelets

Activated platelets

Erythrocytes

Endothelial cell

ECM

MN

PMN

Mφ

PMPs

Platelet mediators

Fig. 2.2 Platelets are integral players in the immune response, linking hemostasis, thrombosis, inflammation, pathogen clearance, and tissue repair: a schematic representation. A growing body of evidence highlights a role for platelets beyond the confines of hemostasis and thrombosis. Some of platelet interfaces in innate immune response are schematized. Platelets are activated at sites of infection/tissue injury. Platelets and platelet-derived mediators contribute to arrest bleeding, to clear pathogens directly or indirectly by acting on various steps of the immune response, and to drive vascular/tissue repair by providing matrix building blocks and a multiplicity of signals that remodel matrix, attracting tissue progenitor cells and reconstructing the vascular frame. In doing so, platelets provide a coherent biological response contributing to cure infection and reestablish tissue architec-ture and homoeostasis. Scales are arbitrary. Platelet-derived microparticles (PMPs) recapitulate sev-eral of activated platelet functions. ECM extracellular matrix, MN monocytes, PMN polymorphonuclear neutrophils, MΦ macrophages [36]. (Used under Creative Commons license)


22

Direct inhibitors however do not require an intermediary to facilitate their anti-coagulant effect. Instead, they directly inhibit clotting factors. Argatroban, bivaliru-din, hirudin, and dabigatran directly inhibit factor IIa, while rivaroxaban, apixaban, and edoxaban directly inhibit factor Xa. While warfarin is an anticoagulant, it is not an inhibitor. Instead it results in the deficiency of vitamin K-dependent clotting fac-tor activity (factors II, VII, IX, X, proteins C, and S).

Platelet function can also be inhibited by directed pharmacotherapy. There are many different drugs that target different platelet function pathways, and they are listed in Fig. 2.3. Inhibitors of coagulation whether involving the platelet or the coagulation factors often contribute to the bleeding phenotype in critically ill patients, particularly given the expanding indications for antithrombotic therapy and the rising prevalence of conditions requiring antithrombotic therapy in the aging population.

Thrombotic Microangiopathy

Thrombotic microangiopathies (TMAs) are a constellation of disorders that are characterized by micro- or macro-vasculopathy and are often accompanied by microangiopathic hemolytic anemia and thrombocytopenia. Organ dysfunction

Aspirin Dipyridamole

Hirudin

Digibatran

Argatroban

LMWH

HeparinBivalirudin

PAR-1 inhibitorsSCH530348

Cilostazol

COX-inhibitorsPhosphodiesterase

inhibitorsDirect Indirect

Thrombin inhibitors

NSAIDS

COX-1

Epinephrine

Plateletactivation

PathwayGpIIbIIIareceptors

GPVI Collagen

Collagen

vWF

Vasopressin

P2Y1

G-protein coupledreceptor (GPCR)

Ticagrelor

Cangrelor

Ticlopidine

Prasugrel

Clopidogrel

Reversible

Thienopyridines

Irreversible

P2Y12

PAF

PAR-1

Thrombin

ADPreceptors

5HT2a

Activated platelet

Platelet-unstable plaque interaction

GpIIbIIIainhibitors

α2β1

GPVIα2β1

cAMP – 5′ AMP

↓cGMP→VASP

AA

TxA2

=

Fig. 2.3 Antiplatelet therapy targets [37]. (Used with permission)

M. Sholzberg

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due to ischemia is characteristic of TMAs and can occur to the brain, kidneys, heart, pancreas, liver, lungs, eyes, and even skin [38]. Relatively common etiolo-gies of TMA in the ICU patient include disseminated intravascular coagulation (DIC), sepsis, malignant hypertension, TMA of pregnancy, thrombotic thrombo-cytopenic purpura (TTP), hemolytic uremic syndrome (HUS), atypical hemo-lytic uremic syndrome (aHUS), drug-induced TMA, and cancer-associated TMA. The most common TMA is DIC [39]. ADAMTS13, complement bio-markers, and coagulation testing provide important information as they will rule out TTP and suggest HUS or DIC, respectively. General diagnostic tests required in patients with suspected TMA include the following: complete blood count, peripheral blood film, reticulocyte count, lactate dehydrogenase, haptoglobin, bilirubin, activated partial thromboplastin time, prothrombin time, and fibrino-gen. Tests to assess for the presence of secondary organ damage could include the following: serum electrolytes, creatinine, urinalysis, liver function, troponin, electrocardiogram, lactic acid, lipase or amylase, and brain imaging studies. The remainder of testing should be guided by features specific to the patient (e.g., beta-human chorionic gonadotropin) or by the suspected specific type of under-lying TMA (e.g., ADAMTS13). Care of non-TTP and non-aHUS TMA is sup-portive and involves directed therapy toward the underlying condition [40]. However, the foundation of TMA treatment is plasma exchange and it should be initiated once the diagnosis of TMA is considered since TTP and HUS are poten-tially fatal conditions.

Disseminated Intravascular Coagulation (DIC)

DIC is a relatively common occurrence in patients who are critically ill [42]. DIC is not a separate diagnosis in itself; rather it is an accompanying symptom/sign of severe systemic illness. Common thresholds for DIC include sepsis, severe trauma, metastatic malignancy, and obstetrical emergencies [43–46]. It is well accepted that hemostatic and inflammatory pathways are intimately intertwined. In fact, many hemostatic players are important activators of inflammatory mediators that enhance immune function. However, if the inflammatory response is exaggerated, it may tip the coagulation balance as in the case of DIC. DIC is thought to occur by excessive release of tissue factor, neutrophil extracellular traps (NETs), and neutrophil nucleo-somes (containing DNA and histones) that result in the formation of microvascular thrombi, impaired tissue perfusion, multiorgan failure, and diffuse consumption and dysregulation of hemostatic components (platelets, coagulation factors, fibrinolytic regulators). Moreover, in sepsis bacterial toxins can activate complement, endothe-lial cells and hemostatic components directly [40]. Thus, sepsis itself can cause TMA even in the absence of true DIC.

There is no single laboratory test that is sufficient to diagnose DIC, instead the diagnosis can be suggested by the score obtained on a system developed by the


24

International Society on Thrombosis and Haemostasis (see Table 2.2) [47, 48]. The DIC score has a sensitivity and specificity above 95% when evaluated in prospective validation studies and is also an independent predictor of death in patients with sepsis [49]. Of note, thrombocytopenia is the most sensitive marker of DIC and is often the first laboratory feature. In fact, thrombocytopenia is pres-ent in over 90% of cases of DIC, and more than half of cases have a platelet count below 50 × 109/L [41]. As for the coagulation assay results in DIC, the sequential changes may be more helpful in suggesting the diagnosis of DIC rather than the individual results [50].

TMA Associated with Malignant Hypertension

Malignant hypertension also occurs more commonly in the critically ill and is a cause of TMA that appears to be rooted in pro-inflammation [40]. However, the exact mechanism of malignant hypertension-associated TMA is poorly understood. It is postulated that sustained extreme hypertension results in a severe endotheliopa-thy and pronounced activation of the renin-angiotensin-aldosterone system which then leads to the TMA [51]. Management is directed at immediate control of the patient’s blood pressure.

1. Risk assessment: does the patient have an underlying disorder known to be associated with overt DIC?

If yes: Proceed;

If no: Do not use this algorithm.

2. Order global coagulation tests (platelet count, prothrombin time, fibrinogen, fibrin-related marker).

3. Score global coagulation test results.

5. Calculate score

If ≥ 5: compatible with overt DIC: repeat score daily.

If < 5: suggestive (not affirmative) for non-overt DIC: repeat next 1–2 days.

• platelet count (> 100 = 0; < 100 = 1; < 50 = 2)• Elevated fibrin related marker (e.g. D-dimers: fibrin degradation products) (no increase = 0; moderate increase = 2; strong increase = 3) • Prolonged prothrombin time (< 3 s = 0; > 3 but < 6 s = 1; > 6 s = 2)• Fibrinogen level (> 1.0g L-1 = 0; < 1.0g L-1 = 1)

Table 2.2 Scoring system for overt disseminated intravascular coagulation (DIC) [48]

Used with permission

M. Sholzberg

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TMA of Pregnancy

Preeclampsia and its related condition, HELLP (hemolysis, elevated liver enzymes, and low platelet count), are associated with high maternal and neonatal mortality [40]. HELLP occurs in 10–20% of patients with severe preeclampsia, but nearly 20% of HELLP cases occur in the absence of preexisting preeclampsia [40]. They are conditions predominantly of the late second trimester, third trimester of preg-nancy, or postpartum period [52]. The precise mechanism of preeclampsia and HELLP is incompletely understood, but increased circulating anti-angiogenic fac-tors, reduced vascular endothelial growth factor, and complement dysfunction appear to be implicated [53]. Treatment of TMA of pregnancy involves aggressive blood pressure control and delivery. Persistent features of TMA beyond 3 days post-partum should prompt reconsideration of the underlying diagnosis as TTP and aHUS may also present peripartum [40].

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare (incidence of 3–4 cases per million) and life-threatening form of TMA which results from deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), an enzyme that cleaves large von Willebrand factor (VWF) multimers. Large VWF multimers function to bind and activate platelets in the microvasculature. TTP can either be inherited (mutation of ADAMTS13 gene lead-ing to low activity levels) or acquired (autoantibody against ADAMTS13). The majority of cases are acquired, and the diagnosis is confirmed by a severe deficiency of ADAMTS13 (i.e., <10% activity) [54, 55]. ADAMTS13 testing remains a critical test to distinguish TTP from other types of TMAs. It is important to note that other TMAs can be associated with low ADAMTS13 activity due to consumption of the enzyme on the basis of high VWF levels which occurs in many diffuse inflamma-tory and/or endotheliopathic conditions [56]; however, ADAMTS13 levels in this context are not below 10%.

Without treatment the mortality associated with TTP is up to 90%. The benefit of plasma exchange for patients with TTP has been shown in a randomized controlled study [57]. Plasma exchange should be used until remission of TTP has been achieved, and typically patients are treated for 5 consecutive days followed by a tapering schedule. The main risks associated with plasma exchange include bleed-ing/infection from central line insertion, citrate toxicity, and transfusion reactions to plasma [58]. Corticosteroids are also commonly initiated when TTP is suspected (since acquired TTP is far more common than inherited) as long as an underlying infection has been ruled out. Prophylactic platelet transfusions should be avoided although risk benefit should be carefully weighed in the severely thrombocytopenic patients.


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Shiga Toxin-Associated Hemolytic Uremic Syndrome

Shiga toxin-associated hemolytic uremic syndrome is caused by a bacterial infection which results in a toxin-induced severe endothelial inflammatory response that leads to microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney disease. It results from ingestion of infected water or food or person-to-person transmission typically via fecal-oral route. Typical bacterial infections associated with HUS include Shiga toxin-producing Escherichia coli (STEC) (including strain 0157:H7) and Shigella dysenteriae type 1. HUS usually occurs 2–10 days after a prodrome of bloody diarrhea. STEC-HUS, the most common bacterial HUS, occurs with an inci-dence of 2 per 100,000 adults and 6.1 per 100,000 children. Rarely, HUS can occur secondary to a neuraminidase-producing Streptococcus pneumoniae. Laboratory confirmation with stool or body fluid culture is required. Plasma exchange is gener-ally not indicated but may be beneficial in some cases with severe TMA. Supportive care remains the mainstay of treatment for bacterial toxin-induced HUS [59].

Atypical Hemolytic Uremic Syndrome (aHUS)

Atypical hemolytic uremic syndrome (aHUS) is a rare condition, affecting both adults and children [60]. aHUS is due to a defect in the regulation of the alternative comple-ment pathway which results in its uncontrolled activation and resultant platelet, leuco-cyte, and endothelial cell stimulation [61–65]. Clinical manifestations of this TMA predominantly include the kidneys, but other end organ damages can also occur and sometimes even predominate [61, 66–70]. It is important to rule out bacterial associ-ated TMA with stool and body fluid cultures. Analysis of the complement pathway is suggested to facilitate the diagnosis of aHUS, and these tests include serum levels of C3, C4, CH50, soluble C5b-9, and anti-CFH autoantibodies. Genetic mutations are identified in up to 70% of patients with aHUS [62–64, 71, 72]. However, the identifi-cation of genetic mutations is not sufficient to make the diagnosis of aHUS. Typically, environmental thresholds are required to stimulate the presentation of TMA, and these thresholds include infections, pregnancy, medications, and malignancy among many others [65, 73, 74]. Management of aHUS involves plasma exchange acutely with ultimate conversion to eculizumab, a monoclonal antibody that blocks the cleavage of C5 which arrests terminal complement activation [62, 75]. This medication has been shown to improve renal and nonrenal recovery in affected patients [76, 77].

Drug-Induced TMA

Drugs are a rare but important cause of TMA. Prompt recognition and cessation of the culprit medication is a critical therapeutic step [78]. Ticlopidine, quinine, inter-feron, and various chemotherapeutic agents have been implicated in TMA. The TMA

M. Sholzberg

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may be idiosyncratic or dose-dependent [79]. In the majority of cases, the TMA is associated with hypertension and acute kidney injury [79]. Plasma exchange is often implemented but is of limited and uncertain utility in these cases.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an adverse reaction associated with exposure to heparin anticoagulation. It is caused by platelet-activating immuno-globulin G (IgG) antibodies that bind platelet factor 4 (PF4)/heparin complexes [80–82]. Arterial and/or venous thromboembolism occurs in 50–75% of affected patients and is often very severe or unusual in presentation [83–85]. HIT is rela-tively uncommon in the ICU and accounts for up to 1% of ICU-associated thrombo-cytopenia [86]. Criteria that suggest the diagnosis of HIT include the 4Ts (see Table 2.3): thrombocytopenia, timing, thrombosis, and other causes of thrombocy-topenia. Decision to test for HIT with anti-PF4/heparin antibodies and/or heparin-dependent platelet-activating antibodies should be based on the score obtained from the 4Ts due to a high risk of false positivity [87–91].

The platelet count in HIT typically falls between days 5 and 10 postexposure to heparin which can be thought of as the day of immunization [93]. Although HIT can be “rapid-onset” if there was a recent exposure to heparin, i.e., within previous weeks to months [93]. The recent nature of exposure is required as HIT antibodies are characteristically transient and become undetectable within 50–80 days [93, 94]. “Delayed-onset” HIT occurs when HIT begins or worsens after discontinuation of heparin, and these individuals often have secondary DIC as a complication of HIT [95–97]. Secondary DIC occurs in approximately 10–20% of patients with HIT and is due to release of platelet microparticles and monocyte activation [98–100].

To make matters more complicated, there is a syndrome called “spontaneous” HIT which is clinically and serologically similar to HIT, but in “spontaneous” HIT there is no preceding exposure to heparin. This syndrome occurs most commonly in those post-orthopedic surgery and post-infection where a template (e.g., negatively charged bacterial wall) is provided for immunization to the patient’s endogenous heparin/PF4 complex [101–103].

Treatment of HIT is focused on cessation of heparin (infused drug, coated lines, intravenous flushes), initiation of non-heparin anticoagulant (therapeutic doses if thromboembolism is identified – e.g., argatroban, fondaparinux, danapa-roid), and avoidance of warfarin initiation until the platelet count is over 150,000 × 109/L due to risk of acquired protein C deficiency-induced venous limb gangrene [104, 105]. Large artery or vein thrombectomy may be required in the event of limb or organ compromise [106]. Finally, prophylactic platelet transfu-sions should be avoided although risk benefit should be carefully weighed in the severely thrombocytopenic patient [92]. It is important to note that use of low molecular weight heparin (as opposed to unfractionated heparin) for thrombopro-phylaxis in the ICU setting should be employed to prevent the development of


28

HIT due to differences in inherent immunogenicity [22, 107, 108]. Furthermore, the evidence to support the use of direct oral anticoagulants for HIT is increasing but is not yet considered standard of care [109].

Single Coagulation Factor Deficiencies and Inhibitors

Hereditary Single Coagulation Factor Deficiencies

Von Willebrand disease and platelet function disorders are the most common inher-ited bleeding disorders. Collectively, they affect 1–2% of the population. Of note, the CBC, PT, and aPTT rarely give a clue to these underlying diagnoses. Hemophilia A and B, deficiencies of factor VIII or IX, respectively, are far more rare but are consistently associated with a prolongation in the aPTT (as long as the factor level

Table 2.3 4Ts scoring system [92]

Points (0, 1, or 2 for each of four categories: maximum possible score = 8)2 1 0

Thrombocytopenia >50% platelet fall to nadir ≥20

30–50% platelet count fall (or >50% directly resulting from surgery); or nadir 10–19

<30% platelet fall; or nadir <10

Timinga of platelet count fall, thrombosis, or other sequelae (1st day of putative immunizing exposure to heparin = day 0)

Days 5–10 onseta (typical/delayed-onset HIT); or ≤1 day (with recent heparin exposure within past 30 days (rapid-onset HIT)

Consistent with days 5–10 fall, but not clear (e.g., missing platelet counts); or ≤1 day (heparin exposure within past 31–100 days) (rapid-onset HIT); or platelet fall after day 10

Platelet count fall ≤4 days (unless picture of rapid-onset HIT – see two left boxes)

Thrombosis or other sequelae (e.g., skin lesions, anaphylactoid reactions)

Proven new thrombosis; or skin necrosis (at injection site); or postintravenous heparin bolus anaphylactoid reaction

Progressive or recurrent thrombosis; or erythematous skin lesions (at injection site); or suspected thrombosis (not proven); hemofilter thrombosis

None

Other cause for thrombocytopenia

No explanation for platelet count fall is evident

Possible other cause is evident

Definite other cause is present

Pretest probability score: 6–8 = high; 4–5 = intermediate; 0–3 = low

Abbreviation: HIT heparin-induced thrombocytopeniaNote: The scoring system shown above includes minor modifications compared with previously published versionsaFirst day of immunizing heparin exposure considered day 0; the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it generally takes 1–3 more days until an arbitrary threshold that defines thrombocytopenia is passed). Usually, heparin administered at or near surgery is the most immunizing situation (i.e., day 0)Used with permission

M. Sholzberg

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is less than 30%). Like any other patient, it is possible that those with inherited bleeding disorders become critically ill, and it is likely that uncontrolled bleeding will complicate or be the cause of their critical state. When faced with a patient who presents with a known inherited bleeding disorder, it is necessary to (1) believe their underlying diagnosis as these patients are usually very medically literate and/or often come with medical documentation of their diagnosis (see Fig. 2.4) and (2) treat it before sending the patient for a diagnostic test or surgical procedure.

Acquired Inhibitors to Single Coagulation Factors

For patients with unusual or unexpected bleeding, the development of an inhibitor to a single clotting factor deficiency should be considered. An inhibitor in this context is an antibody that neutralizes the activity and/or enhances the clearance of

Fig. 2.4 Factor First card, St. Michael’s Hospital, Toronto, Canada Treatment Card. (Used with permission)


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a given clotting factor. The most common acquired inhibitor is the factor VIII, and when this occurs it is called acquired hemophilia. It is a very rare condition with an incidence estimated at 1.48 per million individuals per year [110]. Approximately 50% of these cases are associated with underlying conditions such as malignancy, connective tissue diseases, drug exposures, and pregnancy, while the remainder are idiopathic [111]. In contrast to congenital hemophilia, patients with AHA are typi-cally older, without gender predilection, and rarely experience musculoskeletal bleeding. Instead, mucocutaneous bleeding is typical [110, 112, 113]. There is a spectrum of clinical severity in acquired hemophilia, but many patients present with very severe bleeding, and there is a 22% associated mortality rate [114]. The diag-nosis of AHA should be considered in patients with no prior personal nor family history of bleeding who present with excessive bleeding and an otherwise unex-plained prolonged aPTT. Demonstration of low factor VIII activity and the presence of inhibitory antibodies confirm the diagnosis [115]. Prompt treatment of acquired hemophilia is aimed first at the achievement of hemostasis with pro-hemostatic therapy and supportive blood components and second at eradication of the inhibitor with immunosuppressive therapy [113, 114, 116]. It is critical to connect with a hematologist to facilitate the diagnosis and proper management of one such patient.

Laboratory Evaluation of Coagulation

Static Assays

Hemostatic abnormalities in the ICU are often initially detected by the prothrombin time (PT), activated partial thromboplastin time (aPTT), Clauss fibrinogen assay, and complete blood count (CBC). These assays provide a very basic assessment of the patient’s hemostatic capacity but are not without their limitations. First, the PT and aPTT are limited in their ability to detect clotting factor deficiencies. According to international criteria, the PT and aPTT must be sensitive to detect deficiencies of their relevant coagulation factors when below 30%. Therefore, mild deficiencies will be missed. The PT and aPTT are relatively insensitive to fibrinogen deficiency; thus they will miss this common coagulation aberration in the critically ill. The CBC provides information about the absolute platelet count but provides no infor-mation regarding platelet function. None of these “routinely” available tests assess fibrinolysis. Also, there is very little evidence to support any of these static metrics as guidance measures for clinicians on the amount and timing of blood component transfusion. Moreover, the results are often not available when decisions are being made about blood component replacement in the acutely bleeding patient.

Single test results may not be of particular benefit due to the time lag between sample draw and test result reporting; however, result trends are likely meaningful. Chandler et al. and others since have shown that results from the CBC, INR, and fibrinogen as part of a “rapid hemorrhage panel” can be obtained within 15 min

M. Sholzberg

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which is comparable to the timing of results obtained from viscoelastometric assays of coagulation (i.e., thromboelastography {TEG} and rotational thromboelastome-try {ROTEM}). Therefore, blind- or ratio-based blood component resuscitation should only occur in individuals where test results are not available quickly or when patients are massively hemorrhaging [117]. Viscoelastometric assays of coagulation do overcome some of the pitfalls associated with static assays, but the results must be interpreted within the clinical context and ideally along with the above-listed test results as well.

Current Therapeutic Approaches

General Hemostatic Management Principles in the Bleeding Patient

Critically ill patients who are bleeding severely should be managed aggressively particularly if they are exhibiting signs of hemodynamic compromise. Site-specific bleeding should be controlled surgically when possible. Tranexamic acid should essentially be universally provided with the exception of cases complicated by con-comitant active thromboembolism. Hematuria remains a relative contraindication for the use of tranexamic acid due to risk of obstructive nephropathy; however, it should be considered if other modalities are ineffective or if hematuria is life- threatening. Avoidance of cold body temperature, acidosis, and hypocalcemia should also occur as they all will impair effective hemostasis. In the hospital setting, a massive transfusion protocol should be initiated whenever possible for massive hemorrhage as it has been shown to improve patient outcomes [118–121]. The mas-sive transfusion protocol provides blood components (red cells, platelets, frozen plasma, cryoprecipitate) in rapid succession until the protocol is terminated by the treating physician. Also, treatment of massive hemorrhage should be guided by the clinical picture as well as serial laboratory tests such as the CBC, aPTT, PT, fibrino-gen, and viscoelastometric assays of coagulation (e.g., TEG, ROTEM) if available.

Management of Thrombocytopenia in the Critically Ill Patient

Thrombocytopenia is usually symptomatic of the underlying critical illness; there-fore disease-specific management should improve the platelet count. Therefore, the most important step in the management of thrombocytopenia must include a thor-ough evaluation of the underlying cause. Signs of micro- or macrovascular throm-bosis in the presence of thrombocytopenia however require consideration of anticoagulation and/or plasma exchange [26, 27]. Thrombocytopenia is associated with risk of bleeding, transfusion, and death, but the effectiveness of a platelet


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transfusion to mitigate these risks is uncertain [9, 11, 26, 122]. Moreover, platelet transfusions themselves are associated with important risks including nosocomial infection- and transfusion-associated acute lung injury [123–125].

Bleeding in the patient with thrombocytopenia is uncommon if the platelet count is above 20 × 109/L; however this estimate comes from studies on patients with diminished bone marrow production (who are inherently incapable of throm-bopoietic compensation) and may not be applicable to the ICU patient where the commonest cause of thrombocytopenia is consumption [26, 27]. Therefore, very simply, in the absence of fever, a prophylactic platelet transfusion should be con-sidered in ICU patients with a platelet count below 10 × 109/L. The threshold for prophylactic platelet transfusion, however, should be individualized based on important clinical factors described in Bloody Easy 3: A Guide to Transfusion Medicine, which is publicly available online [126]. The effect of platelet transfu-sions in the critically ill, however, has not been well studied particularly when transfusions are used for bleed prophylaxis [26, 127–129]. However, a recent pro-spective observational cohort study nested in a previous randomized controlled trial on thromboprophylaxis found that rates of major bleeding were no different among thrombocytopenic patients transfused with or without platelets [127]. Therefore, a conservative approach to the management of thrombocytopenia in ICU patients appears warranted. Well-powered clinical trials are needed to defini-tively determine the benefits and harms of platelet transfusions in this patient population.

Management of Coagulopathy

Targeted replacement of missing or dysfunctional clotting factors should be guided by the presence or absence of bleeding and/or substantial bleeding risk factors (e.g., major surgery). However, it has been shown repeatedly that abnormal clot-based assay results (i.e., aPTT or PT) generally do not predict operative bleeding risk. There are, however, some very rare exceptions such as in the setting of peri-liver transplant and at the time of surgical resection of peritoneal and hepatic metastases [130]. Hypofibrinogenemia in the setting of diffuse consumption as assessed by the Clauss fibrinogen assay should be corrected but only when below 0.8–1.0 g/L in the absence of bleeding or 1.5 g/L in the presence of substantial bleeding or risk as is the case in patients with acute promyelocytic leukemia [126].

In cases of confirmed or suspected single clotting factor deficiencies, replace-ment or bypassing therapy is directed at what is missing. These cases should be managed in consultation with a hematologist that has expertise in the management of inherited and acquired bleeding disorders. Prompt hematology consultation is particularly critical nowadays given the advent of novel factor and non-factor replacement therapies for inherited bleeding disorders that make the choice of ther-apy far more complex even for the experienced hematologist.

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Management of the Massively Bleeding Patient with Deficiency of Platelets and Coagulation Factors

In the patient with massive hemorrhage, treatment of bleeding with the use of a massive transfusion protocol is recommended. These protocols were initially devel-oped for trauma patients, in whom death from exsanguination is the most common cause of death within the first hour and accounts for more than half the mortality at 24 h [118]. Massive transfusion protocols are associated with improved patient out-comes, cost savings, and decreased blood component utilization [119–121]. In light of these findings, massive transfusion protocols have since been extrapolated to non-trauma patients with massive hemorrhage [131].

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101. Warkentin TE, Basciano PA, Knopman J, Bernstein RA. Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood. 2014;123(23):3651–4.

102. Jay RM, Warkentin TE. Fatal heparin-induced thrombocytopenia (HIT) during warfarin thromboprophylaxis following orthopedic surgery: another example of ‘spontaneous’ HIT? J Thromb Haemost. 2008;6(9):1598–600.

103. Krauel K, Weber C, Brandt S, Zahringer U, Mamat U, Greinacher A, et al. Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes. Blood. 2012;120(16):3345–52.

104. Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russett JI, Kelton JG. The patho-genesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127(9):804–12.

105. Srinivasan AF, Rice L, Bartholomew JR, Rangaswamy C, La Perna L, Thompson JE, et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med. 2004;164(1):66–70.

106. Warkentin TE, Pai M, Cook RJ. Intraoperative anticoagulation and limb amputations in patients with immune heparin-induced thrombocytopenia who require vascular surgery. J Thromb Haemost. 2012;10(1):148–50.

107. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfraction-ated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8):2710–5.

108. Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108(9):2937–41.

109. Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017;130(9):1104–13.

110. Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood. 2007;109(5):1870–7.

111. Baudo F, de Cataldo F. The problem of acquired hemophilia. Blood. 2015;125(7):1052–3. 112. Knoebl P, Marco P, Baudo F, Collins P, Huth-Kühne A, Nemes L, et al. Demographic and

clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012;10(4):622–31.

113. Tiede A, Scharf R, Dobbelstein C, Werwitzke S. Management of acquired haemophilia A. Hamostaseologie. 2015;35(4):311–8.

114. Baudo F, Collins P, Huth-Kuehne A, Lévesque H, Marco P, Nemes L, et al. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood. 2012;120(1):39–46.

115. Tiede A, Werwitzke S, Scharf RE, editors. Laboratory diagnosis of acquired hemophilia A: limitations, consequences, and challenges. Seminars in thrombosis and hemosta-sis: Thieme Medical Publishers; Semin Thromb Hemost. 2014;40(7):803–11. http://doi.org/10.1055/s-0034-1390004. Epub 2014 Oct 9.

116. Collins PW. Management of acquired haemophilia A. J Thromb Haemost. 2011;9(s1):226–35. 117. Callum JL, Rizoli S. Assessment and management of massive bleeding: coagulation assess-

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118. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60(6 Suppl):S3–11.

119. Cotton BA, Au BK, Nunez TC, Gunter OL, Robertson AM, Young PP. Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury compli-cations. J Trauma. 2009;66(1):41–48; discussion 8–9.

120. Cotton BA, Gunter OL, Isbell J, Au BK, Robertson AM, Morris JA, Jr., et al. Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma. 2008;64(5):1177–1182; discussion 82–3.

121. O'Keeffe T, Refaai M, Tchorz K, Forestner JE, Sarode R. A massive transfusion protocol to decrease blood component use and costs. Arch Surg. 2008;143(7):686–90; discussion 90-1.

122. Ning S, Barty R, Liu Y, Heddle NM, Rochwerg B, Arnold DM. Platelet transfusion practices in the ICU: data from a large transfusion registry. Chest. 2016;150(3):516–23.

123. Aubron C, Flint AW, Bailey M, Pilcher D, Cheng AC, Hegarty C, et al. Is platelet transfusion associated with hospital-acquired infections in critically ill patients? Crit Care. 2017;21:2.

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Chapter 3Understanding Advanced Hematologic Testing

Amy E. Schmidt and Marisa B. Marques

Introduction

Critically ill patients often have anemia, sepsis, multiorgan failure (MOF), coagu-lopathies, and/or infection. For the patient to receive the correct diagnosis and treat-ment, laboratory tests must be carefully ordered and interpreted. Many laboratory tests pertaining to anemia and coagulopathy evaluation and diagnosis will be dis-cussed in this chapter. Test interferences as well as caveats that are important to recognize in test result interpretation will be addressed. Additionally, recent advances in hematologic testing for anemia and coagulopathies will be described.

One emerging area that is of importance in blood conservation is the frequency and volume of laboratory blood draws, but this topic is beyond the scope of this chapter. Laboratory tests are expensive with point-of-care (POC) tests typically costing more. Additionally, laboratory tests require blood draws that contribute to the development of iatrogenic anemia during hospitalization [1]. Patients in the intensive care units (ICU) are quite ill and require careful monitoring, and how fre-quently certain tests should be ordered is unknown. However, many hospitals have begun stressing to their staff the costs of unnecessary testing and the risks to the patients [2]. Frequent lab testing has not been linked to improved patient outcome [3]. Notably, it has been shown that when laboratory tests were reduced, patient outcomes remained the same, and blood component use was decreased [4].

A. E. Schmidt, MD PhD Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USAe-mail: [email protected]

M. B. Marques, MD (*) Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USAe-mail: [email protected]




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Anemia Tests

Anemia is characterized by a decrease in red blood cells (RBCs) and/or hemoglobin (Hgb). There are several forms of anemia that are defined by the mean corpuscular volume (MCV). Typically, RBCs have a MCV of 80–100 fL. Microcytic anemia is characterized by a MCV below the normal range, normocytic anemia has a normal MCV, and macrocytic anemia is characterized by a MCV above the normal range. There are various causes of each of these forms of anemia.

The most common cause of microcytic anemia is iron deficiency. Iron-deficiency anemia (IDA) can be suspected by a variety of different laboratory values in the CBC. Typically, not every laboratory parameter will be an exact fit. Besides a low MCV, patients with IDA often have an increased red blood cell distribution width (RDW), which is indicative of a wide range of red blood cell sizes. The RDW is the coefficient of variation of the erythrocyte size and is calculated by dividing the stan-dard deviation of the MCV by the MCV value and multiplying it by 100 [5]. Interestingly, an increased RDW has been shown to be prognostic and is associated with cardiovascular and cerebrovascular diseases [6]. The increased RDW of iron-deficiency anemia (IDA) is due to the concomitant presence of microcytic RBCs and reticulocytes and possibly nucleated RBCs in the patient’s circulation. Patients usually respond to anemia by increasing their production of reticulocytes. This is reflected as an increase in either the absolute reticulocyte count or as an increase in the reticulocyte percentage. Notably, the reticulocyte percentage should be adjusted to the patient’s anemia to yield the corrected reticulocyte percentage. This value can be used to correctly assess the bone marrow’s response to anemia. Together, the absolute reticulocyte count and the corrected reticulocyte percentage can be used to determine if the patient’s anemia is due to RBC loss or inadequate RBC production. Recently, the reticulocyte hemoglobin has become an important measure in evaluat-ing anemia; this value is frequently reported as mean reticulocyte hemoglobin con-tent (CHr) or reticulocyte hemoglobin equivalent (Ret-He) (Table 3.1). Most automated hematology analyzers have the capability to report one of these values,

Table 3.1 Nonroutine laboratory tests to evaluate a patient with anemia

Test name Comments

Mean reticulocyte hemoglobin content (CHr) or reticulocyte hemoglobin equivalent (Ret-He)

Useful to detect functional iron deficiency

CHr or Ret-He Decreased in iron-deficiency anemia and thalassemias; improves fast with iron supplementation

Mean reticulocyte volume Decreased in iron deficiency; reference range dependent on methodology

Hepcidin (serum, plasma, or urine) Increased in anemia of chronic disease; variable results depending on method used

Plasma methylmalonic acid (MMA) Increased in early or mild vitamin B12 deficiency

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which provide an assessment of functional iron availability for incorporation into RBC production over the previous 3–4 days [7, 8]. A decreased value indicates reduced cellular hemoglobin content as seen in functional iron deficiency. Reticulocyte hemoglobin is also the strongest predictor of IDA in children [9]. Reticulocyte hemoglobin is particularly helpful in diagnosing IDA in the critically ill as ferritin values may be falsely elevated due to inflammation and/or chronic renal disease. Additionally, serum iron values may also be affected by patient dietary intake and may not correctly reflect the patient’s iron status. The CHr/Ret-He decreases with IDA and is one of the first laboratory values to recover with iron supplementation [10, 11]. Notably, CHr/Ret-He can be decreased in thalassemias, and these RBC disorders should be excluded prior to using CHr/Ret-He to assess a patient’s iron status [12].

Mean reticulocyte volume is another parameter that is available; however, there are limited studies on its clinical usefulness. In patients with low iron stores, the mean reticulocyte volume increases quickly after iron therapy and decreases at a similar speed with the development of iron-deficient erythropoiesis. The mean retic-ulocyte volume also decreases quickly following treatment with vitamin B12 and/or folate in macrocytic anemia [13]. One problem with using mean reticulocyte vol-ume is the variation in values obtained from different analyzers.

Quite frequently, an iron panel consisting of serum iron, total iron-binding capac-ity (TIBC), transferrin saturation, and ferritin is ordered to assess microcytic ane-mias. As mentioned earlier, ferritin is an acute phase reactant and often elevated in critically ill patients. Transferrin saturation may also be affected by the presence of inflammation which can cause increased transferrin in the setting of a constant amount of iron which would appear as low transferrin saturation. The transferrin concentration may also be low due to decreased synthesis caused by liver impair-ment, malnutrition, or chronic disease. In these cases, the transferrin saturation could appear increased. Finally, transferrin saturation also experiences substantial fluctuations in values between 17% and 70% due to diurnal variation [14, 15].

Many critically ill patients have normocytic anemia, with anemia of chronic dis-ease being its most common cause, affecting 6% of hospitalized adult patients [16]. There are several causes of normocytic anemia: decreased production, increased destruction, or an uncompensated increase in plasma volume such as that which occurs in fluid overload or pregnancy. Anemia of chronic disease (aka anemia of inflammation) is a diagnosis of exclusion. All iron studies are normal indicating adequate iron stores, but iron delivery to developing RBCs is impaired, and erythro-poietin (EPO) production is typically suppressed. In addition to decreased EPO levels, anemia in critically ill adults also can have high hepcidin levels. Notably hepcidin is increased as a result of inflammation as part of a host defense mecha-nism to reduce iron availability to microbes and malignant cells [17–19]. Hepcidin is a liver-derived peptide hormone that is involved in iron homeostasis, and increased hepcidin decreases iron availability via internalization and destruction of ferropor-tin and decreased iron absorption in the gastrointestinal tract [20]. Decreased fer-roportin levels prevent iron export from cells, essentially resulting in iron being locked in macrophages in the reticuloendothelial system [21]. Erythroferrone is a

3 Understanding Advanced Hematologic Testing

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hormone which mediates hepcidin suppression and subsequent increased iron absorption and mobilization [21, 22]. Hepcidin levels can be measured in critically ill adults to assess its role in normocytic anemia. This testing is likely to be sent out at most hospitals and have a turnaround time of several days. Hepcidin testing is performed either using mass spectrometry or immunoassays [23]. Importantly, hep-cidin results can vary widely depending on the method used and testing center employed. This is due in part to a lack of reference material, no agreed-upon refer-ence method, and no commutable calibrators [24]. Additionally, some studies have shown that there is considerable within-patient variability for hepcidin levels, with hepcidin levels increasing with fasting and showing circadian rhythm and daily variability [25, 26]. Currently, researchers are working on developing hepcidin antagonists to treat anemia of chronic disease [19]. With the advent of such new drugs, hepcidin measurement is likely to become more prominent in clinical practice.

The direct antiglobulin test (DAT), lactate dehydrogenase (LDH), haptoglobin, and bilirubin tests are useful in diagnosing anemia due to increased destruction (hemolysis). A positive DAT, increased LDH, decreased haptoglobin, and increased bilirubin are supportive of a hemolytic anemia diagnosis. The DAT assesses whether the patient’s RBCs have been coated in vivo with IgG and/or complement. This test has a false-negative rate of 5–10% which can be potentially due to extensive hemo-lysis, hemolysis caused by IgA or IgM, low levels of IgG bound to the RBC (below detection limit), low-affinity antibodies, and technical error [27]. The DAT may also be falsely positive in a clotted specimen which can lead to in vitro complement binding, high serum immunoglobulin or protein levels, intravenous immunoglobu-lin, antiphospholipid syndrome, and infection such as HIV. Notably, the DAT can also help distinguish the type of autoimmune hemolytic anemia based upon the thermal amplitude of the antibody. In the absence of recent transfusion, a positive DAT for IgG only indicates warm autoimmune hemolytic anemia. A DAT negative for IgG and positive for C3 is consistent with cold autoimmune hemolytic anemia or cold agglutinin disease. Finally, a mixed-type autoimmune hemolytic anemia can be positive for IgG and C3 [28]. Additionally, the DAT may also be helpful in detecting drug-induced hemolytic anemia, as when there is a positive DAT for IgG but an eluate from the red cells that does not bind to any reagent cell. A thorough history of commonly implicated drugs such as some penicillins and cephalosporins is essential to seal the diagnosis.

LDH is an intracellular enzyme that is very prevalent in RBCs. Thus, although increased serum LDH is a sensitive marker of hemolysis, it is not specific, as increased LDH can be seen in many conditions such as cancer and liver disease. Haptoglobin is a protein that scavenges free hemoglobin and protects the patient from its toxic effects [29]. Decreased haptoglobin is also sensitive but not specific for hemolysis; liver disease, exercise, and blood transfusions can also decrease hap-toglobin levels [10]. Interestingly, approximately 1:1000 Caucasians and 1:25 African-Americans have a complete absence of haptoglobin [30]. Lastly, bilirubin levels, particularly indirect bilirubin, increase with hemolysis due to the liver’s inability to keep up with conjugation and excretion into the bile.


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Two common causes of macrocytic anemia are B12 and folate deficiencies, and serum levels are helpful for diagnosis. However, increased levels of transcobalamin I-bound B12, as can be seen in patients with chronic myelogenous leukemia, liver disease, and other myeloproliferative disorders, can cause normal or high serum B12 even in the setting of B12 deficiency [31]. Normal serum B12 can also be observed in patients with prolonged exposure to nitrous oxide [31]. Decreased serum B12 is not specific to B12 deficiency and can be seen in folate deficiency, pregnancy, multiple myeloma, HIV infection, and in patients that are receiving anticonvulsants. Thus, folate and B12 levels should be checked concomitantly. An alternative to detect B12 deficiency is to measure serum or plasma methylmalonic acid (MMA) and plasma total homocysteine. Increased MMA is highly specific for B12 deficiency, more than a low serum B12 level. Notably, the MMA assay is quite expensive and is typically a sendout test at most hospitals. It is also important to remember that impaired renal function can alter the results of the MMA assay. Total homocysteine testing has much lower specificity and can be increased not only in B12 deficiency but also folate deficiency, renal failure, vitamin B6 deficiency, hypothyroidism, and alcohol abuse, in patients taking certain medications and in carriers of mutations in the homocysteine metabolism pathway [31].

Folate levels can be measured in serum or in RBCs. A serum folate level reflects the patient’s current diet, while the RBC folate is a measure of the folate status over the previous 90 days. Since a decreased folate can be seen in a large number of B12- deficient patients, a diagnosis of folate deficiency is typically reserved for someone with decreased folate and a normal B12 result.

In many patients with the laboratory tests discussed above, the etiology of the anemia remains unclear. For such patients, a bone marrow biopsy (BMBx) may be useful. BMBx may also be helpful in evaluating critically ill patients with immature cells such as blasts identified in the complete cell count (CBC), pancytopenia, extremely low reticulocyte count, serum or urinary monoclonal proteins, or unex-plained severe anemia, particularly with a history of cancer or chemotherapy. Iron staining can be performed on the BMBx to evaluate bone marrow iron stores as long as the specimen contains enough spicules for adequate assessment. Some experts recommend a minimum of seven spicules to be able to accurately assess iron stores [32]. A reticulin stain may also be useful to detect fibrosis within the bone marrow, another cause of anemia. Cytogenetic studies and FISH may also be beneficial in evaluating the BMBx. Lastly, assessment of the BMBx aspirate and core for cellu-larity, dysplasia, increased blasts, increased plasma cells, and other abnormalities can be helpful when no other cause of anemia has been ascertained.

Tests to Evaluate Thrombocytopenia

Thrombocytopenia is typically defined as a platelet count <150 × 106/μL. Thrombocytopenia can be due to decreased production (hypoproliferative), increased breakdown or clearance, or splenic sequestration. Hypoproliferative


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thrombocytopenia may be caused by leukemia or metastatic cancer to the bone marrow, chemotherapy, a primary bone marrow diagnosis such as myelodys-plastic syndrome, viral infections such as hepatitis C or HIV, or alcoholism. It is often accompanied by other cytopenias, such as anemia and leukopenia. Causes of increased platelet destruction/consumption should be divided into immune and nonimmune. The latter includes immune thrombocytopenia (ITP), drug-induced ITP, and heparin-induced thrombocytopenia (HIT). Nonimmune causes are more common in the critical care setting, such as sepsis/disseminated intravascular coagulation (DIC), malignant hypertension, large intravascular devices, thrombotic thrombocytopenic purpura (TTP), and atypical hemolytic uremic syndrome (aHUS), among others [33]. In addition to a complete history, review of the peripheral blood smear aids in the differential diagnosis. A BMBx is rarely needed but may be help-ful in selected cases. A newly developed index to detect ADAMTS13 deficiency, the PLASMIC score, should be utilized in patients with thrombocytopenia and microan-giopathic hemolytic anemia in whom TTP is being considered (Table 3.2) [34]. If the PLASMIC score is intermediate or high, the patient must be treated with therapeutic plasma exchange emergently until the result of the ADAMTS13 activity is available. TTP is a medical emergency, as 90% of patients die without therapeutic apheresis. To diagnose or rule out HIT, another potentially serious complication, there are two indices that can be used to determine the likelihood of the diagnosis prior to ordering a laboratory test [35, 36]. When indicated, the initial test should be heparin-platelet factor 4 (PF4) antibodies by ELISA, which measures heparin-PF4 antibodies of all immunoglobulin classes. This test has a high incidence of false positives which has been reported to occur in 1–3% of dialysis patients, 10–15% of medical patients, and >20% of patients receiving heparin for peripheral vascular surgery [33]. Thus, false-positive HIT results can be a problem in critically ill patients. A positive ELISA result for HIT should be followed by a serotonin release assay, which determines the functional activity of the heparin-platelet factor 4 antibodies [37, 38].

Interpretation and Testing for Coagulation Abnormalities

Coagulopathy is a common problem in the critically ill. Many different condi-tions can result in coagulopathies which make careful assessment important in correctly diagnosing the etiology and administering the most efficacious

Table 3.2 Components of the PLASMIC score – each parameter present contributes one point to the score [34]

P: Platelet count less than 30 × 106/μLL: Laboratory evidence of hemolysis (any)A: Absence of active cancerS: No history of stem cell or solid organ transplantM: Mean corpuscular volume (MCV) less than 90 fLI: International normalized ratio (INR) less than 1.5C: Creatinine less than 2 mg/dL


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treatment. The most common coagulation tests ordered are the prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimer. Some of these tests are currently ordered for uses they were not designed for. This is most true for the PT and aPTT tests. The PT was intended to monitor patients receiving warfarin and the aPTT to monitor heparin therapy. However, they are often utilized to assess a patient’s bleeding risk or tendency. It is impor-tant to note that neither of them has predictive value for bleeding [39]; however, prolongation of either the PT or aPTT has been shown to be a strong predictor of mortality in trauma patients [40]. Furthermore, their use to guide transfusions has resulted in substantial variation in plasma administration practices to the criti-cally ill [41, 42].

Routine Coagulation Assays

As discussed earlier, PT, aPTT, fibrinogen, and D-dimer are among the most fre-quently ordered coagulation tests on critically ill adults. Fibrinogen is also an acute phase reactant and can be elevated in such patients. Additionally, fibrinogen can be decreased due to liver failure or increased consumptions such as in DIC. Thus, the fibrinogen result must be interpreted with caution and measurements compared with each other over time to detect significant changes. The D-dimer assay is useful in detecting fibrinolysis and can be indicative of excessive clotting or sepsis. D-dimers are generated by the breakdown of cross-linked fibrin by plasmin. All D-dimer assays use antibodies against epitopes only exposed once cross-linked fibrin is bro-ken down. While D-dimers are increased in a variety of settings including preg-nancy, burns, sickle cell crisis, surgery, malignancy, infection, liver disease, atrial fibrillation, renal failure, cardiac failure, aortic dissection, and VTE, the D-dimer concentration in DIC is expected to be at least 20 times higher than the reference range for the specific assay. A low D-dimer in a patient with a low pretest probabil-ity of VTE has a very high negative predictive value and can be useful to guide management [56, 57].

Many critically ill patients have prolonged PT and aPTT values. The PT mea-sures the extrinsic and common pathways of coagulation and is most sensitive to deficiencies of factors VII, X, and V and prothrombin. Frequently, the PT is pro-longed due to sepsis/DIC and coagulation factor consumption or poor factor synthe-sis due to liver dysfunction, malnutrition, and GI malabsorption, especially of vitamin K. The aPTT measures the intrinsic and common pathways of coagulation and is most sensitive to deficiencies of factors XII, XI, IX, and VIII and prekalli-krein. In the critically ill, the aPTT is commonly prolonged due to heparin administration or blood sample contamination with heparin, severe DIC/sepsis, and liver failure. The PT and aPTT tests are also affected by anticoagulants that the patients may be receiving for thrombosis prophylaxis or treatment. Critically ill patients with prolonged PT and/or aPTT values with no clear etiology can be evalu-ated further using mixing studies.


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In mixing studies, a fixed volume of the patient’s plasma is incubated at 37 °C with an equal volume of normal plasma, and then the PT and/or aPTT are repeated immediately after 1–2 h (“incubated mixing study”). If the prolonged screening test is due to a factor deficiency, the PT or aPTT in the mix will normalize or “correct,” which is defined as a result in the reference range of the test or within 10% of the result of the normal plasma alone incubated under the same circumstances. If the result of the mixing study does not show correction, it suggests the presence of an inhibitor in the patient’s plasma. The most common inhibitor is heparin, which is the reason why some laboratories perform a thrombin time and an anti-Xa test to rule out the presence of unfractionated heparin and/or a direct factor Xa inhibitor before performing the mixing study. In the setting of multiple factor deficiencies, such as in DIC or severe liver failure, the mixing studies may also not fully correct as per the definition above, but the result of the PT or aPTT in the mix should be shorter than the original PT or aPTT in the patient’s plasma. Thus, interpretation of mixing studies must take into account the most likely cause of the coagulopathy. A less common cause of lack of correction in the aPTT mixing study in a critically ill patient is a lupus anticoagulant, which is often an incidental finding.

In the setting of mixing studies that correct, individual factor levels can be per-formed to evaluate which particular factors are deficient. Vitamin K deficiency will result in decreased levels of prothrombin and factors VII, IX, and X. In liver failure, all coagulation factors except factor VIII should be decreased because factor VIII is made by both the liver and endothelial cells. Liver failure can be distinguished from vitamin K deficiency by measuring factors V and VIII, which are not vitamin K-dependent. Factor V will also be decreased in liver failure, but factor VIII will be normal or even high due to the acute phase reaction [49]. Isolated deficiency of fac-tor X is rare as a congenital defect, but it can be seen in patients with amyloidosis and unexplained bleeding [58, 59].

Testing for Lupus Anticoagulant

Current International Society for Thrombosis and Haemostasis (ISTH) guidelines recommend screening for lupus anticoagulants using two different tests such as a dilute aPTT or silica clotting time and a dilute Russell viper venom time (DRVVT). Dilute refers to the use of limited amount of phospholipid to increase the sensitivity of the assay to antiphospholipid antibodies. If one of these screening tests is pro-longed, a confirmatory test must be done, in which a large amount of phospholipid is added to the patient’s plasma and a decrease in the clotting time is observed if a lupus anticoagulant is present. A positive test for lupus anticoagulant should be repeated 6–12 weeks later to confirm its persistence and to make the diagnosis of antiphospholipid syndrome if the patient has clinical manifestations such as VTE or pregnancy complications. Patients receiving direct thrombin and direct factor Xa inhibitors can have false-positive lupus anticoagulant results and should not be tested [60, 61]. Also, if a lupus anticoagulant is present and is causing a


49

prolongation of the aPTT, the latter is unreliable to monitor heparin, and the anti-Xa assay must be employed. In rare patients with a lupus anticoagulant that prolongs the PT, an alternative test must be used to monitor warfarin. Several studies have shown that under these circumstances, INR values vary significantly depending on the thromboplastin used. Consequently, the extent of anticoagulation was frequently overestimated [62, 63]. Instead, the chromogenic factor X assay should be used to guide therapy.

Chromogenic Factor X Assay

The chromogenic factor X assay (not commonly available in hospital laboratories) is a test of factor X activity that it is not clot-based and contains no phospholipid; therefore it is not affected by lupus anticoagulant [64]. The measurable factor X activity decreases as the patient’s INR increases. A factor X activity of 20–40% cor-responds to an INR of 2.0–3.0 [65]. The chromogenic factor X assay is also useful in patients receiving the thrombin inhibitor, argatroban, while being transitioned to warfarin [66]. However, patients with liver disease and vitamin K deficiency may have decreased factor X activity levels.

Factor VIII Inhibitor

If the aPTT mixing study did not correct and lupus anticoagulant testing was nega-tive, the patient may have a specific factor inhibitor, such as a factor VIII inhibitor. Patients with factor VIII inhibitors typically have hematomas and bleeding at vari-ous sites, which characterize acquired hemophilia [67]. If a factor VIII inhibitor is suspected, close consultation with the coagulation laboratory may be particularly helpful, and treatment with appropriate activated factors must be initiated promptly in the setting of bleeding. Plasma transfusion is not effective. Furthermore, determi-nation of the inhibitor titer using either the Bethesda or Nijmegen-Bethesda assay will help guide patient management.

The Anti-Xa Assay

The anti-Xa assay is the most accurate test to monitor unfractionated heparin (UFH) and the only test to monitor low-molecular-weight heparin (LMWH), when needed. As mentioned above, patients with a lupus anticoagulant who are receiving UFH should be monitored with the anti-Xa, a non-clot-based method to measure the abil-ity of the heparin-antithrombin (AT) complex to inhibit factor Xa. The residual amount of factor Xa activity is inversely proportional to the amount of UFH or


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LMWH in the patient’s plasma and is determined using a calibration curve [68, 69]. The reference range of the anti-Xa assay depends on the type of heparin the patient is receiving, dose schedule, and the indication (prophylactic or therapeutic). For LMWH, the anti-Xa level should be drawn 3–4 h after a subcutaneous dose. The anti-Xa assay can also be used to monitor fondaparinux; however, a separate cali-bration curve using fondaparinux is needed [70].

The anti-Xa assay is also affected by the presence of a direct factor Xa inhibitor in plasma and may be useful to monitor rivaroxaban, apixaban, or edoxaban. However, most laboratories do not have a reference range for any of these drugs due to lack of commercially available controls to generate a calibration curve for each direct factor Xa inhibitor [71, 72]. Importantly, the anti-Xa calibration curves for UFH or LMWH cannot be used to monitor the direct factor Xa inhibitors. The “gold standard” for measurement of the plasma concentration of these agents is high- performance liquid chromatography coupled to mass spectrometry (HPLC-MSMS). A recent study by Bardy et al. showed that the anti-Xa assay was effective in evaluat-ing plasma concentrations of rivaroxaban >52 ng/mL; however, at lower concentra-tions, it was not as accurate in comparison to HPLC-MSMS [73].

Viscoelastic Testing

While the PT and aPTT only measure specific steps of the coagulation cascade in plasma, thromboelastography (TEG) and rotational thromboelastometry (ROTEM) offer a more holistic overview of clot development, stabilization, and dissolution in whole blood, more closely reflecting in vivo hemostasis. Thus, TEG and ROTEM detect platelet dysfunction and fibrinolysis, which are important aspects of coagu-lopathies in the critically ill. Numerous studies have described the usefulness of TEG and ROTEM in assessing trauma patients, guiding blood component use and administration, assessing coagulopathy, monitoring liver transplant surgeries, and assessing heparin reversal following cardiac bypass surgery, among many things [43–48].

In TEG and ROTEM, testing of citrated blood must be performed within 2 h of collection. Fig. 3.1a shows a schematic representation of TEG, where the patient’s blood is added to a preheated cuvette, a pin is suspended from a torsion wire into the cup, and the cup moves with each rotation cycle. As the clot forms, the cup’s impeded movement is transmitted to the pin, and a tracing is generated. In ROTEM (Fig. 3.1b), the pin transmits a signal via an optical detector system and not a torsion wire as in TEG [45]. A diagram of a TEG tracing is shown in Fig. 3.1c. The time until initial fibrin formation is measured by the reaction time (R). The R value is


51

a b

Torsion wire

Pendulum

Oscillating cup4–45°

Oscillating axis (±4.75°)

SpringBall bearings

Sensor pin

Cuvette with sample

Coagulation

Clotting time (R)

Clot kinetics(K)

Clot strength(MA)

Lysis time

a angle

Fibrinolysis

c

Fig. 3.1 TEG. (a). In TEG, the pin is suspended from a torsion wire and is inserted into the cuvette or cup which rotates through an angle of 4–45°. As fibrin strand forms in the cuvette/cup, the impeded movement is transmitted via the pin and torsion wire to a tracing. (b). In ROTEM, the cup is stationary and a ball bearing pin rotates back and forth 4.75°. The movement of the pin is driven by an elastic spring. As long as the blood is liquid, the movement is unrestricted. When the blood starts to clot, the rotation of the pin is restricted as the firmness of the clot increases. (c). The clot time or reaction time (R value) reflects the time to initiate fibrin formation. The kinetics of clot formation (K value) is the time at which the amplitude reflecting clot strength reaches 20 mm. The R and K values are measurements of coagulation. The α angle is the angle between the midline and a line tangential to the developing TEG® trace. The α angle represents the clot kinetics of clot buildup and fibrin cross-linking. The maximum amplitude (MA) is the maximum width of the TEG® trace. It is a measurement of the ultimate clot strength and reflects platelet number and function


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prolonged in the setting of single hereditary (e.g., hemophilia A or B) or multiple and acquired (e.g., warfarin) coagulation factor deficiencies, when the coagulation cascade is inhibited by either unfractionated heparin, direct thrombin inhibitors (e.g., argatroban, bivalirudin, dabigatran), or direct factor Xa inhibitors (e.g., rivar-oxaban, apixaban, edoxaban, etc.). The cutoff R value varies depending on which activator is used in the TEG assay. The kinetics of clot formation (K value) is the time at which the amplitude reflecting clot strength reaches 20 mm. The K value can be prolonged in coagulation factor deficiencies, hypofibrinogenemia, and thrombo-cytopenia. Similar to the R value, the K value is dependent on the activator used. The α angle is the angle between the midline and a line tangential to the developing TEG trace, and it represents the kinetics of clot buildup and fibrin cross-linking. The α angle is increased in hypercoagulable states and decreased in thrombocytopenia or hypofibrinogenemia. The maximum amplitude (MA) predominantly reflects the strength of the clot and is affected by the fibrinogen concentration and platelet count and function. The MA is increased in hypercoagulable states and decreased in thrombocytopenia, platelet dysfunction, and hypofibrinogenemia. Decreased MA values are frequently seen in TEG tracings from patients who have been on cardio-pulmonary bypass or extracorporeal membrane oxygenation (ECMO) [49, 50]. The use of the MA to predict thrombotic states in patients undergoing coronary artery bypass and percutaneous intervention has also been suggested [51]. An MA above 68–70 mm has been evaluated in the literature to assess risk of thrombosis. Although there was only a trend toward worse 30-day outcomes for either myocardial infarc-tion, stroke, or mortality in patients who had MA values >68–70 mm, this study may have been underpowered to examine these issues since a composite of the three outcomes was higher (p = 0.014) in patients with this MA cutoff [52]. Another study evaluated development of venous thromboembolism (VTE) in trauma patients. The rate of deep vein thrombosis (DVT) was double in trauma patients with hypercoagu-lable TEG indices despite prophylaxis, as compared to trauma patients with normal TEG results (odds ratio 2.41, p = 0.026) [43]. Notably, none of the individual TEG indices alone was associated with DVT, but the combination of R <5 min, α angle >72 degrees, and MA >74 mm was associated with DVT development [43].

The TEG and ROTEM measure the viscoelastic properties of blood under static conditions in a cuvette and not under flow that exist in an endothelialized vessel. Thus, they are not wholly reflective of what is occurring in vivo; in addition, they are very difficult to standardize as results are affected by age and gender as well as blood collection site and time delay in processing [53]. Patients receiving heparin should have a heparinase TEG which utilizes the enzyme heparinase to degrade the heparin followed by the addition of kaolin as an activator to test the patient’s visco-elastic coagulation properties. In the absence of heparinase use, patients receiving heparin anticoagulation may have a falsely elevated R value.

As mentioned above, TEG and ROTEM can be used to guide blood component administration; this practice is particularly well-studied for trauma victims. A shortened R value is frequently seen in the acute setting of trauma, and no action is typically needed. A prolonged R value can indicate the need for plasma to replen-ish coagulation factors. A decreased α angle may be an indication for plasma or


53

cryoprecipitate, and a decreased MA supports the use of cryoprecipitate and/or platelet transfusions. Patients with increased MA values and/or an overall increase in the coagulative index (CI) may benefit from anticoagulation. Increased LY30 values are indicative of increased fibrinolysis, and tranexamic acid may be useful under the right circumstances [54].

Despite trauma and injury, many patients with coagulopathy still have normal TEG values at presentation. Savage et al. have described a new TEG value, the MA-R ratio, which they believe reflects a patient’s hyper- and hypocoagulability [55]. Patients with the lowest MA-R ratios had higher mortality [55]. Further, they hypothesized that the lower MA-R ratio is due to decreased fibrinogen and earlier cryoprecipitate transfusion may be beneficial [55].

TEG and ROTEM are point-of-care (POC) tests and are frequently kept in the operating room and not in a centralized laboratory. Hence, as with many POC test devices, special attention is needed to comply with standards with respect to QC/QA and monitoring of user proficiency as is routine in clinical laboratories. Maintenance of these standards is important, non-laboratory-trained individuals often perform these tests, and TEG is classified as a moderately complex test by CLIA. Due to these concerns, many institutions have moved the TEG and ROTEM to either a central or a satellite laboratory where laboratory-trained personnel main-tain the devices and perform the tests. Another advantage of these tests is that the tracings can be transmitted in real time to where the patient is, in order to facilitate semi-real-time decision-making with reliable results.

von Willebrand Disease

von Willebrand disease (vWD) is reported to affect ~1% of people [74, 75]; how-ever, only approximately 0.1% are symptomatic [76]. Patients with vWD have a tendency to bleed at mucosal surfaces such as the nose, oropharynx, and urogenital system. Most people have type 1 vWD, which is a partial quantitative deficiency. Several factors influence the plasma concentration of von Willebrand factor (vWF), such as the blood type, stress, and inflammation [77]. Individuals of blood type O have vWF levels that are 10–30% lower than those of other blood types [78]. This difference is likely due to increased clearance of vWF in the circulation [79]. Several studies have shown that patients that have the blood type O comprise a much larger percentage of individuals diagnosed with vWD than would be expected, suspicious for their misclassification due to constitutively lower vWF [80, 81]. Thus, when evaluating a patient for vWD, it is important to know the blood type; prior surgical, dental, and bleeding history; and test for vWF antigen, vWF activity, and factor VIII activity. Conversely, patients with vWD may have normal test results because they are acutely ill (stress and acute phase reaction).

A smaller percentage of patients with vWD have a qualitative defect of vWF that can be detected by calculating the vWF activity/vWF antigen ratio. Typically, the vWF activity and antigen are present in an essentially 1:1 ratio. When the ratio is


54

<0.7, a qualitative defect is indicated, and a diagnosis of type 2 vWD should be investigated further. In rare patients, vWF activity, vWF antigen, and factor VIII activity are severely depressed, and type 3 vWD is likely. For such patients, vWF replacement with concentrates is the appropriate therapy for bleeding. While patients with type 1 vWD whose vWF levels have normalized as part of an acute phase reactant most often do not require treatment, DDAVP and vWF replacement should be available.

Another cause of bleeding in critically ill patients is acquired vWD (AvWD). These patients do not have a personal or family history of abnormal vWF testing or bleeding. Patients with AvWD frequently have diseases such as lymphoproliferative or myeloproliferative neoplasms, cardiovascular disease, solid tumors, and autoim-mune disorders [82–84]. AvWD should be suspected in patients with mechanical heart valves, ventricular assist devices (VADs), artificial hearts, status post-cardiac bypass, or on extracorporeal membrane oxygenation (ECMO) [85–88]. While the prevalence of AvWD in the general population is estimated at 0.04–0.2% [84], it is likely much higher (although unknown and probably underrecognized) in critically ill patients with one or more of these intravascular devices. AvWD is thought to occur via three mechanisms: (1) loss of high-molecular-weight vWF multimers due to high shear stress and proteolysis, (2) vWF adsorption onto cancer cells resulting in increased clearance, and (3) autoantibodies that impair vWF function and increase its clearance [83, 89]. In mechanism 1, vWF activity is much lower than the vWF antigen; in mechanism 2, both vWF activity and antigen are decreased, or vWF activity is decreased proportionally with the vWF antigen; in mechanism 3, both the vWF activity and antigen are decreased. vWF multimer analysis is helpful in distinguishing between AvWD and vWD. Typically, AvWD is associated with decreased or absent high-molecular-weight vWF multimers [84, 91–93]. However, this pattern is also seen in congenital type 2 vWD. AvWD can also be drug-induced. Several drugs have been implicated, including valproic acid, ciprofloxacin, griseo-fulvin, tetracycline, pesticide, thrombolytic agents, and hydroxyethyl starch. Discontinuation of the offending agent results in resolution of the AvWD [84, 89]. Although less common, AvWD has also been observed with hypothyroidism and uremia and without an underlying predisposing condition [82, 90]. When the diag-nosis of AvWD is suspected, especially in critically ill patients with intravascular devices, the proper levels should be promptly checked in order to replace vWF as necessary.

Hypercoagulability Tests

During the course of a hospital stay, critically ill patients frequently develop blood clots. In many cases, this is despite prophylactic measures. A hypercoagulable work-up may be warranted. A hypercoagulable panel, comprised of antithrombin (AT), protein S, and protein C activity, activated protein C resistance (APCR), prothrombin


55

G20210A gene mutation analysis, and antiphospholipid antibodies (lupus anticoagu-lant, anticardiolipin antibodies, and anti-β2-glycoprotein I antibodies), is rarely indi-cated in the intensive care unit. In the setting of a recent clot, AT, protein S, and protein C levels are likely to be decreased and not reflective of baseline values. Although normal results rule out a deficiency, misinterpretation of abnormally low results is likely and has significant long-term implications for the patient. Furthermore, proteins C and S are vitamin K-dependent and may be decreased because of liver disease, malnutrition, malabsorption, vitamin K deficiency, or current or recent war-farin. Furthermore, protein S activity measures free protein S, which decreases dur-ing an acute phase reaction. It is not surprising, therefore, that decreased levels of protein C and AT have been observed in 40–60% of trauma patients and 90% of sepsis patients [94, 95]. In addition, direct thrombin and direct factor Xa inhibitors can interfere with functional protein S assays [96]. Patients receiving UFH or LMWH may also have decreased levels of AT due to increased clearance. The only indication for testing for AT during an acute VTE episode is when there appears to be heparin resistance, i.e., difficulty reaching a therapeutic anti-Xa level despite increased intra-venous infusion of UFH or subcutaneous doses of LMWH. In such circumstances, a low AT activity may explain lack of response to heparin, and AT replacement is indicated in order to reach the desired target anti-Xa.

Testing a patient with unexplained VTE for factor V Leiden mutation with the APCR assay and for the prothrombin G20210A mutation is not affected by acute illness, but the results of these tests do not affect anticoagulation in the hospital. The presence of these hypercoagulable risk factors plays a role in the duration of treat-ment, which is the basis for the recommendation to perform them after discharge. The APCR evaluates the ability of activated protein C (APC) to cleave and inacti-vate factors Va and VIIIa. In the presence of factor V Leiden mutation, APC is unable to cleave and inactivate factor Va which leads to increased thrombin genera-tion. Although factor V Leiden testing can be done via DNA analysis in a molecular diagnostic laboratory, the APCR is quicker and much less expensive. The APCR is not accurate when a lupus anticoagulant is present and direct oral anticoagulants also interfere with the APCR assay [97]. Except for testing for lupus anticoagulants which is affected by anticoagulation, assessing for the other antibodies that may cause antiphospholipid syndrome may be performed in the intensive care unit. However, once again, the acute management of the patient with VTE does not vary if such a diagnosis is made.

Platelet Function Tests

With the adoption of TEG and ROTEM by many hospitals, interest in critically ill patients’ platelet function has increased. Prior to TEG and ROTEM availability, the methods available to assess platelet function were whole blood platelet aggregome-try, platelet-rich plasma (PRP) platelet aggregometry, and the PFA-100. The first


56

two may be considered the gold standard in platelet function but are not widely available because of their high cost and complexity. The PFA-100 is widely avail-able and a POC test. It assesses the shear rates as blood is aspirated through a car-tridge that has an aperture coated with either collagen and epinephrine or collagen and ADP. The closure time (CT) is determined once the blood ceases to flow through the aperture. PFA-100 testing is affected by the hematocrit (decreased hematocrit is associated with increased CT), platelet count (increased CT with platelet count below 100 × 106/μL), vWF (decreased levels associated with increased CT), platelet inhibitor drugs, uremia, and cardiopulmonary bypass.

To determine if a patient’s platelets are adequately “blocked” by ADP inhibitors such as clopidogrel or prasugrel, GPIIb/IIIa receptor inhibitors, or aspirin (ASA), VerifyNow can be used (Fig. 3.2). The VerifyNow is a POC device that uses whole blood in a turbidimetric assay. It employs fibrinogen-coated beads and measures

Aspirin

Fibrinogen

GPIIb/IIIa

AbciximabEptifibatideTorofiban

ClopidogrelPrasugrel

Thrombin

PAR1 G12/13

G12/13

G12/13 G12/13Ga

Gi

GPIb/IX/VvWF

vWFvWF

vWF

GPVIFcRγ-chain

collagen

PAR4

ADPP2Y1

P2Y12TP-a TP-b

TXA2

TXA2

Fig. 3.2 Schematic representation of platelet receptors and ligands. The GP IIb/IIIa receptor is shown in gray, and its ligand, fibrinogen, is shown in maroon strands. The GP Ib/IX/V receptor is shown in red, black, and yellow, and its ligand, vWF, is shown in blue ovals. The GP VI receptor is shown in purple, and its ligand, collagen, is shown as green strands. The protease-activated receptors (PARs) PAR1 and PAR4 are shown in purple, and their activating serine protease, throm-bin, is shown in orange. The ADP receptors, P2Y1 and P2Y12, are shown in blue, and their ligand, ADP, is shown in pink triangles. The TXA2 receptors, TP-α and TP-β, are shown in red with their ligand, TXA2, shown in blue diamonds. The G-protein-coupled receptors, PAR1, PAR4, P2Y1, P2Y12, TP-α, and TP-β, are shown associated with representative G-proteins in the interior of the platelet. Dense granules are shown as black circles, and α-granules are shown as white ovals. The α-granules are shown carrying fibrinogen and vWF. Prasugrel and clopidogrel act by irreversibly inhibiting the P2Y12 receptor. Aspirin works by irreversibly inhibiting the COX-1 enzyme and preventing arachidonic acid conversion to TXA2. Lastly, abciximab, eptifibatide, and tirofiban work by inhibiting the GP IIb/IIIa receptor


57

differences in platelet aggregation in response to various agonists [98]. To test for platelet response to clopidogrel, the VerifyNow P2Y12 assay can be used. Using this specific cartridge, whole blood from the patient is exposed to 20 μmol ADP and 22 nmol prostaglandin E1 (PGE1). The PGE1 acts to increase the assay specificity by suppressing ADP-mediated P2Y1 intraplatelet signaling. The patient’s platelets will agglutinate around the fibrinogen-coated beads and increase light transmit-tance. The results are reported as P2Y12 reaction units (PRU): the lower the PRU, the higher the clopidogrel inhibition. High platelet reactivity (HPR) after clopido-grel treatment was defined as a PRU ≥240 [99]. The VerifyNow® P2Y12 assay also calculates the percentage of P2Y12 inhibition based upon thrombin receptor-acti-vating peptide (TRAP) activation of platelets via PAR1, which is expressed as base value. Besides the P2Y12 assay, VerifyNow® can perform an ASA assay to exam-ine response to ASA therapy. Using a separate cartridge, whole blood is exposed to 1.0 mM arachidonic acid (AA). The patient’s platelets will agglutinate around the fibrinogen-coated beads and increase light transmittance, and the results are reported as aspirin reaction units (ARU): the lower the ARU, the higher the ASA inhibition of platelet aggregation. In contrast, high platelet reactivity (HPR) after ASA treat-ment was defined as an ARU ≥550 [100]. The VerifyNow system can also be used to assay for GPIIb/IIIa inhibitor therapy, although it is not as widely utilized. Limitations to this testing include non-steroidal anti-inflammatory drugs (NSAIDS), GPIIb/IIIa inhibitors, and other antiplatelet agents which can interfere with the aspi-rin assay; and GPIIb/IIIa inhibitors, anemia, and thrombocytopenia which can inter-fere in the P2Y12 assay.

TEG-based platelet mapping is also available to assess a patient’s platelet response to AA and ADP agonists. Platelet mapping is frequently ordered for patients requiring emergent neurosurgery, for some trauma patients, and for patients in the cardiac ICU. Patients with VADs may also benefit from platelet mapping to assess platelet inhibition in order to prevent clotting of extracorporeal circuits. If a patient is on UFH, HTEG (with heparinase) platelet mapping should be performed. In the platelet mapping assay, a kaolin-activated sample is used to generate a strong thrombin response to maximally activate all platelets and cleave fibrinogen demon-strating the underlying potential for maximum clot strength (MAthrombin). A second assay follows, where all thrombin is blocked, and is used to demonstrate the clot strength from the fibrin component (MAA). Thrombin may also be blocked and platelets activated via the ADP receptor or thromboxane A2 receptor, thus assessing clot strength when platelets are activated through those specific receptors (MAADP or MAAA). The degree of inhibition in platelet mapping is calculated by using the patient’s full hemostatic potential MAthrombin as the baseline and the contribution of platelets activated through specific receptors. For patients on ADP inhibitors such as clopidogrel or prasugrel, the goal MA-ADP is 35–50 mm. For patients on ASA, the goal MAAA is 35–50 mm. A MAAA or MAADP <30 mm is associated with an increased risk of bleeding, and a MAAA or MAADP >50 mm is indicative of little to no inhibi-tion. If the MAA is expanding over time, a functional fibrinogen needs to be done for the platelet mapping assay to be accurate. Functional fibrinogen is measured using the GPIIb/IIIa inhibitor, abciximab [101].


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Fibrinolysis Tests

Increased fibrinolysis is seen in critically ill patients with sepsis/DIC and multior-gan failure. It can also be due to malignancies such as acute promyelocytic leuke-mia and prostate cancer [102]. The most commonly available and used assay for fibrinolysis is the D-dimer assay. In addition, TEG can detect increased fibrinolysis with the LY30 value. Measurement of α2-antiplasmin, a serpin and the main inhibi-tor of plasmin, may be useful in patients with hyperfibrinolysis, but it is rarely available in a hospital- based laboratory. Decreased levels of α2-antiplasmin can lead to increased fibrinolysis such as in patients with systemic amyloidosis. Measurement of fibrin degradation products (FDPs) has been mostly replaced by the D-dimer assay, which is much more accurate compared with the semiquantita-tive tests for FDPs.

Summary

Hematologic testing, including assessment of primary (platelet) and secondary (coagulation cascade) hemostasis, takes various forms in critically ill patients. In addition to understanding the role and the utility of the various assays, it is essential to understand how they perform in the setting of acute illness and multiple comor-bidities and drugs, such as anticoagulants. Furthermore, patients often have more than one laboratory abnormality and the interpretation of their clinical significance may not be straightforward.

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44. Da Luz LT, Nascimento B, Shankarakutty AK, Rizoli S, Adhikari NK. Effect of thromboelas-tography (TEG(R)) and rotational thromboelastometry (ROTEM(R)) on diagnosis of coagu-lopathy, transfusion guidance and mortality in trauma: descriptive systematic review. Crit Care. 2014;18(5):518.

45. Walsh M, Fritz S, Hake D, Son M, Greve S, Jbara M, et al. Targeted Thromboelastographic (TEG) blood component and pharmacologic hemostatic therapy in traumatic and acquired coagulopathy. Curr Drug Targets. 2016;17(8):954–70.

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49. Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006;10(4):222.

50. Muntean W. Coagulation and anticoagulation in extracorporeal membrane oxygenation. Artif Organs. 1999;23(11):979–83.

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52. Rafiq S, Johansson PI, Ostrowski SR, Stissing T, Steinbruchel DA. Hypercoagulability in patients undergoing coronary artery bypass grafting: prevalence, patient characteristics and postoperative outcome. Eur J Cardiothorac Surg. 2012;41(3):550–5.

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57. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diag-nosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29(18):2276–315.

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60. Antovic A, Norberg EM, Berndtsson M, Rasmuson A, Malmstrom RE, Skeppholm M, et al. Effects of direct oral anticoagulants on lupus anticoagulant assays in a real-life setting. Thromb Haemost. 2017;117(9):1700–4.

61. Martinuzzo ME, Barrera LH, Da MA, Otaso JC, Gimenez MI, Oyhamburu J. Frequent false- positive results of lupus anticoagulant tests in plasmas of patients receiving the new oral anticoagulants and enoxaparin. Int J Lab Hematol. 2014;36(2):144–50.

62. Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med. 1997;127(3):177–85.

63. Sanfelippo MJ, Zinsmaster W, Scherr DL, Shaw GR. Use of chromogenic assay of factor X to accept or reject INR results in Warfarin treated patients. Clin Med Res. 2009;7(3):103–5.

64. Robert A, Le Querrec A, Delahousse B, Caron C, Houbouyan L, Boutiere B, et al. Control of oral anticoagulation in patients with the antiphospholipid syndrome--influence of the lupus anticoagulant on International Normalized Ratio. Groupe Methodologie en Hemostase du Groupe d'Etudes sur l'Hemostases et la Thrombose. Thromb Haemost. 1998;80(1):99–103.

65. McGlasson DL, Romick BG, Rubal BJ. Comparison of a chromogenic factor X assay with international normalized ratio for monitoring oral anticoagulation therapy. Blood Coagul Fibrinolysis. 2008;19(6):513–7.

66. Austin JH, Stearns CR, Winkler AM, Paciullo CA. Use of the chromogenic factor X assay in patients transitioning from argatroban to warfarin therapy. Pharmacotherapy. 2012;32(6):493–501.

67. Shander A, Walsh CE, Cromwell C. Acquired hemophilia: a rare but life-threatening poten-tial cause of bleeding in the intensive care unit. Intensive Care Med. 2011;37(8):1240–9.

68. Despotis GJ, Joist JH, Goodnough LT, Santoro SA, Spitznagel E. Whole blood heparin con-centration measurements by automated protamine titration agree with plasma anti-Xa mea-surements. J Thorac Cardiovasc Surg. 1997;113(3):611–3.

69. Saw J, Kereiakes DJ, Mahaffey KW, Applegate RJ, Braden GA, Brent BN, et al. Evaluation of a novel point-of-care enoxaparin monitor with central laboratory anti-Xa levels. Thromb Res. 2003;112(5–6):301–6.

70. Depasse F, Gerotziafas GT, Busson J, Van Dreden P, Samama MM. Assessment of three chromogenic and one clotting assays for the measurement of synthetic pentasaccharide fondaparinux (Arixtra) anti-Xa activity. J Thromb Haemost. 2004;2(2):346–8.

71. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128–39.

72. Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxa-ban: a systematic review. J Thromb Thrombolysis. 2015;39(3):288–94.


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73. Bardy G, Fischer F, Appert A, Baldin B, Steve M, Spreux A, et al. Is anti-factor Xa chromo-genic assay for Rivaroxaban appropriate in clinical practice? Advantages and comparative drawbacks. Thromb Res. 2015;136(2):396–401.

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77. Bowman ML, James PD. Controversies in the diagnosis of Type 1 von Willebrand disease. Int J Lab Hematol. 2017;39(Suppl 1):61–8.

78. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ Jr, Montgomery RR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood. 1987;69(6):1691–5.

79. Gallinaro L, Cattini MG, Sztukowska M, Padrini R, Sartorello F, Pontara E, et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood. 2008;111(7):3540–5.

80. Cumming A, Grundy P, Keeney S, Lester W, Enayat S, Guilliatt A, et al. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb Haemost. 2006;96(5):630–41.

81. Flood VH, Christopherson PA, Gill JC, Friedman KD, Haberichter SL, Bellissimo DB, et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood. 2016;127(20):2481–8.

82. Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H, et al. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost. 2000;84(2):345–9.

83. Mital A. Acquired von Willebrand Syndrome. Adv Clin Exp Med. 2016;25(6):1337–44. 84. Sucker C, Michiels JJ, Zotz RB. Causes, etiology and diagnosis of acquired von Willebrand

disease: a prospective diagnostic workup to establish the most effective therapeutic strategies. Acta Haematol. 2009;121(2–3):177–82.

85. Feldmann C, Zayat R, Goetzenich A, Aljalloud A, Woelke E, Maas J, et al. Perioperative onset of acquired von Willebrand syndrome: comparison between HVAD, HeartMate II and on-pump coronary bypass surgery. PLoS One. 2017;12(2):e0171029.

86. Costello JP, Diab YA, Philippe-Auguste M, Jones MB, Shankar V, Friedman KD, et al. Acquired von Willebrand syndrome in a child following Berlin Heart EXCOR Pediatric Ventricular Assist Device implantation: case report and concise literature review. World J Pediatr Congenit Heart Surg. 2014;5(4):592–8.

87. Nascimbene A, Neelamegham S, Frazier OH, Moake JL, Dong JF. Acquired von Willebrand syndrome associated with left ventricular assist device. Blood. 2016;127(25):3133–41.

88. Reich HJ, Morgan J, Arabia F, Czer L, Moriguchi J, Ramzy D, et al. Comparative analysis of von Willebrand factor profiles after implantation of left ventricular assist device and total artificial heart. J Thromb Haemost. 2017;15(8):1620–4.

89. Michiels JJ, Budde U, van der Planken M, van Vliet HH, Schroyens W, Berneman Z. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol. 2001;14(2):401–36.

90. Manfredi E, van Zaane B, Gerdes VE, Brandjes DP, Squizzato A. Hypothyroidism and acquired von Willebrand's syndrome: a systematic review. Haemophilia. 2008;14(3):423–33.

91. Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol. 2006;81(8):616–23.

92. Federici AB. Use of intravenous immunoglobulin in patients with acquired von Willebrand syndrome. Hum Immunol. 2005;66(4):422–30.

93. Franchini M, Lippi G. Acquired von Willebrand syndrome: an update. Am J Hematol. 2007;82(5):368–75.

94. Gando S, Nanzaki S, Sasaki S, Kemmotsu O. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagula-tion. Thromb Haemost. 1998;79(6):1111–5.


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Chapter 4Current and Emerging Technologies in Hematologic Testing

James E. Littlejohn and Richard L. Applegate II

Hemoglobin Testing and Monitoring

Measurement of hemoglobin (Hb) or hematocrit is of major importance in patient care. Acute blood loss anemia from traumatic, coagulopathic, or surgical causes might require transfusion of packed red blood cells (PRBCs) in order to increase oxygen delivery and reduce tissue hypoxia. It is unclear, however, when the risks of PRBC transfusion outweigh the benefits. There have been many large randomized controlled trials comparing restrictive to liberal transfusion triggers of PRBCs, and it is clear that for most, although not all, patients, more restrictive transfusion trig-gers (7–8 g/dl) reduce PRBC transfusion requirements without increasing morbid-ity and mortality [1]. In previous sections of this textbook, we have established the importance of being mindful of when and how much to transfuse PRBCs in order to correct symptomatic anemia. In this section we will focus on how to both accurately and precisely measure plasma hemoglobin levels so that we can aptly inform these vital transfusion decisions.

Lab and Reagent-Based Testing

Traditional “lab-based” testing has been the mainstay of Hb measurement for decades. In the 1960s, the International Committee for the Standardization in Hematology (ICSH) made recommendations to set a reference method for “hemo-globinometry” and for the manufacture and distribution of an international reference

J. E. Littlejohn, MD, PhD · R. L. ApplegateII, MD (*) UC Davis Medical Center, Department of Anesthesiology and Pain Medicine, Sacramento, CA, USAe-mail: [email protected]



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preparation worldwide. This international group set the standard for routine mea-surement of Hb concentration as photometric determination of hemoglobin- cyanide via colorimeters [2]. Colorimeters are dedicated multiwavelength spectrophotome-ters that automate analysis of blood samples and are the most frequently used method of Hb measurements in hospital laboratories. The standard also recom-mends other methods used for routine hemoglobin measurement to be adjusted to obtain comparability with the hemoglobin-cyanide method [2]. Using this standard, Hb derivatives in the blood (with the exception of sulfhemoglobin) are converted into hemoglobin-cyanide (also referred to as cyanmethemoglobin and cyanferrihe-moglobin) by the use of an appropriate reagent, and photometric determination is made of the concentration which is reported in either grams per liter (g/L), grams per deciliter (g/dL) or in conformity with the international system of units (SI), as millimol per liter (mmol/L). One such device used in central laboratories is the LH system (Beckman Coulter, Brea, CA) which hemolyzes the samples, oxidizes, and then cyanizes the Hb molecule before measuring absorbance at 546 nm.

Over time colorimeter technologies have improved in two different ways. The first is the development of cyanide-free techniques that are preferred in certain regions or hospitals given local regulations and resources available for disposal of medical waste. One such lab-based analyzer that utilizes the cyanide-free system is the ADVIA system (Siemens Medical Solutions Diagnostics, Zurich, Switzerland, https://www.healthcare.siemens.com). The second technological advance in colorimeters is the advent of more precise sensors and the ability to simultaneously measure concentrations at multiple wavelengths. This becomes useful in hemoglobin co-oximetry measurements, in order to establish the differ-ent concentration of Hb and its derivative species. The various co-oximeters now in use typically measure the optical absorbance of blood at 4 up to 128 different wavelengths and automatically compute the fractional concentrations of the four major Hb species (oxy-, deoxy-, carboxy-, and methemoglobin) as well as total hemoglobin concentration [3].

There are numerous systems qualitatively shown to be equivalent to the lab- based standards of Hb determination; however, as the pace of medical care and acuity of illness has increased, so too has the need for more immediate hemoglobin level determinations. Laboratory-based systems, although the gold standard for determination of Hb concentration, often take time to result meaningful information that can potentially adversely affect the care of an actively bleeding patient. The need for more portable devices of Hb determination has led to the development of point-of-care systems.

Point-of-Care Testing

Point-of-care Hb monitoring and blood gas testing devices are divided into two broad categories based on the methodologies used to determine hemoglobin con-centration: those based on conductivity and those based on optical methods of Hb

J. E. Littlejohn and R. L. Applegate II

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quantitation (Fig. 4.1). Regardless of method used for Hb determination, the size and portability of the system is vital to be useful in close proximity to the patient. An example of a point-of-care device that utilizes optical methods is the HemoCue (Brea, CA, http://www.hemocue.us) system which utilizes a drop of blood on a cuvette where sodium deoxycholate hemolyzes erythrocytes and releases Hb, which is chemically converted to an azide compound, and absorbance of this compound is measured at different wavelengths (between 506 and 880 nm). Earlier devices were standardized against the lab-based cyanide method and found to have acceptable correlation in the hands of skilled operators. This method is simple and relatively portable, allowing for ease of use in austere environments. Sources of error in this method have been mitigated with improved design and sensors that can compensate for changes in turbidity, which can easily occur for a variety of reasons in point-of- care situations outside of the hospital such as anemia screening clinics or mobile blood donation centers [4].

Oftentimes, blood gas analysis or other urgent tests are desired along with hemo-globin measurements, and this has given rise to a variety of different systems that can be utilized in hospital settings to provide precise and timely measurements. One such optical point-of-care system is the ABL FLEX (Radiometer Medical, Copenhagen, Denmark; http://www.radiometer.com). In this analyzer, a blood specimen is drawn

Hematocrit %

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Erythrocytes Electricalresistance

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Fig. 4.1 Total hemoglobin measurement methods. Point-of-care (POC) blood gas testing devices use conductivity or optical-based methods. Changes in hematocrit are proportional to the change in electrical conductance. POC devices using conductance to measure hematocrit calculate tHb by means of an equation — enabling total Hb estimation from Hct measurement. POC optical meth-ods rely on spectrophotometric absorbance to provide direct measurement of tHb. Central labora-tory tHb measurement relies on hemolysis followed by oxidation and cyanization. The Hb cyanide product is measured at 546 nm via colorimetric analysis. This Hb cyanide method serves as a refer-ence technique for the majority of lab-based total hemoglobin assays. (Created by Fabian Lara, used with permission)

4 Current and Emerging Technologies in Hematologic Testing

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from the syringe into the cuvette within the analyzer and maintained at 37 °C. One microliter of the specimen is hemolyzed via ultrasound (30 kHz), and Hb content is assessed spectrophotometrically using 128 different wavelengths (478–672 nm). Hb content is calculated via the Lambert-Beer equation, and hematocrit is calculated via a proprietary algorithm.

A fundamentally different method to determine Hb concentrations in point-of- care analyzers is conductance. Such systems measure the electrical conductance of a whole blood sample. Plasma conducts electrical current, while blood cells act as insulators. Corrections are applied for sample temperature and the relative conduc-tivity of the plasma component. A final correction is determined from the measured concentrations of sodium and potassium in the sample [5]. Both epoc (Siemens Medical Solutions Diagnostics, Zurich, Switzerland, https://www.healthcare.sie-mens.com) and iSTAT (Abbott, Princeton, NJ) analyzers employ this method of hemoglobin determination. In these and similar systems, hematocrit is measured by AC conductometry using two electrodes [6]. The conductance of the blood sample in the fluidic path between the two electrodes, after correction for variable plasma conductivity through the measurement of sodium concentration, is inversely pro-portional to the hematocrit value. The Hb value is a calculated value based on the measured hematocrit.

There are often discrepancies observed between the hematocrit values deter-mined by routine point-of-care analysis compared to routine analysis in the central lab. These are due to many factors, but some major factors should be taken into account by practitioners, especially when caring for critically ill patients. Random errors will result from each system’s imprecision, and given the error when com-pared with two different methods, the samples can be considerably different in a random way. There are also systematic differences between each system’s calibra-tions. This error will be constant sample to sample. Finally there is a method and sample-dependent error, which affects different measurement methods in different ways, given the limitations and potential for interference from each method. This method and sample-dependent error is often observed as a random difference between dissimilar methods; however, the error is due to a specific patient charac-teristic that can cause a result that might not accurately reflect the patient’s true physiology. It is thus imperative that providers be aware of intricacies of each methodology.

Devices that utilize conductance methodologies to determine hematocrit are sen-sitive to electrolyte concentrations as well as other nonconducting elements such as proteins, lipids, and white blood cells that could artificially alter the presumed hematocrit concentration, since the method does not distinguish red blood cells from other nonconducting elements in the measured sample. Most systems are cali-brated to read hematocrit accurately when these other elements are at normal levels. In the case of cardiopulmonary bypass, for instance, if albumin or other colloid is not added to the priming solution, plasma protein will be diluted, and conductivity reading will then be systematically low by a significant factor. This is also an issue in other extremes of physiology such as burn patients and premature neonates whose total protein levels are significantly deranged, as well as patients receiving large




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volumes of saline-based fluids, as perhaps might happen in patients with septic shock or traumatic hemorrhage.

Taken together, systematic differences and errors in measurement can be clini-cally significant and must be understood and accounted for by practitioners. An example of the significance of systematic differences between hemoglobin/hemato-crit measurement methods was demonstrated by Bosshart et al. in 2010 [7]. They compared two different optical systems, one “lab-based” device (the ADIVA 2120, which employs a cyanide-free reagent in order to measure Hb concentration) and one “point-of-care” device (ABLflex 800, spectrophotometer Hb assessment). The ADIVA uses two sequential methods of hemoglobin measurement: high-angle refractive index and a cyanide-free reagent that oxidizes the iron content in hemo-globin after red cell hemolysis. The ligated heme groups are solubilized and gener-ate a green end product, which is measured photometrically. Both values for hemoglobin are determined and then compared by an internal algorithm.

Although the two methods provided similar hematocrit values, the ABLflex 800 showed an approximately 1.4% higher hematocrit than the ADIVA 2120 method. These methodological differences must be considered in comparison to defined institutional transfusion triggers in order to standardize transfusion practice. Given the variety and availability of different systems on the market and variability of regional preference, it is impossible to create one international standard for mea-surement. Thus each institutional care team must use the same analytical procedure in each patient care scenario, in order to precisely and accurately inform the deci-sion to transfuse red blood cells. This group estimated approximately 21% of their samples that might lead to a different transfusion management [8].

In addition to the potential for significant systematic error between similar devices using the same methodology, current laboratory methods are invasive, time- consuming, require removal of precious red blood cells, and provide only intermit-tent hemoglobin measurements [9]. A significant cause of anemia in hospitalized patients is the process of blood draws for laboratory testing. A recent study demon-strated phlebotomy rates to be as high as 40ccs over a 24-h period in critically ill patients [5]. In this same study, a connection between anemia and blood transfu-sions is demonstrated in the critically ill. They finally demonstrate epidemiologic evidence of an association between blood transfusions and both diminished organ function and mortality. Taken together, the ability to closely monitor hemoglobin concentrations without removing red blood cells could significantly reduce the major risks associated with lab draws in our sickest patients.

Noninvasive and Continuous Hb Monitoring

Since the introduction of pulse oximetry in the 1980s, noninvasive blood analysis has been the focus of numerous research efforts and clinical applications. Noninvasive blood sampling has many advantages, including swift results, avoid-ance of infection and risks of needle sticks, repeated measurement over time,


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painless acquisition, and obviates the need to remove blood for measurement [5]. Rapid, continuous, noninvasive measurement of total Hb is a technology that pres-ents significant advantages for the care of critically ill patients in the ED, OR, and ICU. Recently, multiple devices utilizing spectrophotometry and co-oximetry have been introduced for this purpose.

Presently there are three devices that use noninvasive spectrophotometry for Hb measurement, differing in sensor type. The first type utilizes occlusion spectros-copy. It involves fitting a portable ring-type cuff and sensor on the patient’s finger. A pneumatic cuff in that ring applies pressure and temporarily stops blood flow. Optical elements in a multiwavelength sensor perform measurement of the light transmitted through the finger in wavelengths between 600 and 1500 nm. The dif-ferential light absorption before and after blood flow obstruction is used to deter-mine Hb level (NBM 200; OrSense Co., Raleigh NC) [4].

The second sensor type is based on transcutaneous reflection spectroscopy. It is a handheld device that uses a button sensor adherent to the palmar side of the finger of the non-dominant hand. A sensor placed on the skin projects white light into underlying tissue and measures differential absorption of the various tissue compo-nents. The signal returned to the unit is broken down into specific wavelengths, measured, and converted to a quantitative Hb measurement (HemoSpect; MBR Optical Systems GmbH & Co., Wuppertal Germany) [4].

The third sensor type is called pulse co-oximetry and utilizes a multiwavelength pulse co-oximetry sensor, which acquires blood constituent data based on light absorption through a finger probe. Based on light attenuation characteristics, the device calculates Hb (Radical-7 pulse co-oximeter; Masimo corporation, Irvine CA, USA). Adequate perfusion to the extremity is essential for this device to function properly. These pulse co-oximetry devices are perhaps one of the best-studied types of this technology at this time and have been evaluated in many different clinical settings. Its current design allows for spot and also continuous noninvasive Hb (SpHb) monitoring, which offers a unique opportunity to change the paradigm of hemoglobin monitoring and transfusion management in patients at risk of bleeding. None of the studies published thus far have demonstrated successful rigorous moni-toring of hemoglobin levels below 7.0 g/dL; however, despite this limitation, this technology poses considerable promise in advancing Hb monitoring in periopera-tive, emergency, and critical care settings.

In 2010, Macknet published a comparison between continuous pulse co- oximetry and a lab-based co-oximeter (ABL820, Radiometer, Copenhagen Denmark) in 20 healthy volunteers undergoing hemodilution and concluded that continuous pulse co-oximetry hemoglobin measurement is accurate to within around 1.0 g/dL, com-pared to the lab-based co-oximeter Hb [9]. The next year, SpHb readings were com-pared to conventional lab (Siemens ADVIA 2120) testing measurements in 300 consecutive ED patients, challenging SpHb accuracy. Hemoglobin concentration could not be obtained on the pulse co-oximeter in 24 of these patients. Of the 276 patients in whom a reading was obtained, the pulse co-oximeter values were signifi-cantly lower by approximately 1.6 g/dL. There were 31 (13%) disagreeing pairs of values, defining one value less than 9.0 g/dL and the other above this level (Fig. 4.2a).


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This group concluded that although this technology was efficient and potentially widely available, the results were systematically biased and too unreliable to guide transfusion decisions [10].

Also in 2011, SpHb was evaluated in 29 complex spine surgery patients who had Hb from 6.9 to 13.9 g/dL, comparing to lab-based hemoglobin measurement. Bland- Altman analysis showed agreement of SpHb to the lab-based Hb values over the range of values; limits of agreement were −2.0 to 1.8 g/dL, with absolute bias 0.8 +/− 0.6 g/dL. The Bland-Altman difference plot, as shown in Fig. 4.2, is probably the most commonly used graphical representation of device accuracy data [13]. Although the rages of agreement were large, they concluded that the ability to continuously

5 10Hb-Masimo (g/dL)

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etw

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mog

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Fig. 4.2 (a) Linear relationship depicting relationship between hemoglobin measurement by the ADVIA 2010 and the Masimo Radical-7 Pulse-Co-oximeter [10] and (b) Bland-Altman plot with limits of agreement for all hemoglobin concentration (SpHb) and total hemoglo-bin (tHb) measurements (n-360) [11], Sp-Hb indicates noninvasive Masimo hemoglobin, Lab-Hb laboratory hemoglobin [12]. (Used with permission)


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monitor hemoglobin may provide more timely information on hemoglobin status and thus has the potential to improve blood management during surgery, despite the potential for inaccurate readings [11]. Intraoperative physiology may impact the accuracy of SpHb in important ways that could differ in various surgical procedures. Compared to the patients undergoing spine surgery, wider limits of agreement (−2.3 to 3.3 g/dl, mean bias 0.5 ± 1.44 g/dl) were found in 360 samples obtained from 91 patients undergoing major abdominal or pelvic surgery in whom Hb ranged from 6.0 to 16.0 g/dl (Fig. 4.2b) [12]. This study demonstrated a weak correlation between changes in SpHb compared to changes in arterial Hb, particularly in patients with larger estimated blood loss or lower Hb values. In 2016, SpHb measurements were compared to a blood gas analyzer using conductance to measure hematocrit (Stat Profile Critical Care X-Press, Nova Biomedical, USA) in 40 patients undergoing liver transplantation [14]. There were 11 times that SpHb was unable to be obtained on a patient at the time of comparison to blood gas analysis, and 28 others were excluded for poor signal quality. Of the 161 paired measurements obtained, there was a moderate correlation between SpHb and lab-based Hb (r = 0.59); however, the bias of 2.28 g/dL was prohibitively high, rendering the clinical utility of SpHb in this patient population not precise enough to give meaningful results.

In 2011, evaluation of SpHb in ICU patients was compared to three different invasive Hb analysis methods; point-of-care (HemoCue 301), a lab co-oximeter (Siemens Radpoint 405), and a standard lab hematology analyzer (Sysmex XT-2000i) as a reference device. In 62 patients, 471 blood samples were analyzed, and the group concluded that when compared to laboratory reference values, Hb measurement with continuous pulse co-oximetry has accuracy similar to widely used, invasive methods of Hb measurement at bedside and has the added advantage of providing continuous measurements, which is ideal for patients in the ICU [15].

In 2015, a spot check pulse co-oximeter (Pronto-7, Masimo) was evaluated for efficacy and accuracy as a Hb measuring device in trauma patients by Joseph et al. Five hundred twnty-five patients were enrolled, in whom attempted spot check Hb was successful in 86%. In comparison to standard lab values, SpHb had strong cor-relation with 76% accuracy and 95.4% sensitivity and concluded that application of spot check Hb measurements has potential benefit in the trauma patient population [16]. It was estimated that the presence of tar, soot, nail polish, older age, and peripheral circulation deficits contributed to the inability to measure 14% of their study patients.

In 2015, evaluation of SpHb in neurosurgery demonstrated that adding this tech-nology to standard of care (the lab-based GEN-S hematology analyzer, Beckman- Coulter Inc., Brea, CA) reduced red blood cell transfusions by almost an entire unit per patient receiving blood transfusions. This group noted an absolute accuracy of 0.8 g/dL with the lab analysis [17].

In 2016, the accuracy of SpHb was compared to i-STAT handheld devices (Abbott, Princeton, NJ) in cardiopulmonary bypass patients undergoing coronary artery or valve surgery. In these 35 patients, SpHb was found to have a consistently positive bias, overestimating Hb levels by almost 1 g/dL as well as a lack of preci-sion, given the wide limits of agreement and low correlation coefficients when com-


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pared to i-STAT, pre-bypass. Interestingly, the bias and inaccuracies were noted to be worse after bypass [18]. It is important to note, however, that the comparator in this study was a point-of-care device that uses conductance as a means of calculat-ing hematocrit and SpHb was not compared to a laboratory standard as in other studies. As described earlier, conductance technologies can be impaired when changes in vascular composition occur, as are the case in cardiopulmonary bypass and the considerable variation in priming solutions and methodologies.

SpHb could be valuable in critically ill pediatric patients at risk of bleeding, given their lower total blood volumes and the increased relative burden on each child that is imposed with each volumetric blood draw for hemoglobin monitoring. In a 2017 study, SpHb was compared to lab-based Hb determinations in 21 pediat-ric trauma patients with blunt solid organ injury. Noninvasive Hb monitoring dem-onstrated clinically acceptable accuracy when following hemoglobin trends; the slight variances noted did not affect clinical management. Thus SpHb represents a potentially valuable adjunct to traditional laboratory hemoglobin monitoring in such patients [19]. In 2017, Garcia-Soler et al. published a comparison of SpHb and conventional lab testing (Siemens ADVIA 2120) in pediatric patients weigh-ing greater than 3 kg at risk of bleeding. With 284 measurements in 80 separate patients, they demonstrated a good overall correlation to the lab technique, although there were wide limits of agreement. They argue that its main advantage is continuous monitoring of patients at risk of bleeding and acknowledge that the reliability is limited in cases with poor peripheral perfusion (unable to pick up a signal) [20].

Finally, in 2017, the precision of SpHb monitoring was evaluated in trauma patients with low Hb levels (less than 8 g/dL). In 113 patients, noninvasive hemo-globin measurements were compared to lab-based Hb measurement (LH 750, Beckman Coulter), and they showed excellent accuracy, correlation, and agreement to lab-based measurements with mean bias of 0.12 g/dl and 95% confidence interval of −0.56 to 0.79 g/dl [21].

There is no doubt that noninvasive Hb measurements can expedite decision- making in patients that are critically ill and/or have ongoing occult bleeding. Unfortunately, accuracy is of major concern with this technology. One of the most significant limitations is that this technology relies on peripheral circulation. In patients with poor peripheral circulation, the results, if obtained, do not seem to be reliably clinically useful at this time. In studies from 2010 to 2017, it should be noted that the SpHb sensors and software have been improving. For example, a meta-analysis of studies published up to 2013 reported pooled mean difference between SpHb (versions C, D, E, and Pronto G) to reference hemoglobin of 0.10 ± 1.37 g/dL (95% limits of agreement −2.59 to 2.80 g/dL), which the authors concluded mandated caution regarding basing transfusion decisions on SpHb alone [22]. However, some of the more recent studies cited above show narrower limits of agreement. Each study used the most up-to-date sensor available at the time, but details of improvements made are proprietary. These sensor improvements over time could account for the apparent trend toward improved accuracy over the years and conclusions in these studies.


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Taken together, however, within the ranges of hemoglobin levels between 7 and 15 g/dL, there is reasonable SpHb to lab or point-of-care Hb correlation in most patient populations and the potential for this to be further improved over time with more precise sensors. At this time SpHb monitoring can at least be considered by the practitioner as an adjunct to currently employed methods in patients at high risk of anemia and bleeding. Both further refinement in the technology and more prospec-tive analysis surrounding the precise limitations of peripheral perfusion during times of vasoconstriction are needed. Overall it is felt that this technology has the potential to improve care of patients at risk of bleeding in many different clinical scenarios.

Oxygen Reserve Index

In addition to continuous hemoglobin monitoring, multi-wave pulse co-oximetry can be used to measure tissue oxygen supply, which is the net product of cardiac output and oxygen content. Oxygen content is determined by hemoglobin concen-tration, arterial oxygen saturation (SaO2), and partial pressure of arterial oxygen (PaO2). It is accepted that dissolved oxygen increases by 0.3 ml/100 ml of blood for each 100-mm Hg increase in PaO2, and this dissolved oxygen can meet some of the metabolic demand, decreasing the release of oxygen from hemoglobin. This, in turn, will alter venous oxygen saturation, provided oxygen consumption is stable, as is often the case during anesthesia and surgery. During situations in which SaO2 is 100%, and if Hb and cardiac output are also stable, then venous oxygen saturation will increase as PaO2 is increased. Change in venous oxygen saturation results in changes in background light absorption at the multiple emitted wavelengths employed. The absorption ratios are mapped and via a proprietary provide a calcu-lated dimensionless index between 0.0 and 1.0, called the oxygen reserve index (ORI). ORI is not a measure of PaO2 directly but an index that is related to absorp-tion patterns of tissues, arterial, and venous Hb and may provide a way to distin-guish between mild or greater hyperoxia when SpO2 is over 98%.

Two studies on ORI have been published in 2016. The relationship between ORI and PaO2 during surgery was evaluated in 106 adult patients and suggested that when the ORI could be measured (92.1% of the time), an ORI >0.24 can distinguish PaO2 >/= 100 mm Hg (when pulse oxygen saturation (SpO2) is >98%). Similarly, ORI >0.55 can distinguish PaO2 >/= 150 mm Hg in most cases [23]. A pilot study of 25 healthy children undergoing induction of general anesthesia showed ORI suc-cessfully detected impending desaturation roughly 31.5 s sooner before notable changes in SpO2 occurred. The authors argue that this represents a clinically signifi-cant warning period, giving clinicians an opportunity for corrective action sooner than otherwise would be noted with conventional pulse oximetry [24]. The useful-ness of ORI needs to be further evaluated prospectively; however, there are potential benefits that should be considered. At this time it is thought that ORI may serve to indicate a PaO2 trend (rising or falling) when SpO2 is over 98%. It is also possible that falling ORI could indicate PaO2 decreases before SpO2 falls, thus providing an advance warning of impending desaturation events [25].


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Coagulation Testing and Monitoring

As of 2018, the FDA has approved three direct oral anticoagulants (DOACs) (dabi-gatran, rivaroxaban, and apixaban) for prevention of strokes and systemic emboli in patients with non-valvular atrial fibrillation. FDA has also approved rivaroxaban and dabigatran for both treatment of pulmonary emboli and deep vein thrombosis and prevention of DVT after hip and knee replacement surgeries [26] as well as betrixaban for prevention of DVT in patients hospitalized for acute medical illness in 2017 [27]. DOACs offer non-inferior efficacy and improved safety compared to vitamin K antagonists (VKAs) for the prevention and treatment of VTE and for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation [28]. DOACs have considerable advantages over VKAs: first there are fewer significant dietary interactions; second, DOACs do not require lab monitoring and dose adjust-ment, and thus, perioperative management and guidelines have been simplified. However, it is difficult to both measure and interpret the anticoagulation effect of DOACs and thus their increased utilization can be problematic when it comes to predicting and measuring the need for urgent/emergent reversal. Currently there are no unified acceptable ways to measure their activity.

There are circumstances when measuring the activity of DOACs may be useful to clinicians such as when determining bleeding potential prior to high-risk invasive procedures, assessment of risk and benefits of dialysis and/or administration of pro-coagulant “reversal agents”, recent stroke, evaluation of therapy failure (when a VTE occurs under treatment), and concern for excessive bleeding risk in patients with worsening renal function in the setting of critical illness.

Direct measurement of plasma drug concentrations by liquid chromatography tandem mass spectrometry is only available in reference laboratories and is thus not a practical method of monitoring DOAC activity [26]. Measurement of DOAC activity by standard assays is difficult because the response to a DOAC may vary greatly depending upon many variables including the reagent and/or analyzer used, the time that the sample is drawn relative to the last dose of medication, and the presence of factors such as lupus anticoagulant or deficiency of other clotting fac-tors [29]. Standard coagulation tests such as PT/INR, thrombin time (TT), and anti- Xa activity are variably affected by the DOACs, and an understanding of these effects can be useful until more precise assays are available. There is also a lack of reports and data describing any potential impact of DOACs in platelet function test-ing methods. Therapeutic ranges for monitoring warfarin (PT/INR), heparin (aPTT, anti-Xa activity), or LMWH (anti-Xa activity) must not be applied to DOACs [26].

Prothrombin Time/International Normalized Ratio (PT/INR)

Standard coagulation assays such as the PT/INR are readily available in all hospitals and originally developed to monitor therapy on warfarin, but do not give precise or reliable information when performed on patients with certain complicated


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coagulopathies and/or in the presence of DOACs. PT is not very sensitive to the DTI dabigatran, even less so than aPTT, and may result with normal values in the pres-ence of therapeutic or even supratherapeutic levels of dabigatran [30]. Commercial thromboplastin reagents vary widely in their sensitivity to dabigatran. Rivaroxaban prolongs PT in a concentration-dependent manner, but the effect varies widely with different thromboplastin because of their differing sensitivities to the drug [31]. The PT has insufficient sensitivity to exclude therapeutic levels of rivaroxaban. However, given those understandings, the general consensus is that PT can at least be used as a screening test for the presence of clinically significant amounts of both rivaroxa-ban and dabigatran in the absence of other more precise tests [31].

As with rivaroxaban, the PT is insufficiently sensitive to edoxaban to exclude therapeutic levels, and there is wide variation in sensitivity among different throm-boplastin reagents. PT is even less sensitive to apixaban, making it a poor choice, even for screening of potential supratherapeutic levels of apixaban [32].

Of interest, historically PT/INR and other “traditional” plasmatic coagulation tests have been products relegated to analyzers that exist in the central lab and require timely processing (separation of plasma from red cells prior to reactions). Point-of-care methodologies have been developed that show reasonable precision with the traditional laboratory methods within the range of PT which is clinically relevant (0.8–8.0 s) and is worth considering for application in certain clinical cir-cumstances [5].

Activated Partial Thromboplastin Time (aPTT)

Standard coagulation assays such at the aPTT are also readily available in all hospi-tals, and as discussed before, because there are simply no available and precise tests for DOACs as of yet, many argue that this test can also be used as a broad “first- line” assay to provide qualitative assessment of both rivaroxaban and dabigatran [31]. The aPTT exhibits a curvilinear relationship with dabigatran concentration with a flattening of the dose-response curve at levels greater than 200–300 ng/ml and thus can provide useful qualitative assessment of anticoagulation activity but not accurate quantitative information, especially at higher concentrations [29, 33] Similar to PT, the aPTT test is also insufficiently sensitive to exclude the presence of clinically significant levels of dabigatran. In one study of plasma samples taken from patients taking dabigatran 150 mg BID at steady state, 18% of subjects had a normal trough aPTT [30].

Even though aPTT is somewhat reliable for dabigatran, it is less sensitive than the PT when it comes to factor Xa inhibitors and, in general, does not have a specific role in the laboratory assessment of anticoagulation with these agents. Rivaroxaban prolongs the aPTT, but this assay is less sensitive than the PT and is not generally suitable for measurement of rivaroxaban activity [31]. Apixaban and edoxaban pro-


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long aPTT even less, if at all, even at supratherapeutic levels in the case of apixaban. Thus, a normal aPTT does not exclude potentially clinically significant levels of rivaroxaban, apixaban, or edoxaban [28].

Activated Clotting Time (ACT)

ACT is commonly used to monitor anticoagulation with unfractionated heparin dur-ing cardiopulmonary bypass (CPB) surgery, vascular surgery, and other endovascu-lar procedures, although it does not directly measure heparin anticoagulant activity. Since it is a point-of-care assay, it has the considerable advantage of timely results; however, this assay has several drawbacks, including limited heparin specificity. Clotting factor deficiencies, hemodilution, hypothermia, thrombocytopenia, and platelet dysfunction as well as the use of aprotinin have been shown to influence assay results, thus mimicking adequate heparinization that in turn may lead to inad-equate heparinization [34]. Because it has previously been shown to correlate poorly with actual plasma heparin levels during CPB, several studies have been undertaken with the aim of directly measuring heparin activity levels in order to optimize anti-coagulation during procedures. However, due to its simplicity and historical utiliza-tion, it is the de facto “standard” and remains the mainstay of POC heparin activity measurement in most CBP cases, until a more precise test is validated.

Thrombin Time (TT) and Dilute Thrombin Time (dTT)

The thrombin time (TT) is a test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added [35]. The TT is actually too sensitive to the effects of dabigatran to be useful as a test to quantitate activity; however, a normal TT effectively excluded the presence of dabigatran across many studies [36]. Depending on which reagent is used, dabigatran concentrations well below therapeutic thresholds will cause the TT to become immeasurable. However, it can be useful in excluding the presence of dabigatran: if the TT is normal, then it can be concluded that there is very little to no dabigatran in circulation [28].

The sensitivity of thrombin time can be overcome by diluting the plasma sample with normal plasma; this is a test known as the dilute thrombin time (dTT). When calibrated for dabigatran measurement, the dTT demonstrates reasonable accuracy compared to LC-MS/MS across and above the therapeutic range of dabigatran with weaker correlation at low and high levels. Although there are commercial versions of this assay, it does not seem to be widely utilized [28]. At present, calibrated dTT and ecarin-based assays are the tests of choice for the measurement of dabigitran [28].


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Ecarin-Based Assays

Ecarin is a metalloproteinase that cleaves prothrombin to an active intermediate called meizothrombin. Dabigatran inhibits meizothrombin with comparable activity to its inhibition of thrombin. This is used as a measurement of dabigatran levels/activity. Two such ecarin-based assays are available. The ecarin clotting time (ECT) is a test in which ecarin is added to citrated blood or plasma and time-to-clot-forma-tion is measured [37]. The second assay is the ecarin chromogenic assay (ECA), where meizothrombin generation is measured with a chromogenic substrate in the presence of an excess of prothrombin [38]. The ECT and ECA are not widely avail-able and are limited by lack of standardization, as well as variability in sensitivity to dabigatran among different lots of ecarin.

Factor X and Anti-factor Xa Activity Assays

Conventional anti-factor Xa chromogenic substrate and clotting assays have been developed for measuring the concentration of anticoagulants that inhibit anti-factor Xa. They are most frequently used for monitoring unfractionated heparin in patients receiving prophylaxis or treatment of thromboembolism. It is important to note that the anti-factor Xa activity assay is not the same test as the factor X activity assay or the chromogenic factor X assay. The factor X assay measures the amount of factor X in a patient’s blood, whereas the anti-factor Xa activity assay measures the abil-ity of the patient’s serum to inhibit exogenous factor Xa. The factor X assay is a clotting time-based assay that is used to diagnose a deficiency in factor X. Because unfractionated or low-molecular-weight heparins, fondaparinux, and rivaroxaban exert most of their effect by inhibiting factor Xa (not by causing a factor X defi-ciency), the factor X assay usually does not have a role in monitoring a response to these therapies. However, the factor X assay has been used to monitor warfarin therapy in patients who are also being treated with argatroban, other direct throm-bin inhibitors, or patients with a known lupus anticoagulant [31]. Both of these methods are unsuitable for point-of-care monitoring in the operating room because they require complex equipment and processing procedures [34]. The majority of studies in this chapter, unless otherwise noted, refer to the anti-factor Xa activity assays.

With the advent of the direct oral anticoagulants (DOACs), the anti-factor Xa chromogenic assay has been actively investigated as a potential test to both detect and monitor activity of these agents. When calibrated with drug-specific standards, the anti-factor Xa assay has been shown to have a high degree of correlation across therapeutic ranges for rivaroxaban, apixaban, and edoxaban [39, 40] Drug-specific calibration increases accuracy for purposes of quantification, but this modification is likely not necessary if the test is only needed to exclude clinically relevant levels


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of drug (as is the case in emergent and trauma circumstances). However, despite the potential as a reasonable test to detect activity of the DOACs, this test is not yet widely available. Although many centers offer an anti-Xa assay for measurement of heparin activity, few seem to have established standard curves for quantification of rivaroxaban and others [28]. Although anti-factor Xa chromogenic assays can pro-vide accurate results over a wide range of rivaroxaban concentrations, the addition of exogenous antithrombin results in falsely elevated results, bringing into question reliability in the clinical setting (given the variability of antithrombin levels in dif-ferent patients and clinical situations) [41]. In the absence of drug-specific calibra-tion curves, a curve calibrated for unfractionated heparin or low-molecular-weight heparin has been suggested to be a reasonable surrogate test for excluding drug levels, in emergent circumstances [42].

Heparin Activity Assays

Hepcon/HMS

There is limited data published on the agreement between techniques for monitor-ing heparin levels. The Hepcon is a bedside clotting test based on heparin-protamine titration to quantify heparin concentration in whole blood during bypass surgery. It was validated against laboratory anti-Xa assay plasma heparin concentration deter-minations in a study with 42 adult cardiopulmonary bypass patients and found to have satisfactory agreement; however, it was also shown to not compare well with point-of-care ACT analyzers (both the Hemochron and HemoTec) [34]. Given inherent technical challenges, the lack of dramatic change in sensitivity from cur-rent techniques, and the variability in results, this assay has not gained universal popularity in clinical practice.

Heptest POC-Hi (HPOCH)

Heptest POC-Hi (HPOCH) is a single stage point-of-care assay developed for the quantification of high levels of anti-factor Xa and anti-factor IIa activities in citrated whole blood. It operates on the same biochemical principle as that of the original Heptest heparin assay. It was studied and compared to ACT as well as anti-factor Xa heparin plasma levels in 125 patients undergoing cardiopulmonary bypass surgery and found to correlate closely both pre- and post-bypass. During CPB, although HPOCH results correlated well with plasma anti-Xa activity levels, it did not cor-relate with ACT results. The group concluded that because this test is more specific for the heparin anticoagulant itself, more prospective clinical studies were war-ranted, comparing the new assay with established measures using ACT [34]. So far, it has not gained mainstream acceptance.


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Viscoelastic Hemostatic Point-of-Care Assays

Thromboelastography measures the viscoelastic properties of a clot through all phases of hemostasis, from enzymatic production of thrombin through the fibrino-lytic phase. There are two main variations of viscoelastic hemostatic assays in the literature: thromboelastography (TEG, Haemonetics, USA) and thromboelastome-try (ROTEM, TEM International, Switzerland). Both systems are available as a point-of-care device. Although earlier models of the TEG were sensitive to motion artifact of the unit, the most recent version (the TEG 6) has overcome this limitation. Both systems measure a volume of the patient’s whole blood (microliters), after mix-ing with a predetermined coagulation activator and in the presence of predetermined inhibitory agents depending on which coagulation parameter is being measured. The devices often have multiple “channels” in which a variety of different tests can be run simultaneously in order to quickly characterize more precisely any potential coagulopathy. Viscoelastic tests such as TEG and ROTEM have been suggested as potential tests for the assessment of the anticoagulant effect of DOACs [31]. Currently there is no FDA-approved point-of-care assay to identify the presence and extent of DOAC effect and to distinguish the type of DOAC present (if any) [43].

The standard TEG parameters measured are the reaction time (R), kinetics (K), alpha (α), maximum amplitude (MA), and a measure of fibrinolysis at 30 minutes (LY30). The R time, recorded in minutes, is a quantitative representation of the initiation phase of enzymatic clotting (thrombin generation), from 0 to 2 mm on the TEG diagram. Kinetics (K), recorded in minutes, is a measure of the time to reach 20 mm from 2 mm. Alpha is the angle recorded in degrees formed by the tangent to the TEG tracing measured from R and is reflective of the velocity of clot strength generation. Maximum amplitude (MA) as measured in millimeters is an evaluation of the maximal thrombin-induced platelet-fibrin clot strength. LY30 is reflective of clot lysis and is recorded as the % reduction in MA at 30 min after maximum platelet- fibrin clot strength has been reached (Fig. 4.3b) [44]. The typical TEG acti-vator is kaolin. The rapid TEG (rTEG) test incorporates both tissue factor and kaolin to generate conventional kaolin parameters as well as the TEG-activated clotting time (ACT) parameter (measured in seconds) [45]. In addition, velocity curves derived from the abovementioned kaolin and rTEG tests can be plotted, and curves produced to represent the speed of clot propagation, in other words the maximum rate of thrombus generation (MRTG) and the time to MRTG (TMRTG). The addi-tion of ecarin to the kaolin test significantly alters the R time, K time, and TMRTG in such a way as to potentially distinguish between the two different classes of DOACs (DTI vs. factor Xa inhibitors) [45].

Reports on TEG parameters to detect rivaroxaban are inconsistent; however, the new fully automated TEG system (described later) shows potential promise [43, 45], Using the TEG 5000, Dias et al. observed that both R time and TMRTG param-eters in the kaolin test were sensitive to apixaban and dabigatran. They also found that the rTEG test ACT parameter is sensitive to all three DOACs (dabigatran, riva-roxaban, and apixaban). In the presence of anti-Xa inhibitors, the ecarin test pro-moted significant shortening of kaolin R-times to the hypercoagulable range, while


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in the presence of a direct thrombin inhibitor, only a small dose-proportional R time shortening was observed, allowing them to potentially distinguish between the pres-ence of DTI from anti-Xa inhibitors. The TEG 5000 platform is limited by high interindividual variability and in some instances lack of specificity to specific agents; however, it is showing promise in potentially distinguishing between the two different classes of DOACs in the currently FDA-approved drugs [28].

The TEG 6 s is a fully automatic four-channel diagnostic instrument that is a portable cartridge-based point-of-care system, shown to be equivalent in perfor-mance to the original TEG 5000. It has the addition of two new assays: the direct thrombin inhibitor assay and the anti-factor Xa assay are currently being developed for detection of DTI and anti-factor Xa agent anticoagulant effects. In a recent study, the anticoagulant effects of dabigatran, apixaban, and rivaroxaban were eval-uated, and a reasonable algorithm was developed in order to elucidate class-specific

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Fig. 4.3 (a) a typical ROTEM tracing and (b) a typical TEG tracing [44]. (Used with permission)


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activity in a patient’s blood [43]. Although further large-scale trials are needed, the multichannel TEG 6 s oral anticoagulant detection system had a high sensitivity and specificity in identifying patients on DOAC therapy, although edoxaban was not studied since it was not currently FDA-approved [43].

Similar to TEG, the basic tests that ROTEM can perform involve a measurement of enzymatic clot formation initiation (thrombin generation) in both intrinsic (INTEM) and extrinsic (EXTEM) pathways. Results are reported as variables on a graph similar to the TEG but with different variables. These are the clot time (CT, measured in seconds), clot formation time (CFT, measured in seconds), alpha angle (alpha, measured in degrees), maximum clot firmness (MCF, measured in mm), and lysis index measured 30 min after the CT (LI30, measured as a %).

Rivaroxaban has been shown to prolong the EXTEM and INTEM time in a dose- dependent fashion; however, there may be situations in which the tests fail to deter-mine clinically significant levels of the drugs [46]. None of the DOACs have been shown to have a significant influence on MCF, alpha angle, or CFT, regardless of test (EXTEM, INTEM, or FIBTEM). However, the clotting time (CT) in both INTEM and EXTEM may be prolonged in the presence of therapeutic levels of dif-ferent DOACs. INTEM CT was less sensitive than EXTEM CT to anticoagulant effect, whatever DOAC tested. Dabigatran, for instance, does seem to prolong the CTs in either INTEM and EXTEM in a linear fashion, but this is somewhat incon-sistent at lower therapeutic levels of dabigatran [47]. The EXTEM is fairly equiva-lently sensitive to rivaroxaban, but EXTEM sensitivity for edoxaban and apixaban is much less. It is reasonable to conclude that ROTEM is, at this time, not a reliable and effective assay to identify and/or quantitate the activity of the DOACs in a patient’s blood. A positive result (prolongation in the CT) could indeed signal DOAC effect, but a negative result does not preclude the presence and/or activity of these drugs. Ultimately, the results are nonspecific and lack precision, making ROTEM, at this time, not suitable for routine monitoring of activity levels of factor Xa inhibitors.

Concerns that have arisen surrounding both TEG and ROTEM include the need for daily calibration and specialized operators, mechanical manipulation of the clot, long data reporting time, large instrument size, high cost, and the lack of standard-ized procedures. It is thought that the combination of some, or all, of these factors has limited the widespread use and adoption of TEG and ROTEM for routine anti-coagulation monitoring. It is also important to note that these assays are general measures of secondary hemostasis and in no way describe any potential deficits in primary hemostasis.

Thrombin Generation Assay

The thrombin generation assay (TGA) was developed to more precisely describe a patient’s ability to create thrombin and is being investigated as a potentially useful modality to monitor antithrombotic drugs [48]. In this assay, whole blood or plasma is supplemented with triggers such as tissue factor or other sources of phospholipid


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combined with calcium to initiate coagulation. Thrombin generation is evaluated by mixing the patient’s plasma with tissue factor, phospholipid, fluorogenic substrate, and calcium. Thrombin generation resulting from the balance of production and decay due to both of pro- and anticoagulant factors present is followed and charted over time. The TGA has been reported to detect the effects of rivaroxaban in a dose- dependent manner. Although the TGA seems to be a promising candidate to better elucidate a patient’s overall coagulation potential, further studies combining TGA results with clinical data are needed to release the TGA for routine use in the clinical laboratory [48].

Other Assays

The dilute Russell viper venom time (DRVVT) is traditionally used for the assess-ment of antiphospholipid syndrome. This test is based on the ability of the venom of the Russell’s viper to induce thrombosis, thought to be predominantly via activa-tion of factors V and X [36]. The DRVVT has been studied as a more precise way to measure the effect of direct oral anticoagulants and has been shown to be pro-longed in the presence of dabigatran. Unfortunately, it often overestimates the true plasma level [49]. DRVVT assays also demonstrate prolongation in the presence of Xa inhibitors but similarly tend to overestimate drug concentration in an unpredict-able manner, making it difficult to calibrate reliably [50]. A chromogenic anti-IIa assay is also under investigation and appears to correlate with HPLC-MS/MS results, but data are limited, and the assay is not widely available [51].

Aggregometry, Platelet Mapping, and Platelet Function Tests

The emerging cell-based model of hemostasis describes a complex process that occurs dynamically, in the midst of blood flow, on the surface of damaged endothe-lium, involving adhesion of platelets, aggregation, cross-linking with fibrin, retrac-tion, and fibrinolysis. Thus, ideal hemostasis assays should preferably measure all of these processes at relevant shear conditions and provide results in a timely man-ner in the setting of bleeding. Some elaborate systems exist that mimic systems of perfusion and shear stresses and measure platelet function in a whole blood environ-ment; however, their current designs preclude them from mainstream utilization and/or any close proximity to patients in urgent circumstances. For purposes of this section, we will focus only on the currently available methods that have been clini-cally studied and reported in the hemostasis literature.

In general, methods measure either aggregation and/or adhesion. Classical light transmission aggregometry was designed to monitor treatment response to the com-mon classes of antiplatelet drugs, aspirin, ADP-receptor antagonists and GPIIb/IIIa antagonists by adding arachidonic acid, ADP, a strong platelet agonist such as thrombin PAR1 receptor-activating peptide (TRAP), or collagen [8]. In multiplate


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(Roche, Switzerland), the whole blood sample, anticoagulated with citrate or hiru-din, is added to a disposable cuvette containing electrodes to which platelets adhere and aggregate following addition of collagen, TRAP, ADP, arachidonic acid, or ris-tocetin. This causes a change in impedance, which is registered by a sensor and measured. VerifyNow (Accumetrics, USA) is a fully automated cartridge-based instrument for assessment of antiplatelet medications, using similar reagents designed to stimulate known receptor targets of current antiplatelet medications. Citrated whole blood is mixed with platelet agonist (ADP, arachidonic acid, or TRAP) and fibrinogen-coated beads to which activated platelets will bind and agglutinate, causing increase of light transmittance that is recorded. Plateletworks (Helena Laboratories, USA) aggregation kits are based upon comparing platelet counts before and after aggregation with ADP, arachidonic acid, or collagen in citrated tubes. Results are expressed as % aggregation or % inhibition. Although a number of studies have been done trying to establish a way to use these tests to improve outcomes of patients taking antiplatelet agents, they have failed to demon-strate a benefit in improving clinical outcomes [35].

The classical adhesion test is to count platelets before and after the passage of heparinized blood through a glass bead-filled column. Commercially available tests include the platelet function analyzer 100 (PFA-100, Siemens, USA) and the cone and plate(let) analyzer (CPA) (Impact-R, DiaMed, Switzerland). Both of these tests measure platelet adhesion and aggregation under conditions of high shear and require anticoagulated whole blood. The PFA-100 measures the time to occlusion of blood flow through a collagen-coated membrane in the presence of epinephrine or ADP. The Impact-R uses a polystyrene well and plasma proteins that adhere to the surface of the wall. Shear stress is applied by rotating a conical device immersed in the sample, leading to platelet adhesion and aggregation. The platelets are visualized and quanti-fied by staining and expressed as a percentage of surface covered by aggregates [35].

The predominant limitation of these methodologies revolves around our limited understanding of platelets in general and how they function in the dynamic process of coagulation. These tests focus on known platelet receptors, agonists, and antago-nists used to stimulate and inhibit platelet activity. Furthermore, the methods to actually measure whole blood agglutination across a membrane designed to aggregate platelets and clot require specialized equipment and are labor-intensive, thus limiting usefulness in the acute clinical setting. At the moment, no clinical studies have supported the general use of aggregometry, platelet mapping, or plate-let function assays in the clinical setting.

Emerging Technologies

Optical Sensing of Anticoagulation Status

In 2017, the novel use of an optical sensor utilizing laser speckle rheology (LHR) to measure anticoagulation and hemodilution status in whole blood with rapid turn-around was reported. Using a few drops of whole blood, changes in blood viscoelas-ticity are measured during coagulation from a time series of laser speckle patterns.


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Laser speckle occurs by the interference of scattered laser light and is exquisitely sensitive to the viscoelastic susceptibility of the medium. The increasing stiffness of blood during coagulation elicits a slower rate of speckle fluctuations in a clot com-pared with unclotted blood. Clotting time and clot stiffness measured by LSR have been shown to be closely correlated with plasma-based PT, aPTT, and fibrinogen levels in patients with a wide range of coagulation abnormalities. This same group demonstrated using LSR as a tool to quantify anticoagulation status in response to treatment with anticoagulants agents (VKA, heparin, Xa, and thrombin inhibition). Blood samples from 12 patients warfarin treated were analyzed. LHR results cor-related well with PT and aPTT as well as the whole blood technique of thrombo-elastography (TEG). The same group used swine blood to assess the accuracy and sensitivity of LSR in measuring the dose-dependent response to heparin, rivaroxa-ban, and argatroban and compared results with standard reference TEG measure-ments. They observed that anticoagulant treatments prolonged LSR clotting time in a dose-dependent manner that correlated closely with TEG [52]. Further prospec-tive studies and FDA approval are needed, but these authors suggest that LSR could be considered as a modality for routine anticoagulation monitoring at the point-of- care level or for patient self-testing, given the ease of utilization of this methodology.

Resonant Acoustic Spectroscopy

A portable blood clot micro-elastometry device has been introduced that is based on resonant acoustic spectroscopy, in which a sample of well-defined dimensions exhibits a fundamental longitudinal resonance mode proportional to the square root of the clot strength. In contrast to commercial thromboelastography, the resonant acoustic method offers improved repeatability and accuracy due to the high signal- to- noise ratio of the resonant vibration. In 2015 a proof-of-concept paper was pub-lished that introduced this technology and demonstrated that it could measure a difference in clot stiffness that is sensitive to heparin levels below 0.05u/ml and postulate that this could have future applications in sensing heparin levels of post-surgical cardiopulmonary bypass patients [53].

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Chapter 5Hematologic Impact of Fluid Replacement

Christopher R. Barnes and Anthony M. Roche

Introduction

Intravenous fluids remain one of the most widely used therapies in medicine. Yet they are often poorly understood despite their ubiquitous utilization in both the acute and critical care settings. In addition to their role in perioperative care and the management of certain neurologic conditions, they also play a crucial role in the sepsis bundle care model, for the purposes of volume expansion, managing dehy-dration, and electrolyte and acid-base disturbances.

Intravenous fluids can be broadly categorized as crystalloids or colloids, while the crystalloids can be further subdivided as either resuscitative or non- resuscitative. It follows therefore that each crystalloid has an optimal use scenario. Although this is not always the case (as with hypertonic preparations in neurosurgery), it is never-theless a useful clinical concept.

Resuscitation crystalloids generally have electrolyte formulations that equate to extracellular fluid. Despite the continued use of 0.9% saline in fluid resuscitation management due to its osmolality, its electrolyte composition is that of 154 mEq/L sodium and 154 mEq chloride. These are both supraphysiological quantities, with-out any further buffering or electrolytes, which is in stark contrast with balanced electrolyte formulations (e.g., lactated Ringer’s, Plasma-Lyte, and Normosol) that better resemble the makeup of extracellular fluid. With this, there is an expanding body of evidence suggesting that 0.9% saline is not necessarily the best choice for resuscitation and will be covered in greater detail later in the chapter (Table 5.1).

C. R. Barnes, MD (*) · A. M. Roche, MBChB, FRCA, MMed Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USAe-mail: [email protected]; [email protected]




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Coagulation derangements can be common with many different intravenous flu-ids. This obviously depends on the type of fluid, the formulation, the dose (or volume administered), and electrolyte content. As a result, this may affect which fluids are utilized in which volumes for different acute care conditions.

Vascular biology of intravenous fluids has until recently been poorly understood. The emergence of a better understanding relating to the endothelial glycocalyx has also advanced a better fluid utilization in acute care and critical care settings. The glycocalyx is a remarkable endothelial structure which is profoundly affected by multiple pathologic states, including volume overload and therefore can lead to sig-nificant further derangements in fluid homeostasis.

Colloids

For the purposes of this chapter, it will be prudent to focus on colloids and resuscita-tion crystalloids, as non-resuscitation crystalloids (e.g., 5% dextrose in water or 5% dextrose in 0.45% saline) are generally not administered in large volumes over short periods of time. It follows that besides minor electrolyte or volume-related distur-bances in those with organ dysfunction, routine non-resuscitation crystalloid admin-istration is unlikely to cause major hematologic disturbances.

Colloids are generally considered as either natural or synthetic in composition. The synthetic hydroxyethyl starches accounted for a substantial portion of the fluid litera-ture until the discovery that their administration in septic or critically ill patients caused kidney injury and increased mortality [1–3]. Although there have been studies contra-dicting this discovery, these studies were generally performed in a different, otherwise healthy patient population, quite often in elective cases in the operating room environ-ment [4, 5]. The overwhelming balance of opinion and literature is that hydroxyethyl starches (HES) should not be used in critical care environments. This discomfort with clinicians with regard to use of starches has also distilled down to the operating room (OR) setting, where starches have now effectively been removed from many shelves as a result. In the USA, the majority of remaining synthetic colloids are the dextrans, with some institutions still judiciously using HES-based products. The dextrans are no lon-ger used for volume resuscitation but rather for specific surgical indications.

Table 5.1 Composition of common intravenous fluids

Na+ K+ Ca2+ Mg2+ Cl−Buffers

OsmolarityLactate Acetate GluconatemEq/L (mOsmol/L)

Human plasma 135–145

3.5–5.1

8.0–10.5

1.5–2.5

95–105

– – – 280–300

0.9% saline 154 – – – 154 – – – 308Lactated Ringer’s

130 4 2.7 – 109 28 – – 273

Normosol-R 140 5 – 3 98 – 27 23 294Plasma-Lyte A 140 5 – 3 98 – 27 23 294

C. R. Barnes and A. M. Roche

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Human albumin solution (HAS) is currently the most widely used colloid in medicine. It is a natural product produced by fractionation of human plasma. It is available in iso-oncotic concentrations of 3.5–5%, as well as a hyperoncotic solu-tions of 20–25%. HAS is most commonly used for volume resuscitation, especially in patients who are clinically hypoalbuminemic, or those with significant liver dis-ease. With that said, there is currently not an overwhelming body of evidence sup-porting its use over crystalloid solutions. The SAFE study, conducted in Australia and New Zealand, showed that HAS was no worse than 0.9% saline solution uti-lized in a critical care patient population [6]. This was in contradiction to a previous meta-analysis which suggested an increased mortality with the use of HAS solution [7]. It should be known though that the use of HAS in an important subset of patients, those with traumatic brain injury (TBI), was associated with significantly worse outcomes, including an increase in mortality rate.

More recently, there are an increasing number of studies in critical care indicat-ing that albumin supplementation to minimum levels of 30 g/L, as well as fluid resuscitation using HAS in severe sepsis or septic shock may improve survival [8]. Sort et al. described improved survival with HAS-based volume resuscitation in patients with cirrhosis and spontaneous bacterial peritonitis (SBP) [9]. A more recent study also described the mortality benefit of albumin supplementation in cir-rhotic patients with infections other than SBP [10]. Furthermore, a systematic review published in 2013 confirms the mortality benefit of albumin supplementation in cirrhotic patients with infections [11].

Acid-base Effects of Intravenous Fluids

Although 0.9% saline is arguably the widest used intravenous fluid globally, it makes little sense clinically. Saline infusion therapy was developed by Dr. Thomas Latta (Edinburgh, Scotland, Date?) during the cholera epidemic in the nineteenth century. At that stage little was known about electrolyte composition in fluids and so too to intravenous infusions. Latta’s publication in The Lancet in 1832 described that the infusion of salts in fluids led to improved outcomes and is the seminal work on salt-based fluid infusions [12]. What remains more fascinating is that saline remains the most commonly administered fluid almost 200 years later. It could be postulated that medical culture of fluid administration has become ingrained to such a degree that clinicians have not remained up to date on the evidence regarding balanced electrolyte formulations and their preferred role in volume resuscitation. With the advent of a better understanding of acid-base effects of intravenous fluids, the clinician is now able to make carefully judged decisions regarding fluid choices.

Stewart’s physicochemical approach to human acid-base management underpins the current thinking of fluid and electrolyte infusions. Stewart’s theory, first pub-lished in the 1970s and early 1980s, described the strong ion difference (SID) as being one of the major drivers of human acid-base disturbances [13–15]. Specifically, there are three major processes involved in determining pH or specifically H+ ion concentration:

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• PaCO2• Weak acids• SID

Furthermore, two basic physics principles also affect how the Stewart approach functions. The first is the law of electrochemical neutrality, which describes that in any solution, the sum of all positive and negative ions or compounds equals a net charge of zero, and the second is the law of conservation of mass, which means that the total amount of a substance remains constant, unless it is added to or generated, or removed, or destroyed. Finally, although not a physical law, Stewart described that the body, which is 65–70% water, is an inexhaustible supply of H+ and OH-.

As stated above, carbon dioxide (CO2) directly affects H+ concentration by the mechanism of increasing or reducing carbonic acid production via carbonic anhy-drase enzymatic activity and thereby its dissociation into H+ and HCO3-.

CO H O H CO HCO HCarbonic Anhydrase2 2 2 3 3+ « +¬ ®¾¾¾¾¾ - +

Complicating one’s understanding slightly is the body’s inexhaustible supply of H+ and OH−. Due to its dynamic nature, the dissociation of water into these ions is also largely dictated by CO2 and the strong ions. This plays a further role in reac-tions observed in maintaining the acid-base status and more importantly electro-chemical neutrality.

Stewart’s second principle is that of weak acids (or weak electrolytes), which are acids or electrolytes in the body that are only partially ionized at pH levels encoun-tered physiologically, such as plasma proteins like albumin and phosphates. These play a role in the mathematical model Stewart originally described, along with CO2 and the strong ion difference (SID, described below) and hence the final H+ ion concentration. As the total weak acid drops, in isolation, an increase can be expected in the pH. Even though weak acids are important in acid-base regulation, and noted in certain units, they are not commonly used for clinical interpretations of acid-base derangements. The observation that the only clinically relevant weak acids are inor-ganic phosphates, albumin was later confirmed by Fencl’s group, noting that a charge of approximately 12 mEq/L can be attributed to these acids and that globu-lins play a negligible role.

Probably the most interesting discovery in Stewart’s theory was that of the strong ion difference (SID). This principle rests on the chemistry of strong ions in the body (or aqueous solutions). Strong ions (or electrolytes) are almost completely ionized in aqueous solutions. The most notable of the strong ions are Na+, K+, Ca2+, Mg2+, Cl−, and lactate. At this stage, it is prudent to remember the basis of the physico-chemical approach, which is firstly that of electrochemical neutrality being main-tained at all times and secondly the conservation of mass.

In plasma, when all the strong ions mentioned above, both anions and cations, are added together, the result does not end up as zero – this is the strong ion differ-ence. Weak acids, for example, have not been taken into account in the equation. Stewart originally described the equation as follows:


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Na K Cl Lactate SID+ ++( ) +( ) =– -

The SID is determined by the charge of the ions as well as the quantity; in healthy volunteers it usually equals approximately 40–49 milliequivalents per liter (mEq/L) and can therefore be affected by changes in plasma electrolyte concentrations. This SID, which is an independent mechanism of acid-base regulation, determines (along with CO2 and weak acids) what the plasma hydrogen ion concentration will be. The electrochemical forces generated by this SID determine water dissociation; hence H+ ion concentration required to “balance” plasma ionic charges. The net result always has to be a plasma ionic charge equal to zero (electrochemical neutrality). As one can see, H+ is not the driving force of the reaction; it is the dependent variable, along with OH− to a much lesser degree. To continually balance these electrochemi-cal forces, a decrease in H+ concentration is observed with increases in the SID, and H+ concentration increases as the SID decreases.

Given this, one can surmise that an increased plasma chloride ion concentration relative to sodium and potassium concentrations will produce a reduction in plasma strong ion difference, leading to an increased hydrogen ion concentration and there-fore acidosis. It is by this mechanism that excess 0.9% saline administration causes a hyperchloremic metabolic acidosis [16–18].

It is known that hyperchloremia causes renal afferent arteriolar vasoconstriction with subsequent reduction in glomerular filtration rate (GFR), as well as reduced renal cortical perfusion [19, 20]. These may be the mechanisms by which hyper-chloremia reduces urine output. Furthermore hyperchloremia may reduce splanch-nic regional perfusion and so too may amplify the inflammatory response, especially in sepsis [21, 22].

It is not unreasonable to wonder if such a hyperchloremic acidosis is of any clini-cal relevance. Earlier comparative studies described side effects of saline-induced hyperchloremic acidosis, e.g., mild cognitive dysfunction, gastric discomfort and disturbance, and reduced urine output, but little was known about significant out-come differences [23]. This has since changed in surgical, critical care and emer-gency medicine environments, where hyperchloremia and its associated acidosis have been shown to cause increased complications, kidney injury, and notably mor-tality [24–26].

The emerging body of evidence in critical care is especially alarming for signifi-cantly increased risk of adverse outcomes with hyperchloremia. In an open-label sequential study of 760 critical care patients receiving either 0.9% saline-based or a chloride-restricted fluid strategy, Yunos et al. described an increased peak serum creatinine, increased incidence of acute kidney injury (AKI), as well as an increased requirement for renal replacement therapy [27]. This group followed up with simi-lar outcomes in a study of almost 3000 patients [25].

Large retrospective database analyses have been helpful in determining how these effects may impact large patient populations. Shaw et al. utilized a propensity- matched analysis of over 30,000 patients to measure the effects of saline versus balanced electrolyte solutions in major surgery. In their analysis, saline solution was


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associated with more complications, higher rates of postoperative infections, more blood transfusions, and more renal failure requiring dialysis. The authors noted an almost five-fold greater frequency of AKI with 0.9% saline [24]. McCluskey et al. evaluated the effects of hyperchloremia; also in a propensity-matched cohort study in major non-cardiac, non-transplant surgery [28]. Their well-structured theory is that in their study population, the vast majority of hyperchloremia is caused by excess saline administration. The hyperchloremia group were at increased risk of mortality, had a longer hospital length of stay, and had increased postoperative renal dysfunction defined by RIFLE criteria.

There is a common misconception in patients with renal dysfunction that potas-sium avoidance in intravenous fluids is preferred. This generally leads to clinicians choosing 0.9% saline as the fluid of choice for volume management in this patient population. A randomized controlled double-blind study by O’Malley et al., com-paring 0.9% saline versus lactated Ringer’s solution in renal transplantation surgery, showed a greater degree of hyperchloremia, acidosis, and hyperkalemia in the group randomized to receive saline [29]. This is likely due to extracellular shift of potas-sium caused by the resultant hyperchloremic acidosis.

Needless to say, in the critical care patient population, this recent evidence strongly suggests that the avoidance of hyperchloremia should be paramount. There is little evidence to support the routine use of saline in these patients, and unless specifically otherwise indicated, balanced electrolyte solutions should be the fluid management of choice.

Coagulation and Hemostasis

A natural inkling would be to suspect that crystalloids and colloids both cause a dilutional coagulopathy, even at low to moderate doses. Much of this may stem from the trauma literature where the coagulopathy of trauma is known to cause profound, complex coagulopathies [30]. Indeed this is not necessarily always the case in perioperative and critical care medicine.

If plasma dilution occurs, one sees [1] an altered balance between procoagulant and anticoagulant systems (all intravenous fluids cause a greater decrease in anti-thrombin III than that which would be associated with hemodilution per se, the greater effects probably seen with crystalloids) and [2] an effect of the diluting agent on platelets and the chemistry of polymerization (e.g., dextrans). This may cause an altered clot structure and function [31–33].

Crystalloids and colloids are not created equal, especially with coagulation. One has to consider both the role of the crystalloid and especially the colloid in altering coagulation function.

It is not common knowledge that normal saline (0.9% NaCl) and other crystal-loid solutions induce a state of hypercoagulability in mild to moderate hemodilution


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(20–40%), as judged by thrombelastography (TEG®) [32, 34]. The crystalloids used in most of the earlier studies were saline-based; however, Ringer’s type solu-tion also causes hypercoagulability. Probably more importantly, there is data to sug-gest that crystalloid solutions may indeed increase postoperative deep venous thrombosis rates in certain groups of surgical patients [35]. Heather and colleagues suggest a preoperative saline dilution test to predict the probability of postoperative deep venous thromboses [36]. One could consider it clinically important to be aware of the potential for inducing a hypercoagulable state in a patient who is already at risk of thromboembolic disease.

Although largely a moot point at the current time, with the hydroxyethyl starches falling out of favor, as a group they are known to inhibit in vitro coagulation func-tion to varying degrees. Clearly, dose is important but so, too, are mean molecular weight, degree of hydroxyethyl substitution, as well as C2/C6 substitution ratio, as these can all affect coagulation function [37–42]. Much of this is likely due to a glycoprotein IIb/IIIa type effect. This effect is generally not observed in vivo when clinicians stay within manufacturers’ recommended dosing guidelines.

Rheology

The Merriam-Webster dictionary describes rheology as the science dealing with the deformation and flow of matter, also as the ability to flow or be deformed [43]. Blood rheology is a similar concept, where different circumstances or blood components can improve or inhibit red cell deformability and flow. There is data to suggest that the dextran group of colloids improves blood rheology and thereby improves tissue perfusion [44–46]. Dextrans are neutral polysaccha-rides, which are synthesized from saccharose by Leuconostoc mesenteroides streptococcus.

Neurology

Mannitol, hypertonic saline, as well as hypertonic saline-dextran formulations are all known to reduce intracranial pressure (ICP). They are all seen as temporizing mea-sures to reduce ICP until such time as more definitive management can be achieved, e.g., craniotomy, craniectomy, or clot evacuation. These fluids work largely by osmotic and/or oncotic effects. However caution must be exercised especially with large or repeated doses, as this can lead to acute kidney injury. What was initially of significant interest regarding the anti-inflammatory role of hypertonic saline and dextran espe-cially in traumatic brain injury has now become more controversial, as the more recent literature has not overwhelmingly supported the earlier reported benefits.


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Kidney

Besides the impact of hyperchloremia inducing acute kidney injury as discussed earlier, there are other risks to the kidney. The hydroxyethyl starches are now also known to cause significant kidney injury [1–3, 47]. Their use has largely fallen out of favor due to the starch molecules causing renal tubular colloidal inclusions [48]. This is a pathophysiological process similar to that observed with repeated mannitol administration. Although it is not known to be the only mechanism, this is thought to be the biggest contributing factor to hydroxyethyl starch or mannitol-induced acute kidney injury. The biggest contributing clinical factors are colloid dose and pre-existing disease, especially in the presence of sepsis in a critical care patient population. As a result, hydroxyethyl starches are currently not recommended for use in critical care.

Glycocalyx

The endothelial glycocalyx is an intravascular fringe on the luminal surface of vas-cular endothelium. It is a delicate, hairlike fringe that was only discovered relatively recently. Advances in preparation and fixation of histological slices have now revealed this astonishing structure. Since then, much has been learnt of its crucial function in vascular biology. Becker et al. described it as “...an intravascular fringe of astounding functional significance” [49].

The glycocalyx is a delicate, hydrated, and gel-like structure comprised of (1) sulfated proteoglycans and glycosaminoglycans (heparan sulfate, chondroitin sul-fate, hyaluronic acid), (2) glycoproteins (oligosaccharides, sialic acid), and (3) syn-decans (transmembrane proteins). It has a net negative charge, which is crucial in both vascular biology as well as fluid and intravascular versus interstitial protein turnover [49–52].

The endothelium and glycocalyx are involved in multiple processes, including interaction and management or regulation of plasma proteins (including albumin), enzymes, enzyme inhibitors, growth factors, cytokines, cationic amino acids, cations, and fluid balance. The glycocalyx has a critical role in the transduction of mechanical shear stresses to the endothelium and thereby nitric oxide production. It has a mostly anti-inflammatory role, yet is involved in multiple components of the inflammatory cascade, has a role in coagulation (via anticoagulants), and is crucial in cell signaling. Being an extremely sensitive structure, it can easily be damaged by ischemia reperfu-sion, the inflammatory response, hypoxia, volume overload, and atrial natriuretic peptide (most likely due to volume overload). Acute or chronic effects of glycocalyx destruction or dysfunction are tissue edema, systemic inflammatory response syn-drome/sepsis, hypercoagulability, diabetic angiopathy, and atherogenesis [49–51].

Prior to previous understanding, the vascular endothelial cell is no longer consid-ered the first barrier in intravascular versus interstitial fluid regulation. This primary


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barrier role is managed by the glycocalyx, due to its luminal presence and net nega-tive charge. The charge itself is largely due to the inclusion of free-moving and bound negatively charged albumin and plasma proteins within the glycocalyx struc-ture. At the base of the glycocalyx is a protein-free buffer zone, one where fluids can diffuse freely between the interstitial space, the protein-free zone, and the vascular lumen, however, which is dependent on a few more factors. Current evidence indi-cates that a small amount of fluid extravasates between small capillary pores, whereas the majority of influx and efflux of fluid happens in the large venular pores, with no filtration as previously believed, at the arteriolar side. Furthermore as previ-ously suggested, hydrostatic pressure is involved but so, too, is the intricate balance of oncotic pressures within the glycocalyx, the protein-free zone, as well as the extravascular interstitial space. Clearly, the glycocalyx’s integrity, as well as the role of bound albumin, is extremely important in fluid balance. In normal health, with adequate albumin and protein levels, fluid homeostasis is a delicate balance effec-tively managed by the endothelial cell-glycocalyx complex [49, 51, 52].

Acute disruption of the glycocalyx (e.g., in sepsis, ischemia-reperfusion) wreaks havoc on fluid management, as the abovementioned intricate balance is destroyed, albeit sometimes even temporarily. The net effect is an acute inability to retain suf-ficient intravascular fluids, with vast volumes escaping to the interstitium. If the glycocalyx is injured or severely disrupted, it takes an average of 5–7 days to regen-erate [49]. The time point is often observed clinically when a patient’s daily fluid balance starts to return to neutral or even negative values. This, too, fits clinically with the classical description of patient’s “third spacing,” i.e., no longer responding to fluid boluses in a meaningful way, during the acute stages of their critical illness or immediate perioperative care.

In circumstances where the glycocalyx is not necessarily injured but rather with mild to moderate degrees of volume overload, the increase in glycocalyx shear stress and torque is transduced to the endothelium and subendothelium tissues by stress fibers. This can lead to a varying degree of interendothelial tight- and adher-ens junction disruption, which in turn manifests as opening of previously closed endothelial junctions and ultimately fluid extravasation. Fluid retention ensues, potentially further injuring the glycocalyx, leading to more fluid extravasation [51]. This vicious cycle often requires more intravenous fluid administration to maintain the intravascular volume. Most intravenous fluid comprise both fluid and electro-lytes (besides 5% dextrose in water), so it should be recalled that both the fluid and the electrolytes need to eventually be cleared, the latter being an energy-dependent process for the kidneys.

Intravascular Volume Management

Based on the knowledge that the glycocalyx is a crucial structure which is easily harmed in disease states, the logical concern would be how a clinician can protect it as best possible. Firstly, in moderate to severe sepsis, or patients receiving large


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doses of chemotherapy, or those with ischemia-reperfusion states, there is little a clinician can do to protect the glycocalyx from injury. However, clinicians can reduce the risk of further damage in these scenarios or prevent it from occurring. This too can be said for patients who do not already have an injured glycocalyx, as one may often see, for example, with perioperative critical care cases. The clini-cian’s challenge then is to fastidiously manage intravenous fluid administration, with the goal to get it just right [53–56]. Inadequate fluid administration risks potential tissue hypoperfusion and its associated complications, whereas volume overload leads to adverse outcomes due to edema-induced complications [57]. There are many proposed methods of achieving this balance, each of which is based on a specific acute, chronic, or acute-on-chronic disease process. The detailed methods of achieving this lie outside of the scope of this chapter besides emphasizing that a carefully considered, sensible goal-directed approach is required, both in surgery and critical care [54, 55, 58, 59]. Furthermore, “goal-directed” does not immediately imply the use of cardiac output monitoring, perfu-sion indices, or invasive arterial pressure variation with positive pressure ventilation, for example. Although advanced technology may be required, it is more important for the clinician to set clear goals of fluid administration (and/or inotropic and vasoactives therapies) based on existing and current patient condition, allowing for real-time feedback and reevaluation, adjusting goals where indicated. One of the sensible approaches to critical care intravascular volume management versus ino-tropic/vasoactive therapies revolves around firstly identifying if a problem exists or not. The usual measures of acid-base status, lactate, and especially blood pressures are a reasonable start. In the setting of metabolic acidosis or blood pressure derangement, for example, it is recommended that the clinician returns to basic measures:

BP CO SVR= ´

where BP is blood pressure, CO is cardiac output (comprised of stroke volume and heart rate), and SVR is systemic vascular resistance. This is a setting where some form of cardiac output monitoring is suggested, as it would be difficult to make adequate clinical judgments on prescribing vasoactive or inotropic agents in the absence of sound clinical data. The clinician should base interventions on cor-recting the derangements. For example, in a hypotensive patient with a metabolic acidosis, first assess if the patient’s cardiac output is sufficient or not. If the cardiac output is low (based on an indexed value), assess if there is an opportunity for recruiting stroke volume with intravascular volume challenges (or other dynamic indices, e.g., stroke volume variation, pulse pressure variation). In circumstances where stroke volume is unresponsive to intravascular volume (or where the dynamic indices indicate no fluid challenge-recruitable stroke volume), it may be worthwhile considering an inotropic agent (e.g., epinephrine, dobutamine, norepinephrine). The blind administration of a pure vasoactive infusion (e.g., phenylephrine, vasopressin) in this setting cannot be recommended. Conversely, if the same hypotensive patient’s cardiac output or index is sufficient or above normal ranges, it indicates a low sys-


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temic vascular resistance, and this warrants a vasoactive infusion (phenylephrine, vasopressin, or potentially norepinephrine). Although there are no large studies evaluating this principle in detail, it remains sensible, logical care.

Final Words

Fluid administration is a complex challenge and hotly debated in critical care. It can make a significant difference on patient outcomes, and care should be exercised when prescribing or administering fluids. The task of administering the correct amount of fluid, as well as electrolytes, can be challenging. However the astute cli-nician is expected to perform this task in critical care. There are many end-organ effects of fluids on the kidneys, brain, and gastrointestinal tract, for example. Fluids can also profoundly affect the coagulation system, capable of inducing anything from a hypercoagulability to a hypocoagulable state. Saline-based fluid strategies should be utilized with caution, especially as hyperchloremic acidosis is strongly associated with adverse outcomes. There are few absolute indications for 0.9% saline administration for intravascular volume resuscitation or optimization; there-fore its widespread administration in critical care is contraindicated outside of spe-cific clinical indications.

Avoid hypovolemia as well as volume overload, with the goal of maintaining a patient’s volume state in the optimal range. This is the core remaining principle of intravascular volume management.

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cular disturbances and tissue injury following ischemia/reperfusion in striated muscle. Shock. 1998;9(5):345–51.

47. Myburgh JA, Finfer S, Billot L, Investigators C. Hydroxyethyl starch or saline in intensive care. N Engl J Med. 2013;368(8):775.

48. Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H. Hydroxyethyl starch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet. 1993;342(8865):248–9.

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51. Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycoca-lyx layer. Annu Rev Biomed Eng. 2007;9:121–67.


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52. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of trans-vascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108(3):384–94.

53. Chappell D, Dorfler N, Jacob M, Rehm M, Welsch U, Conzen P, et al. Glycocalyx protection reduces leukocyte adhesion after ischemia/reperfusion. Shock. 2010;34(2):133–9.

54. Chappell D, Jacob M. Role of the glycocalyx in fluid management: small things matter. Best Pract Res Clin Anaesthesiol. 2014;28(3):227–34.

55. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A rational approach to periop-erative fluid management. Anesthesiology. 2008;109(4):723–40.

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57. Bellamy MC. Wet, dry or something else? Br J Anaesth. 2006;97(6):755–7. 58. Myles PS, Andrews S, Nicholson J, Lobo DN, Mythen M. Contemporary approaches to peri-

operative IV fluid therapy. World J Surg. 2017;41(10):2457–63. 59. Thacker JK, Mountford WK, Ernst FR, Krukas MR, Mythen MM. Perioperative fluid utiliza-

tion variability and association with outcomes: considerations for enhanced recovery efforts in sample US surgical populations. Ann Surg. 2016;263(3):502–10.



Chapter 6Hematologic Advances in Trauma Resuscitation

Lena M. Napolitano

Introduction

Trauma is the third most common cause of death in the United States. Hemorrhagic shock is the leading cause of preventable mortality in both civilian and military trauma. Treatment of traumatic injuries accounts for 20% of all allogeneic red blood cell (RBC) transfusion use in the United States. We have achieved major advances in the treatment of traumatic hemorrhage and hemorrhagic shock due to a greater understanding of trauma-induced coagulopathy early after injury. This chapter will review the significant advances in trauma resuscitation that we have achieved, our current knowledge of trauma-induced coagulopathy and guideline-based recom-mendations for damage control resuscitation.

Blood Transfusion in Trauma

At present, the only oxygen-carrying resuscitation fluid available for use in trauma patients with hemorrhage due to traumatic injuries is allogeneic RBC transfusion. The aim of treatment of hemorrhagic shock with RBC transfusion is the rapid and effective restoration of an adequate blood volume to maximize tissue oxygen deliv-ery. Furthermore, the goal of transfusion of blood and components is to maintain the patient’s blood composition within safe limits with regard to hemostasis, oxygen- carrying capacity, oncotic pressure, and biochemistry. The additional administration of other blood components (plasma and platelets, in addition to RBCs) is necessary for the prevention of dilutional coagulopathy and dilutional thrombocytopenia.

L. M. Napolitano, MD, FACS, FCCP, MCCM Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USAe-mail: [email protected]



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The Advanced Trauma Life Support course of the American College of Surgeons currently recommends starting two large-bore IVs in patients who are seriously injured and, if they are hypotensive, giving 1 L of isotonic crystalloid solution. If the patient remains hypotensive in shock, then RBCs should be transfused [1]. These guidelines were based on the recognition that prolonged shock frequently led to organ failure that could be prevented by fluid and blood component resuscitation.

Most frequently, uncross-matched RBC units are administered to trauma patients requiring emergent RBC transfusion, and the increasing use of uncross-matched RBC transfusion has been identified as an independent predictor of mortality and the need for massive transfusion (MT) [2]. The use of fresh whole blood has also been required in the combat casualty setting due to a lack of sufficient stored blood components, and therefore combat casualty reports also document administration of fresh whole blood [3].

Uncross-matched blood is used if the patient has hemodynamic instability due to hemorrhagic shock and cross-matched blood is not yet available. Type-specific blood is used as soon as possible for hemorrhagic shock to minimize exposure to anti-A and anti-B antibodies in type O blood. In patients requiring RBC transfusion in hem-orrhagic shock, transfusion rate depends on bleeding rate, and we should not rely on hemoglobin as an assessment of adequacy of blood component resuscitation.

Massive Transfusion

Massive transfusion (MT) is required as a treatment for uncontrolled hemorrhage, and trauma is the most common etiology [4, 5]. Massive blood transfusion is com-monly defined as administration of ≥10 U of allogeneic RBCs to an individual patient or transfusion of more than one blood volume in 24 h.

A number of “dynamic” definitions of MT have been used, particularly in order to initiate MT institutional protocols. Risk factors for MT in trauma include tachycardia, hypotension, acidosis, penetrating mechanism, hemoperitoneum by sonography, and anemia. Several predictive models for MT have been developed, with all variables necessary to calculate the score easily available upon emergency room arrival [6–10].

A recent systematic review of methods for early identification of patients requir-ing massive transfusion included 84 studies describing any predictor-outcome asso-ciation, including 47 multivariable models. They identified 35 distinct predictors of which systolic blood pressure, age, heart rate, and mechanism of injury were most frequently studied. But they confirmed that the quality of multivariable models was generally poor with only 21 (45%) meeting a commonly recommended sample size threshold of ten events per predictor. They concluded that there is a need for a well- designed clinical prediction model for early identification of MT patients [11].

Trauma patients requiring MT have high mortality rates, ranging from 19% to 84%. Data from more recent studies document a significant reduction in mortality in trauma patients requiring MT, with most recent series reporting a mortality rate of approximately 25% (Table 6.1). Mortality is directly related to the severity of the

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hemorrhagic shock and the total number of PRBC units transfused [12]. Interestingly, in a single-center retrospective study of trauma patients requiring MT of more than 50 U of blood components in the first 24 h, the overall mortality was 57%, but there was no significant difference in mortality rate between patients who received >75 U of blood components in the first day versus those who received 51–75 U [13].

Damage Control Resuscitation (DCR)

The resuscitation of severely injured bleeding patients has evolved from a previous crystalloid-based resuscitation strategy with use of blood components based on laboratory testing into a treatment strategy termed damage control resuscitation (DCR). Damage control resuscitation (DCR) currently includes immediate hemor-rhage control, early blood component transfusion, avoidance of crystalloid resusci-tation, hypotensive or delayed resuscitation, treatment of early trauma-induced coagulopathy using viscoelastic testing, and restoration of physiologic and hemato-logic stability.

Table 6.1 Mortality rates associated with massive transfusion for trauma

Study Year Patients Mean # RBC unitsMortality rate (%)

Phillips 1987 56 33 61Wudel 1991 92 33 48Cosgriff 1997 – 24 43Velmahos 1998 141 32 69.5Cinat 1999 45 63 71Vaslef 2002 44 33 57Como 2004 147 25 39Huber-Wagner 2007 1062 19.5 35–60Mitra 2007 119 8 in 4 h 27.7Gonzalez 2007 97 – 30Borgman 2007 246 – 19–65Holcomb 2008 467 – 26–59Duchesne 2008 135 – 55.5Maegele 2008 713 – 24.3–45.5Sperry 2008 415 14 33.5Knudson 2010 380 28 54.5 (30)Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study

2013 905 Median 6 (4–11) (not all MT)

25% in-hospital mortality

Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs. a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR Randomized Clinical Trial

2015 680 16 vs. 15 total blood components (not all MT)

22.4% vs. 26.1%30-day mortality

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DCR in Combat Casualty Care

DCR was initially established as a US Department of Defense Clinical Practice Guideline [14] in 2004 and is now the standard of care for battlefield resuscitation and in civilian trauma centers.

The first report of the beneficial effects of hemostatic resuscitation in trauma was a retrospective review of 246 patients at a US Army combat support hospital, each of who received a MT (≥10 U of PRBCs in 24 h). They reported that a high 1:1.4 plasma to PRBC ratio was independently associated with improved survival to hos-pital discharge, primarily by decreasing death from hemorrhage. The authors con-cluded that massive transfusion protocols should utilize a 1:1 ratio of plasma to PRBCs for all patients who are hypocoagulable with traumatic injuries [15].

DCR in Civilian Trauma Care

Although the practice of DCR was initiated in military combat casualty care [16], it has also been critically examined in civilian trauma, and the concept is also applied to other patient populations requiring massive blood transfusion for severe hemor-rhage. Multiple clinical studies in civilian trauma patient populations have addressed the topic of DCR on trauma patient outcomes [17–20]. Some have advocated the use of whole blood for early trauma resuscitation for hemorrhagic shock [21]. Many retrospective and single-institution studies have reported improved outcomes using DCR compared with more traditional transfusion practices [22–27]. But other stud-ies have not confirmed these findings [28, 29].

Since hemorrhage is a major cause of trauma deaths and coagulopathy exacer-bates hemorrhage and is commonly seen during major trauma, prompt reversal of coagulopathy using DCR has been advocated as the optimal practice for MT in trauma [30, 31]. Reversal of coagulopathy involves normalization of body tempera-ture, elimination of the causes of DIC, and transfusion with plasma, platelets, and cryoprecipitate as needed. Many advocated that coagulopathy can best be reversed when severe trauma victims are transfused with the equivalent of whole blood.

An emerging consensus for DCR in trauma patients with hemorrhage at that time was:

• Expedite early control of hemorrhage to prevent consumptive coagulopathy and thrombocytopenia, and reduce the need for blood components.

• Limit isotonic crystalloid infusion to prevent dilutional coagulopathy and thrombocytopenia.

• Hypotensive resuscitation (SBP, 80–100 mmHg) until definitive hemorrhage control is established to avoid “popping the clot.”

• Transfuse components in a 1:1:1 ratio of RBCs/FFP/platelets (one five-pack of pooled platelets counted as 5 U).

• Use viscoelastic testing to guide transfusion therapy and assess for fibrinolysis.

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• Frequent laboratory monitoring (arterial lactate to assess adequacy of resuscita-tion, ionized calcium, and electrolytes).

Additional strategies are recommended to limit complications related to DCR (Table 6.2).

A systematic review of 37 studies, most of which were observational in nature, documented that in patients undergoing MT, plasma infusion at high plasma:RBC ratios was associated with a significant reduction in the risk of death (OR, 0.38, 95% CI: 0.24–0.60) and multiple organ failure (OR 0.40, 95% CI: 0.26–0.60). However, the quality of this evidence was very low due to substantial unexplained heterogene-ity and several other biases. In patients undergoing surgery without MT, plasma infusion was associated with a trend toward increased mortality (OR, 1.22; 95% CI: 0.73–2.03). Plasma transfusion was associated with increased risk of developing ALI (OR, 2.92; 95% CI: 1.99–4.29) [32]. Evidence-based practice guidelines for plasma transfusion by the American Society of Hematology recommended that plasma be transfused to patients requiring MT, however, could not recommend a specific plasma/RBC ratio [33].

Although DCR was associated with reduced mortality in many studies, many recognized the potential adverse effects associated with transfusion of blood component therapy. A number of studies have documented increased risk for ALI and ARDS with both blood and plasma transfusions [34–36]. TRALI and TACO are now the leading cause of transfusion-associated mortality, even though they are both probably underdiagnosed and underreported. [37–39]

Table 6.2 Strategies to reduce complications with damage control resuscitation and MT

Complication Strategies to reduce complication

Hypothermia Warm the roomSurface warm the patient with heating blankets and heating lampsHeat and humidity inspired gases for ventilatorsWarm all IV fluids and blood components administered

Coagulopathy Transfuse RBC/FFP/platelets in 1:1:1 ratioViscoelastic testing (ROTEM, TEG) to guide blood component resuscitation and evaluate for fibrinolysisCheck coagulation testing, including fibrinogenTransfuse cryoprecipitate if fibrinogen concentration low

Thrombocytopenia Transfuse platelets to keep platelet count >100,000 to form stable clotElectrolyte abnormalities

Hypocalcemia (due to citrate chelation), correct with calcium IVMeasure blood potassium, calcium (ionized), and magnesium concentrationsReplete electrolytes to normal values as indicated

Acid-based disorders Sodium bicarbonate or tromethamine for severe metabolic acidosis with hemodynamic instability or renal failure

TRALI Use restrictive transfusion strategy once hemorrhage controlledUse FFP from men or nulliparous women

TACO Discontinue crystalloid fluid resuscitationConsider IV diuretic use


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In a study of ARDS patients in combat casualty care, we confirmed that increased plasma and crystalloid infusion were independent risk factors for ARDS. These findings support a practice of decreased plasma/crystalloid transfusion in trauma resuscitation once hemorrhage control is established to achieve the mortality benefit of DCR and ARDS prevention [40].

This equipoise, between the beneficial effect of DCR in mortality reduction and potential increased life-threatening complications, led to two important clinical tri-als to ascertain the optimal transfusion management strategy in acute trauma resus-citation – the PROMMTT and PROPPR clinical trials.

The PROMMTT Study: Observational Trial to Identify Current Practice

The Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study [41] enrolled 905 trauma patients requiring early blood transfusion with a 25% in-hospital mortality rate. Early 24-h mortality was due to hemorrhage, with the majority (60%) within 3 h of admission, and median time to hemorrhagic death was 2.6 h. Increased ratio of plasma/RBCs (adjusted HR 0.31, 95% CI 0.16–0.58) and platelets/RBCs (adjusted HR 0.55, 95% CI 0.31–0.98) was independently asso-ciated with decreased 6-h mortality when hemorrhagic death predominated. In the first 6 h, patients with plasma/RBC ratio <1:2 were 3–4 times more likely to die than patients with ratios of 1:1 or higher. After 24 h, plasma and platelet ratios were unassociated with mortality, when non-hemorrhagic causes prevailed. These results of the PROMMTT study led to the first randomized clinical trial to compare transfu-sion ratios in acute trauma resuscitation.

The PROPPR Trial: First Randomized Trial to Compare Transfusion Ratios in Trauma

The Pragmatic, Randomized, Optimal Platelet, and Plasma Ratios (PROPPR) trial was the first multicenter randomized trial to compare two transfusion ratios (plasma, platelets, RBC ratio 1:1:1 vs. 1:1:2) with mortality (24-h and 30-day) as the primary endpoint. [42] The study enrolled 680 injured patients from scene predicted to need MT (defined as receiving 10 or more units of RBCs within the first 24 h). There were no significant differences in 24-h or 30-day mortality in the two groups, but more patients in the 1:1:1 group achieved hemostasis (86.1% vs. 78.1%, p = 0.006), and fewer experienced death due to exsanguination by 24 h. The authors concluded that given the lower percentage of deaths from exsanguination and no safety differ-ences, clinicians should consider using a 1:1:1 transfusion protocol while patients are actively bleeding and then transition to laboratory-guided treatment once

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hemorrhage control is achieved. Additional data from the PROPPR trial show that at 3 h after randomization, there was a significant difference in all-cause mortality, with 20 deaths (5.9%) in the 1:1:1 group vs. 38 deaths (11.1%) in the 1:1:2 group (p = 0.02) with the increased mortality predominantly due to exsanguination deaths.

Interestingly, a secondary analysis [43] of the PROPPR trial documented that there was no significant difference in ARDS rates (14.8% vs. 18.4%), ventilator-free (24 vs. 24) or ICU-free days (17.5 vs. 18), hospital length of stay (22 vs. 18 days), or 30-day mortality (28% vs. 28%). Risk factors for ARDS included blunt injury (OR 3.61 [1.53–8.81] p < 0.01) and increasing chest AIS (OR 1.40 [1.15–1.71] p < 0.01). Each 500 mL of crystalloid infused during hours 0–6 was associated with a 9% increase in the rate of ARDS (OR 1.09 [1.04–1.14] p < 0.01). Blood given at 0–6 or 7–24 h were not risk factors for ARDS. The authors concluded that acute crystalloid exposure, but not blood components, is a potentially modifiable risk fac-tor for the prevention of ARDS following hemorrhage.

Guidelines for Damage Control Resuscitation and Massive Transfusion

Trauma-related deaths due to hemorrhage occur early, with median time to hemor-rhagic death 2–2.6 h in four prospective resuscitation trauma studies [44]. Based on these data and outcome studies comparing transfusion ratios, multiple national and international guidelines for damage control resuscitation have been developed (Table 6.3).

The Joint Trauma System Clinical Practice Guidelines on Damage Control Resuscitation were the first DCR guidelines developed and implemented in combat casualty care in 2004 and recommended hemostatic resuscitation with blood com-ponents for the early treatment of hemorrhage in trauma [45]. DCR is limited to keep blood pressure at approximately 90 mmHg, preventing renewed bleeding from recently clotted vessels. Plasma is used as a primary resuscitation fluid in at least a 1:1 or 1:2 ratio with PRBCs. Ongoing hemorrhage is treated with use of MT proto-col for blood component resuscitation. Crystalloid use is minimized.

The recent Eastern Association for the Surgery of Trauma Damage Control Resuscitation Guidelines [46] recommend the use of a MT/DCR protocol to target a high ratio of plasma and platelets to RBCs, best achieved by transfusing equal amounts of RBCs, plasma, and platelets during the early empiric phase of resuscita-tion. This guideline included 31 studies which met criteria for quantitative meta- analysis. This analysis confirmed that mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43–0.87, p = 0.006) and with a high ratio of plasma/RBC and platelet/RBC (relatively more plasma and platelets) vs. a low ratio (OR 0.60, 95% CI 0.46–0.77, p < 0.0001; OR 0.44, 95% CI 0.28–0.71, p = 0.0003). They concluded that DCR can significant improve outcomes in severely injured bleeding patients.


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The ACS TQIP Massive Transfusion in Trauma Guidelines also recommend a foundation ratio in acute trauma resuscitation: “transfuse in a ratio between 1:1 and 1:2 plasma:RBC; transfuse one single donor apheresis unit or random donor platelet pool for each 6 units RBCs” [47].

The National Institute for Health and Care Excellence (NICE) Guideline on Major Trauma: Assessment and Initial Management for the United Kingdom provides guidance on the assessment and management of major trauma, including resuscitation following major blood loss associated with trauma. It includes an important section on management of hemorrhage and management of shock, and the guidelines are similar to the ACS TQIP Guidelines.

Table 6.3 National and international damage control resuscitation (DCR) guidelines

Guideline Recommendations

Eastern Association for the Surgery of Trauma Damage Control Resuscitation Guideline

We recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of plasma and platelets to RBC. This is best achieved by transfusing equal amounts of RBC, plasma, and platelets during the early, empiric phase of resuscitationWe cannot recommend for or against the use of rVIIa based on the available evidenceWe conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients

Joint Trauma System Clinical Practice Guidelines on Damage Control Resuscitation

Hemostatic resuscitation with blood components for the early treatment of hemorrhage in trauma. DCR is limited to keep blood pressure at approximately 90 mmHg, preventing renewed bleeding from recently clotted vessels. Plasma is used as a primary resuscitation fluid in at least a 1:1 or 1:2 ratio with PRBCs. Ongoing hemorrhage is treated with use of MT protocol for blood component resuscitation. Crystalloid use is minimized

ACS TQIP Massive Transfusion in Trauma Guidelines

Recommend a “foundation ratio” in acute trauma resuscitation: Transfuse in a ratio between 1:1 and 1:2 plasma/RBC Transfuse one single donor apheresis unit or random donor

platelet pool for each 6 units RBCsMajor Trauma: Assessment and Initial Management Guideline.National Clinical Guideline Centre (UK). National Institute for Health and Care Excellence (NICE, UK): Clinical Guidelines. 2016 Feb

For patients with active bleeding, use a restrictive approach to volume resuscitation until definitive early control of bleeding has been achievedFor adults use a ratio of 1 unit plasma to 1 unit RBCs to replace fluid volumeIn hospital settings do not use crystalloids for patients with active bleedingFor patients with active bleeding, start with a fixed-ratio protocol for blood components, and change to a protocol guided by laboratory coagulation results at the earliest opportunityUse intravenous TXA as soon as possible in patients with major trauma and active or suspected active bleeding. Do not use intravenous TXA more than 3 h after injury in patients with major trauma unless there is evidence of hyperfibrinolysisHospital trusts should have specific major hemorrhage protocol

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Optimal dose, timing, and ratio of blood components in MT are still controver-sial with a recent systematic review (including 16 RCTs) concluding that “there is insufficient basis to recommend a 1:1:1 over a 1:1:2 ratio or standard care for adult patients with critical bleeding requiring massive transfusion” and additional high- quality studies are warranted [48].

Hypotensive or Delayed Resuscitation

The concept of delaying resuscitation or only resuscitating to a low to low-normal blood pressure (“hypotensive resuscitation”) in the actively hemorrhaging patient until definitive hemorrhage control is achieved has been advocated based on pre-clinical studies that documented that vigorous fluid resuscitation in uncontrolled hemorrhagic shock was associated with increased hemorrhage and mortality. Maintaining a low blood pressure goal with “hypotensive resuscitation” aims to reduce the amount of blood lost through the site of injury until definitive hemor-rhage control is achieved.

In a randomized prospective clinical trial of immediate versus delayed fluid resuscitation in patients (n = 598) with penetrating torso trauma who presented with a prehospital systolic blood pressure of ≤90 mmHg with an overall mortality rate of 34%, there was significantly increased mortality (38% vs. 30%, p = 0.04), length of stay, and postoperative complication rates in the immediate versus the delayed group [49]. In a single-center study that randomized patients (n = 110) presenting in hemorrhagic shock to one of two fluid resuscitation protocols (target systolic blood pressure >100 vs. 70 mmHg) titrated to this endpoint until definitive hemostasis was achieved, no difference in overall survival (92.7% in both groups) was identified. Although no mortality benefit was identified with hypotensive resuscitation in this study, it was noted that a number of study limitations were present: failure to achieve target systolic blood pressure in hypotensive group (mean systolic blood pressure 100 vs. 114 mmHg in control group), small sample size, mix of blunt (49%) and penetrating (51%) trauma patients, and lengthy time for duration of active hemor-rhage (2.97 ± 1.75 h vs. 2.57 ± 1.46 h, p = 0.20) [50].

Despite the limitations of these clinical studies, “hypotensive” resuscitation has become increasingly accepted in the prehospital and early resuscitation phase of trauma, prior to definitive hemorrhage control, since aggressive fluid resuscitation may increase bleeding [51].

Lethal Triad of Acidosis, Hypothermia, and Coagulopathy

Acidosis, hypothermia, and coagulopathy were identified more than 20 years ago as a deadly triad for patients presenting with exsanguinating hemorrhage. This led to fundamental changes in initial management of severely injured patients. Despite


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these major advances, hemorrhage remains a leading cause of early death in trauma patients. Uncontrolled hemorrhage in trauma leads to the lethal triad of acidosis, hypothermia, and coagulopathy. Most severely injured patients are coagulopathic at hospital admission, before resuscitation interventions. Failure to control and treat hemorrhage promptly in such patients resulted in a “bloody vicious cycle” (Fig. 6.1) of hemorrhage, resuscitation, hemodilution, and coagulopathy, leading to more hemorrhage [52–54].

Trauma-Induced Coagulopathy

Trauma-induced coagulopathy (TIC) exacerbates hemorrhage and is associated with worse outcomes including increased mortality. Trauma-induced coagulopathy is now known to be very complex, and there are many underlying mechanisms which ultimately result in an inability for the trauma patient to make a stable clot at a site of active hemorrhage (Fig. 6.2) [55]. It is currently thought that TIC is initi-ated by systemic hypoperfusion which results in increased protein C activation (resulting in systemic anticoagulation) and fibrinolytic activity resulting in coagu-lopathy and fibrinolysis. It has been documented that admission plasma thrombo-modulin and protein C levels are predictive of clinical outcomes following major trauma [56]. Additional studies have confirmed these findings, documenting that the

Injury

Pre-hospitalresuscitation

In-hospitalresuscitation

Hemostaticintervention

Post-resuscitation

Hyperfibrinolysis &hypocoagulable state

Acute TraumaticCoagulopathy

Resuscitation-AssociatedCoagulopathy

Consumption ofcoagulation factorsDilution

Acidosis

Hypothermia

Trauma-Induced Coagulopathy

Fig. 6.1 The bloody vicious cycle. The pathogenesis of the “bloody vicious cycle” following major torso trauma is multifactorial and manifests as a triad of refractory coagulopathy, progres-sive hypothermia, and persistent metabolic acidosis. (From Moore [52])

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combination of increased injury severity and increased hypoperfusion was signifi-cantly associated with increased activated protein C activity, prolonged PT and PTT, increased fibrinolysis, and depletion of factors I, II, V, VII, VIII, IX, and X [57–59].

Viscoelastic Testing for Massive Transfusion

Viscoelastic testing with thromboelastography (TEG) or rotational thromboelas-tometry (ROTEM) is helpful in the treatment of trauma-induced coagulopathy and detection of fibrinolysis after trauma [60]. Both hyperfibrinolysis and fibrinolysis shutdown are associated with increased mortality after trauma, and TEG/ROTEM testing can assist in determination of which patients might benefit from antifibrino-lytic therapy [61]. Many MT protocols include early TEG/ROTEM testing to guide transfusion therapy in bleeding patients, with repeat testing at select intervals to correct coagulopathy (Fig. 6.3). But a recent survey of Level I and II Trauma Centers reported that only 9% routinely used viscoelastic testing in their MT protocol [62].

TraumaTissue Injury

Inflammation

Genetic factors

Comorbidities

Hyperfibrinolysis &hypocoagulable state

Trauma-InducedCoagulopathy

Hypothermia

Acidosis

Dilution

Consumption ofcoagulation factors

Hemorrhage

Acute TraumaticCoagulopathy

Traumatic shockTissue hypoperfusion

Fig. 6.2 Mechanisms of trauma-induced coagulopathy (TIC). Mechanisms of trauma-induced coagulopathy (TIC) due to many different pathways, and modulated by baseline patient factors such as genetics and comorbidities. TIC is a separate entity from iatrogenic causes of coagulopathy including hemodilution and preinjury anticoagulant therapy. (From Chang et al. [55])


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Goal-directed hemostatic resuscitation of trauma-induced coagulopathy was tested in a pragmatic single-center randomized clinical trial comparing TEG to MTP guided by conventional coagulation assays (n = 111). TEG-guided resuscita-tion was associated with increased 28-day survival (36.4% vs. 19.6%, p = 0.032) and decreased early (6-h) deaths (7.1% vs. 21.8%) and decreased plasma/platelet units in the first 2 h of resuscitation. But limitations of this trial include small sam-ple size and low fragility index [63]. Additional trials are clearly warranted.

Fibrinolysis in Trauma

Fibrinolysis is a physiologic process that maintains microvascular patency by break-ing down excessive fibrin clot. Trauma patients with severe hemorrhage may have early hyperfibrinolysis in addition to coagulopathy (both dilutional and consump-tive) [64–66]. Hyperfibrinolysis is closely associated with lethal hemorrhagic shock and is independent of injury severity. Both hyperfibrinolysis and fibrinolysis shut-down (an acute impairment of fibrinolysis) are associated with increased mortality after trauma. Hyperfibrinolysis is associated with a doubling of mortality in some trauma studies.

A recent study examined the incidence and outcomes of fibrinolysis phenotypes in two urban trauma centers. Adult trauma patients (n = 2540) with injury severity

SCGH ROTEM Algorithm for Critical Bleeding

Key Points: This algorithm is for use in patients with CRITICAL BLEEDING only. Only treat abnormal values if active bleeding or at high risk of bleeding.Repeat ROTEM analysis 10 mins after intervention to assess response.

ABNORMALROTEM

FIB

RIN

OLY

SIS

FIB

RIN

OG

EN

PL

AT

EL

ET

SFA

CTO

RS

CRITERIA

Early DiagnosisEXTEM A5≤35mm

or FIBTEM CT >600s

High likelihood ofexcess fibrinolysis

Tranexamic acid 1gConsider repeat dose if has lost

over 1 blood volumesince initial dose

(If no contra-indications)Excess fibrinolysis

Low fibrinogen Cryoprecipitate(see dosing guide)

Platelets: 1 adult dose(correlate with platelet count)

Platelets and fibrinogen(correlate with platelet count)

Correct fibrinogenand reassess

FFP 1-4U or(+ Fibrinogen if indicated)

Low platelets

Low plateletsand Low fibrinogen

Low fibrinogen

Low coagulation factors

Low fibrinogen andLow coagulation factors

Late DiagnosisEXTEM or FIBTEM ML ≥5%

FIBTEM A5 ≤10mm

EXTEM A5 ≤35mmand

FIBTEM A5>10mm

EXTEM A5 ≤25mmand

FIBTEM A5≤10mm

EXTEM CT 80-140s andFIBTEM A5≤10mm

EXTEM CT >80s butFIBTEM A5>10mm

EXTEM CT >140s butFIBTEM A5≤10mm

Fibrinogen Dosing GuideFIBTEM A5 Target: ≥12mm

FIBTEM A5 Cryoprecipitate*

9-10mm7-8mm

4-6mm

<4mm

2-3mm4-5mm

6-8mm

≥9mm

10 Units

*Cryoprecipitate dosing is for standard adult units(Cryo 5 units - Fibtem A5 increase of approx 2mm)

15 Units

20 Units

20-25 Units

Increase required Cryoprecipitate*

DIAGNOSIS INTERVENTION CORRECTEDROTEM

Fig. 6.3 Viscoelastic testing by rotational thromboelastometry (ROTEM) for treatment of trauma- induced coagulopathy. (From http://scghed.com/wp-content/uploads/2017/05/Massive-Transfusion-Protocol-2017.pdf)

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score (ISS) > 15 had admission fibrinolysis phenotypes determined by TEG clot lysis at 30 min (LY30). Fibrinolysis shutdown was defined as LY30 ≤ 0.8%, physi-ologic fibrinolysis as LY30 of 0.9–2.9%, and hyperfibrinolysis as LY30 ≥ 3%. Median ISS was 25 with a mortality rate of 21%. Fibrinolysis shutdown was the most common phenotype (46%) followed by physiologic (36%) and hyperfibrinoly-sis (18%). Hyperfibrinolysis was associated with the highest death rate (34%), fol-lowed by shutdown (22%), and physiologic (14%, p < 0.001). Significantly higher mortality risk was associated with hyperfibrinolysis (OR 3.3, 95% CI 2.4–4.6, p < 0.0001) and fibrinolysis shutdown (OR 1.6, 95% CI 1.3–2.1, p = 0.0003) com-pared with physiologic after adjusting for age, ISS, mechanism, head injury, and blood pressure (Fig. 6.4). This important study confirmed evidence of distinct phe-notypes of coagulation impairment and that individualized hemostatic and coagula-tion therapy may be required in trauma resuscitation. Furthermore, persistent fibrinolysis shutdown at 1 week post-injury has also been associated with increased late mortality in severely injured patients [67].

Tranexamic Acid (TXA) in Trauma

CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2) was a large randomized clinical trial that examined the efficacy of in-hospital TXA in trauma. This study confirmed that all-cause mortality was reduced from 16.0% to 14.5% (1.5% absolute reduction, RR 0.91, 95% CI 0.91 (0.85–0.97), p = 0.0035, NNT 67) and risk of death caused by bleeding was reduced from 5.7% to 4.9% (0.8% reduction, NNT 121) [68]. Early (given ≤1 h after injury) TXA treat-ment was more protective for bleeding deaths than when given 1–3 h after injury. In contrast, TXA given after 3 h was associated with increased risk of death.

We have previously reviewed the significant limitations of the CRASH-2 trial and the difficulty in translating the international study results performed in many non-trauma centers to large established civilian trauma centers and trauma systems of care [69]. In the CRASH 2 subgroup analysis, the most significant mortality benefit for TXA was in the severe shock cohort (with admission systolic blood pres-sure ≤75 mmHg) with 28-day all-cause mortality of 30.6% for TXA vs. 35.1% for placebo (RR 0.87, 99% CI 0.76–0.99).

We recommended that a rational approach for TXA use in civilian trauma centers for adult trauma patients was in adult trauma patients with:

• Severe hemorrhagic shock (admission systolic blood pressure ≤75 mmHg).• Known predictors of fibrinolysis.• Known fibrinolysis by TEG (LY30 > 3%) or ROTEM.• Only administer TXA if less than 3 h from time of injury.• Use TXA study dose: TXA 1 g IV over 10 min, then 1 g IV over 8 h.

Studies from three large urban civilian trauma centers examined the impact of implementation of a protocol for in-hospital TXA administration on trauma outcomes.


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1.00

Shutdown0

5

10

15

20% P

atie

nts

25

30

35

40

45

50Mortality

Incidence

Physiologic Hyperfibrinolysis

0.80

0.60

0.40

Per

cent

of g

roup

mor

talit

y

0.20

0.00Shutdown Physiologic Hyper

Mortality fromHemorrhagegreatest in thetrauma patientswithhyperfibrinolysis

BrainOtherHemorrhageOrgan failure

Fig. 6.4 Incidence and mortality of severely injured trauma patients stratified by fibrinolysis phenotype. Data from two urban trauma centers (Denver and UT Houston), n = 2540, adult trauma patients, median age 39 years, median ISS 25, mortality 21%. TEG performed in 1 h of trauma admission. (From Moore et al. [61])

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Two studies [70, 71] found no impact on outcome, and one study [72] reported improved survival in severe shock patients. Most recently, a retrospective multicenter study of six Level 1 trauma centers in Paris, France, reported that there was no effect of TXA use in the whole population but mortality was lowered by the use of TXA in patients requiring RBC transfusion in the emergency department (HR = 0.3, CI 95 = 0.3–0.6). They concluded that the use of TXA in the management of severely injured trauma patients, in a mature trauma care system, was not associated with reduc-tion in the hospital mortality. An independent association with a better survival was found in a selected population of patients requiring pRBC transfusion in the ER [73].

The recent Eastern Association for the Surgery of Trauma Damage Control Resuscitation guidelines [46] conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients. In a recent survey of Level I and Level II trauma centers, tranexamic acid was part of the MT protocols at 64% of centers [62]. A number of clinical trials are ongoing to further investigate the efficacy of TXA in trauma (Table 6.4), including the potential use of TXA in the prehospital setting [74].

DCR Implementation Using Massive Transfusion Protocols

The implementation of DCR in most trauma centers is done via the use of massive transfusion (MT) protocols. MT protocols should be established with standardized policies to facilitate DCR in trauma patients with hemorrhage and to reduce compli-cations related to transfusion therapy.

Table 6.4 Tranexamic acid (TXA) clinical trials in trauma

Study Dose Indication

CRASH-2 1 g bolus followed by a 1 g infusion over 8 h

Adult trauma patients with significant hemorrhage (SBP <90 mmHg or heart rate >110 bpm, or both), or considered at risk of significant hemorrhage, and within 8 h of injury

MATTERs 1 g bolus repeated at discretion of treating surgeon

Patients who received at least 1 unit of PRBCs within 24 h of admission following combat related injury

TAMPITI *Ongoing trial: one time bolus of 2 or 4 g

Adult trauma patients ordered to receive at least 1 blood component and/or immediate transfer to operating room to control bleeding and within 2 h of injury

STAAMP *Ongoing trial: one time bolus of 1 g prehospital dose

Adult trauma patients being transported via air medical services from scene or referring hospital, with SBP <90 mmHg or heart rate >110 bpm, and within 2 h of injury

PATCH *Ongoing trial: 1 g prehospital bolus followed by 1 g in-hospital infusion over 8 h

Adult trauma patients being transported to a trauma center with a coagulopathy of severe trauma (COAST) score of 3 or greater and within 3 h of injury


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The standard goal of MT therapy in past years was to supply isotonic crystalloids and plasma-poor RBC concentrates to maintain normovolemia and tissue oxygen supply. This, however, frequently led to dilutional coagulopathy, which was acceler-ated by hypothermia, acidosis, shock-induced impairment of hepatic function, DIC due to tissue injury, and increased consumption of clotting factors and platelets at extensive wound sites in injured patients.

We now recognize that patients who have sustained severe hemorrhage and require MT commonly have an early trauma-induced coagulopathy that is present on admission and worsens with crystalloid and RBC transfusions alone due to dilu-tional and consumptive coagulopathy. Therefore, the key aim of modern MT proto-cols is the timely administration of plasma and platelet concentrates as required to replace acute blood loss and treat impaired hemostasis.

Massive Transfusion Protocols

Massive transfusion (MT) protocols have long been in place at major trauma centers for the treatment of patients with severe hemorrhagic shock. In the past, MT proto-cols provided RBCs but still required the clinician to issue specific requests for other blood component therapy (plasma, platelets, cryoprecipitate). It was previ-ously recommended that transfusion of additional blood components wait until standard laboratory evidence of dilutional and consumptive coagulopathy and thrombocytopenia were present. Viscoelastic testing was not used.

Recent studies report most severely injured patients to be coagulopathic at admission, before resuscitation interventions, and that traditional MT practices grossly underestimate what is needed to correct the coagulopathy. In the current era, MT protocols now focus on the prevention of coagulopathy and thrombocytopenia (Fig. 6.5). A high plasma to RBC ratio (a 1:1:1 ratio, equal parts PRBCs, FFP, and platelets) for early initial blood component therapy is now recommended for MT based on a more physiologic regimen similar to whole blood transfusion. This DCR approach focuses on the early correction of coagulopathy and avoidance of dilu-tional coagulopathy, which has been associated with improved survival. MT proto-cols have now been revised to include other blood component therapy in addition to RBC units and have been associated with improved outcomes in trauma.

A recent American Association for the Surgery of Trauma survey on massive transfusion practices among United States trauma centers (191 surgeons, 125 institutions, 70% Level I and 18% Level II trauma centers) documented that almost all (123) institutions had a MT protocol [62].

Interestingly, 54% reported having an MT protocol for less than 5 years. There was significant variability in the recommended blood component therapy. Only 9% routinely used viscoelastic testing in their MT protocol, and only 7% used a vali-dated scoring system to guide MT protocol activation. The authors concluded that the lack of consistent practices in MT protocols underscores the need for outcome- based studies to guide transfusion practices in trauma.

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Transfusion After Hemorrhage Control

Once the definitive hemorrhage control has been established, a restrictive approach to blood transfusion should be implemented. Guidelines for transfusion in the trauma patient have been established as a standard operating procedure to guide RBC transfusion therapy for critically ill patients after the immediate resuscitation phase and to minimize the adverse consequences of potentially unnecessary transfu-sions. This guideline considers that the acute hemorrhage has been controlled, the initial resuscitation has been completed, and the patient is stable in the ICU with no evidence of ongoing bleeding and recommends a hemoglobin threshold of <7 g/dL for PRBC transfusion [75].

The Transfusion Requirements in Critical Care (TRICC) trial confirmed that ICU patient 30-day mortality was not different in patients randomized to a restric-tive (transfuse if hemoglobin <7 g/dL) or liberal (transfuse if hemoglobin <10 g/dL) transfusion strategy [76]. Guidelines for RBC transfusion in ICU patients recom-mend transfusion when hemoglobin <7 g/dL in most ICU patients. In ICU patients with acute cardiac ischemia, the recommendation is to transfuse RBCs if hemoglo-bin <8 g/dL. [77, 78] These evidence-based guidelines also recommend the following:

Appropriate Initial Interventions:Intravenous access - 2 large bore IVs and Central Venous Cath

University of Michigan 7/5/16 Rev 7

Identify and Manage Bleeding

(Surgery, Angiographic Embolization, Endoscopy)

Adult: 4U RBCs in<4 hours and ongoing bleeding

Clinical Team Activates MTP & Designates Clinical Contact

Clinical Contact phones Blood Bank (BB) at 936-6888 and:

50 KGMassive Transfusion Protocol (MTP) - ADULT

Labs: T&S, CBC, Pits, INR, PT, PTT, Fibrinogen, Electrolytes,BUN/Creatinine, ionized calcium, ROTEM

Continual monitoring: VS, U/O, Acid-base status

Aggressive re-warming

Prevent/Reverse acidosisCorrect hypocalcemia: CaGluconate or CaCI

Target goal ionized calcium 1.2 - 1.3

If use CaCl 1 gm, give slowly IVRepeat lab testing to evaluate coagulopathy

Stop crystalloid - avoid dilutional coagulopathy

Other considerations:

Anticipate hypocalcemia and infuse 1g calcium gluconate per1-2 units PRBC’s transfused

Cell salvage: Anes Tech via front desk 93-64270 (Main & CVCOR)Heparin reversal: Protamine 1mg IV/100 U heparin

Warfarin reversal: Vitamin K10 mg IV; Consider Prothromin Comp4 Factor PCC Kcentra INR 2-4 25units/kg, INR>4-6, 35 units/kg, INR>6,

50 units/kg; repeat doing not recommendedChronic Ranal Failure + VW Factor, DDAVP 0.3 µg/kg IV x 1dose

Consider antifibrinolytics:Tranexamic acid 1 gm bolus plus infusion 1 gm over 8 hrsAmicar 5 gm IV bolus then 1 gm/hr IV infusion

Additional helpAnesthesia: Page 8003; Trauma Chief (via web or operator)

Rapid Response Team pager 90911 or call stat page 141

General Guidelines for Lab-based Blood ComponentReplacement in Adults:

Product

RBCs N/A MD discretion

FFP INR > 1.5 4 units FFP

YES

No

CBC, Platelets

Clinical Contact calls BB at 6-6888for another MTP pack

**MD can adjust pack based onlabs PRN

BB Prepares MTP PackMTP Pack: 5U RBCs; 5U FFP; One 5-pack Platelets or one apheresis platelet

This will result is an approximate 1:1:1 ratio

Provides name of clinical contact person to Blood Band (BB)

Provides MR#, sex, name, location of patient

Records name of BB contact, calls if location/contact information changes

Sends person with to pick up the coolerpatient name and MRN

Ensures that MTP protocol electronic order is entered in CareLink

INR/PT, PTTFibrinogenABG (lonizedCalcium,Potassium,Lactate,Hematocrit)

WITH Orange Card

Hemostasis &resolution of

coagulopathy?

Stop MTP

Repeat Labs

Notify BB & return any unusedblood ASAP

Resume standard ordersD/C MTP Electronic order

Platelets < 100,000 One 5-pack Plts

Cryoprecipitate Fibrinogen < 100 Two 5-packs Cryo

Consider for DoseIf persistent coagulopathy

consider:

4 Factor PCC: Kcentra INR 2-425units/kg, INR>4-6, 35units/kg,INR>6, 50 units/kg; repeat doing notrecommended

rFVlla: 90 m/kg dose

Fig. 6.5 University of Michigan massive transfusion and DCR protocol


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1. RBC transfusion is indicated for patients with evidence of hemorrhagic shock. 2. A “restrictive” strategy of RBC transfusion (transfuse when Hb < 7 g/dL) is as

effective as a “liberal” transfusion strategy (transfusion when Hb < 10 g/dL) in critically ill patients with hemodynamically stable anemia, except possibly in patients with acute myocardial ischemia.

3. The use of only Hb concentration as a “threshold” for transfusion should be avoided. Decision for RBC transfusion should be based on individual patient’s intravascular volume status, evidence of shock, duration and extent of anemia, and cardiopulmonary physiologic parameters.

4. In the absence of acute hemorrhage, RBC transfusion should be given as single units.

5. RBC transfusion should not be considered as an absolute method to improve tis-sue oxygen consumption in critically ill patients.

Based on all current data and guidelines, a simple algorithm for RBC transfusion is evident [79]. The 2016 Clinical Practice Guidelines from the American Association of Blood Banks (AABB) on RBC Transfusion Thresholds and Storage [80] recom-mend “It is good practice to consider the hemoglobin level, the overall clinical con-text, patient preferences, and alternative therapies when making transfusion decisions regarding an individual patient.” Two evidence-based recommendations were made, recommending a transfusion threshold of 7 g/dL in most patients:

• Recommendation 1: A restrictive RBC transfusion threshold in which the trans-fusion is not indicated until the hemoglobin level is 7 g/dL is recommended for hospitalized adult patients who are hemodynamically stable, including critically ill patients, rather than when the hemoglobin level is 10 g/dL (strong recommen-dation, moderate-quality evidence). A restrictive RBC transfusion threshold of 8 g/dL is recommended for patients undergoing orthopedic surgery, cardiac sur-gery, and those with preexisting cardiovascular disease (strong recommendation, moderate-quality evidence). The restrictive transfusion threshold of 7 g/dL is likely comparable with 8 g/dL, but RCT evidence is not available for all patient categories. These recommendations do not apply to patients with acute coronary syndrome, severe thrombocytopenia (patients treated for hematological or oncological reasons who are at risk of bleeding), and chronic transfusion–depen-dent anemia (not recommended due to insufficient evidence).

• Recommendation 2: Patients, including neonates, should receive RBC units selected at any point within their licensed dating period (standard issue) rather than limiting patients to transfusion of only fresh (storage length: <10 days) RBC units (strong recommendation, moderate-quality evidence).

Summary

Trauma patients with severe hemorrhage and hemorrhagic shock are at high risk of death, with high mortality rates (25–40%). New advances in trauma resuscitation advocate early treatment of the bleeding patient with prompt definitive hemorrhage

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control, hypotensive resuscitation, and damage control resuscitation with blood components (RBCs, plasma, platelets, cryoprecipitate) and massive transfusion pro-tocols to achieve improved survival. Trauma-induced coagulopathy is complex, and hypoperfusion and severity of traumatic injury induce activation of protein C and fibrinolysis, resulting in increased hemorrhage and inadequate clot formation, resulting in challenges with hemorrhage control. Altered fibrinolysis (hyperfibri-nolysis or fibrinolysis shutdown) early after injury is associated with increased mor-tality. Viscoelastic testing is helpful in guiding hemostatic resuscitation for the bleeding trauma patient. Tranexamic acid may improve survival in trauma patients with severe hemorrhagic shock if administered early (within 3 h) after injury. Once definitive hemorrhage control is achieved, all efforts to minimize the use of RBC transfusion are warranted.

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62. Etchill E, Sperry J, Zuckerbraun B, Alarcon L, Brown J, Schuster K, Kaplan L, Piper G, Peitzman A, Neal MD. The confusion continues: results from an American Association for the Surgery of Trauma survey on massive transfusion practices among United States trauma centers. Transfusion. 2016 Oct;56(10):2478–86.

63. Gonzalez E, Moore EE, Moore HB, Chapman MP, Chin TL, Ghasabyan A, Wohlauer MV, Barnett CC, Bensard DD, Biffl WL, Burlew CC, Johnson JL, Pieracci FM, Jurkovich GJ, Banerjee A, Silliman CC, Sauaia A. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conven-tional coagulation assays. Ann Surg. 2016 Jun;263(6):1051–9.

64. Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64(5):1211–7. discussion 1217

65. Frith D, Goslings JC, Gaarder C, et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost. 2010;8(9):1919–25.

66. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65:748–54.

67. Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrino-lysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg. 2017 Apr;224(4):575–82.

68. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, et al. CRASH-2 trial collabo-rators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32.

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70. Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, Livingstone AS, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76:1373–8.

71. Harvin JA, Peirce CA, Mims MM, Hudson JA, Podbielski JM, Wade CE, et al. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015;78:905–9. discussion 909–11

72. Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg. 2015;261:390–4.

73. Boutonnet M, Abback P, Le Saché F, Harrois A, Follin A, Imbert N, Cap AP, Trichereau J, Ausset S, The Traumabase Group. Tranexamic acid in severe trauma patients managed in a mature trauma care system. J Trauma Acute Care Surg. 2018 Jun;84(6S Suppl 1):S54–62. https://doi.org/10.1097/TA.0000000000001880.

74. Napolitano LM. Prehospital tranexamic acid: what is the current evidence? Trauma Surg Acute Care Open. 2017;2:1–7. https://doi.org/10.1136/tsaco-2016-000056.

75. West MA, Shapiro MB, Nathens AB, et al. Guidelines for transfusion in the trauma patient. Inflammation and host response to injury, a large-scale collaborative project: patient-oriented research core––standard operating procedures for clinical care. J Trauma. 2006;61:436–9.

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77. Napolitano LM, Kurek S, Luchette FA, American College of Critical Care Medicine of the Society of Critical Care Medicine; Eastern Association for the Surgery of Trauma Practice Management Workgroup, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124–57. Erratum in: Crit Care Med. 2010;38(7):1621

78. Napolitano LM, Kurek S, Luchette FA, EAST Practice Management Workgroup; American College of Critical Care Medicine (ACCM) Taskforce of the Society of Critical Care Medicine (SCCM), et al. Clinical practice guideline: red blood cell transfusion in adult trauma and criti-cal care. J Trauma. 2009;67(6):1439–42.

79. Napolitano LM. Anemia and red blood cell transfusion: advances in critical care. Crit Care Clin. 2017 Apr;33(2):345–64.

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Chapter 7Hematologic Issues in Sepsis

Tulin Budak-Alpdogan, Jeffrey Levine, and Phil Dellinger

Thrombocytopenia

Sepsis accounts for 10–20% of ICU admissions [1–4], and the incidence of throm-bocytopenia in sepsis ranges between 43.2% and 70.6% [5–7]. Though thrombocy-topenia is a common laboratory finding for critically ill patients and indicates poor prognosis [8–16], there are still many unresolved controversies regarding the man-agement of thrombocytopenia in critically ill patients.

The Incidence and Outcome of Thrombocytopenia in ICU

At the time of ICU admission, approximately 50% of patients, ranging between 8.3% and 67.6%, have thrombocytopenia, while 14–44% of patients develop throm-bocytopenia during their ICU stay [16, 17]. The cutoff values chosen for thrombo-cytopenia, differences in patient populations, and ICU characteristics are considered to account for the large variation between series.

From the clinical perspective, in most cases the development of thrombocytope-nia in the ICU indicates serious organ system derangement and physiologic decom-pensation rather than a primary hematologic disorder. Multivariate analysis identified risk factors associated with ICU-acquired thrombocytopenia as severity

T. Budak-Alpdogan (*) · J. Levine Division of Hematology and Oncology, Department of Medicine, Cooper University Hospital, Camden, NJ, USAe-mail: [email protected]

P. Dellinger Department of Medicine, Cooper University Hospital, Camden, NJ, USA



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of illness, organ dysfunction, sepsis, vasopressor use, and renal failure [16–18]. The presence of thrombocytopenia and its severity, especially severe thrombocytopenia with platelet counts below 50 × 109/L, are associated with bleeding, increased risk of transfusion (red cells, platelets, plasma, or cryoprecipitate) [17, 19], and adverse clinical outcomes including death, though few deaths are directly attributable to bleeding [17–21]. Multivariate analysis of six observational studies found thrombo-cytopenia to be an independent predictor of mortality [17]. In the PROTECT trial, both moderate and severe thrombocytopenias were associated with increased ICU and hospital length of stay as well as the need for organ support [19].

The recovery rate of thrombocytopenia further predicts outcome; a blunted plate-let count recovery is associated with increased mortality risk [22], while rapid recovery suggests survival [13]. A large prospective study has shown that the plate-let counts in sepsis drop rapidly after ICU admission and usually reach their nadir on day 4 [21]. By day 7 the platelet count recovers to the admission value and by day 9 exceeds the admission value [21]. Non-survivors were much more likely to not experience platelet recovery [8, 21]. These observations suggest that if the plate-let count decreases after partial recovery in a patient admitted for sepsis, the wors-ening thrombocytopenia should not be blamed on the initial infection. Instead, alternative causes such as HIT, drug-induced thrombocytopenia, dilution, or a sec-ondary infection should be sought [6, 20, 21, 23, 24].

Thrombopoiesis and Mechanisms of Thrombocytopenia in Sepsis

Peripheral blood platelet counts are tightly controlled by interactions regulating platelet production from the bone marrow, pooling in the liver and spleen, and elim-ination in the reticuloendothelial system [25, 26]. Normal platelet count in humans ranges from 150 to 400 × 109/L, and platelets have a circulating life span of approxi-mately 10 days. About one-third of platelets are sequestered in the spleen at any time. To maintain a normal platelet count, approximately 100 × 109 platelets are released from mature megakaryocytes into circulation each day [25]. Several mech-anisms that contribute to thrombocytopenia including hemodilution, platelet con-sumption, decreased platelet production, increased sequestration of platelets, immune-mediated destruction, and pseudo-thrombocytopenia [16, 20, 23] are sum-marized in Table 7.1. In the ICU setting, often more than one mechanism is respon-sible for low platelet counts.

Causes of thrombocytopenia in the septic patient are often multifactorial includ-ing consumption, immune-mediated thrombocytopenia, and suppression of platelet production. Additionally, critical care patients frequently have many comorbid ill-nesses that decrease platelet counts through platelet sequestration or drug-induced

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Table 7.1 Mechanisms of thrombocytopenia in the ICU

Mechanisms Differential diagnosis

Decreased production Preexisting bone marrow disease; aplastic anemia, leukemia, myelodysplastic syndrome, solid tumor infiltrationIntoxication; alcohol and other drugsViral infections; HIV, CMV, EBV, HCVRadiationCytotoxic chemotherapy

Platelet sequestration Splenic sequestration, i.e., liver disease, cirrhosis, portal hypertensionAcute sequestration crisis; HbSS in infants and HbSC including adultsDisorders with hepatosplenomegaly; osteomyelofibrosis, lymphoid/leukemia with organomegaly, storage disorders

Platelet consumption Blood lossMassive blunt traumaDisseminated intravascular coagulation (DIC), i.e., shock, infection, sepsis obstetrical complicationsSepsisExtracorporeal circuit, i.e., extracorporeal membrane oxygenation (ECMO)

Platelet destruction Immune thrombocytopenia; primary or secondary to systemic lupus erythematosus, hepatitis, or chronic lymphocytic leukemiaDrug-induced thrombocytopenia; new drug within 7–14 days, improves with drug cessation, possible to detect drug-dependent antibodiesHeparin-induced thrombocytopenia; 50% platelet count decrease between days 5 and 10 of heparin treatment, platelet nadir between 20 and 80 × 109/L, thromboembolic events, positive heparin- dependent platelet-activating anti-PF4 antibodiesThrombotic microangiopathies; thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), hemolysis/elevated liver enzymes/low platelets (HELLP) syndrome; coombs- negative hemolysis, fragmented red blood cells, platelets between 10 and 40 × 109/L, elevated lactate dehydrogenase, neurological and/or renal symptomsPosttransfusion purpura; platelet count nadir below 10 × 109/L, 5–12 days after transfusion, and bleeding risk high titer anti-HPA-1a antibodiesAlloimmunization; in transfusion-dependent patients, anti-HLA antibodies, refractory to transfusion, requires HLA-matched transfusionPassive alloimmune thrombocytopenia; thrombocytopenia after plasma containing transfusions, transient platelet count decrease due to passive transfer of anti-HLA-antibodies

Pseudothrombocytopenia In vitro platelet aggregation in EDTA, peripheral smear with platelet clumpsPreceding therapy with GPIIb/IIA receptor antagonists

Hemodilution Massive fluid infusion or transfusion due to bleeding

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thrombocytopenia including the HIT syndrome. Of these mechanisms, consumptive coagulopathy is probably the most significant cause of thrombocytopenia in the septic patient.

Suppression of platelet production is frequently cited as a cause of thrombocyto-penia in septic patients; however inflammatory cytokines are known to blunt erythropoiesis but also usually stimulate thrombopoiesis. In a small series, bone marrow aspirates of septic patients revealed normal numbers of megakaryocytes [27]. Circulating levels of thrombopoietin are often elevated in sepsis [28], and numbers of reticulated platelets have been shown to be increased in septic neonates with thrombocytopenia. Therefore, the data so far is not convincing for direct mega-karyopoiesis inhibition. Relative insufficiency due to increased consumption is more plausible [7, 29].

Increasingly platelets are recognized to have a role as immune effectors in addi-tion to their well-known role in hemostasis [30], and thrombocytopenia has been associated with a dysregulated host immune response in sepsis patients [31].

In the normal physiologic state, coagulation is finely regulated between proco-agulant and anticoagulant pathways. Sepsis results in dysregulation of these two pathways, overwhelming activation of the procoagulant pathway, suppression of the anticoagulant pathway, and widespread fibrin deposition throughout the microvas-culature resulting in further organ dysfunction [32–34]. Paradoxically, this proco-agulant state can also increase bleeding risk as procoagulant factors, fibrinogen, and platelets are consumed [34]. Disseminated intravascular coagulation (DIC) is a final common syndrome, which, in sepsis, is caused by a heterogeneous group of infectious insults that result in microvascular thrombin deposition in numerous organs and multiple organ dysfunction. Even in the absence of overt DIC, coagula-tion activation markers, i.e., thrombin-antithrombin complexes and prothrombin fragment 1.2, are increased in sepsis. Though there has been enough evidence that sepsis-induced endothelial damage activates procoagulant pathways, clinical trials that evaluated treatment with anticoagulant factors, i.e., tissue factor pathway inhib-itor, antithrombin, and activated protein C, had negative or mixed results [34–37].

Hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syn-drome has been increasingly reported in patients with thrombocytopenia and sepsis [38]. Treatment options for this diagnosis include dexamethasone, cyclosporine, and etoposide.

In animal studies, during cellular injury in sepsis, extracellular histones are released, and histones induce platelet aggregation causing a drop in platelet counts [39]. Clinical studies have shown correlation between histone plasma levels and thrombocytopenia [40], but the validity of this correlation in the clinical setting requires further evaluation.

Although not as severe as TTP [41], ADAMTS 13 levels are shown to be reduced in sepsis patients and may contribute to ongoing microcirculation insufficiency, thrombosis, and organ failure.

Immune complex and bacterial wall exposure activate complement pathways during sepsis. Complements bind and activate platelets therefore contributing to platelet consumption [20].


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Evaluation of Thrombocytopenia in Shock and Sepsis

Evaluation of thrombocytopenia in critically ill septic patient requires a stepwise approach. Prior medical history, comorbidities, detailed drug or toxin exposure his-tory, and prior blood count results provide invaluable information. Prior blood count results can reveal preceding bone marrow disorders such as myelodysplasia, chronic ITP, and lymphoproliferative disorders. The course of disease presentation, i.e., acute onset, gradual decline, and acute decompensation, over known chronic medi-cal problems should be taken into account for management planning.

The course of thrombocytopenia during the hospital stay also defines treatment and management.

Patients that experience rapid platelet count decreases in a few days and then rapidly recover after improvement of critical illness usually have acute multisystem inflammatory process, i.e., burns, pancreatitis, or sepsis. In sepsis, platelet count nadir happens within 2 days of presentation, and median recovery takes about 6 days. Median time from vasopressor discontinuation to platelet count recovery above 100 × 109/L is approximately 2 days.

On the other hand, major trauma, surgery, massive transfusion, or cardiopulmo-nary bypass usually induces rapid, immediate platelet count decrease, and if the process is not complicated, patients experience rapid recovery of their platelet counts. Platelet counts start to increase 3–4 days after surgery and should continue to improve over the next 1–2 weeks. As thrombopoietic factors, i.e., thrombopoi-etin, IL-6, and acute-phase cytokines, are released, patients can have platelet counts above their baseline through recovery [8, 14, 21, 23, 24, 42].

Patients who experience low platelet counts at presentation and throughout the duration of the ICU stay should be considered to have an underlying bone marrow process or hypersplenism, and as such, thrombocytopenia evaluation should include imaging studies as well as bone marrow aspiration and biopsy.

The incidence of chemotherapy-induced thrombocytopenia varies greatly depending on the treatment used; the highest rates of this condition are associ-ated with gemcitabine- and platinum-based regimens [43]. Thrombocytopenia due to cytotoxic chemotherapy usually occurs between 1 and 2 weeks after treat-ment and then recovers rapidly [44]. Chemotherapeutic agents such as gem-citabine can induce thrombotic thrombocytopenic purpura or hemolytic uremic syndrome [45, 46].

Patients, who develop gradually worsening thrombocytopenia throughout their ICU stay, occasionally as their clinical course is improving, should be evaluated for iatrogenic thrombocytopenia, i.e., drug-related immune thrombocytopenia, heparin- induced thrombocytopenia, or posttransfusion purpura. In these cases, early recog-nition and testing for etiology provide definitive treatment options, i.e., removal of the offending drug, intravenous immunoglobulin, and change in anticoagulation.

Patients who develop thrombocytopenia rapidly within a few days of ICU admis-sion and continue to have moderate-to-severe thrombocytopenia with persistent multiorgan failure have the worst prognosis. These patients traditionally have


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persistent thrombocytopenia as an indicator of the severity of the underlying disease such as sepsis, DIC, or shock.

Severe thrombocytopenia, defined by a platelet count nadir below 20 × 109/L, has a limited differential diagnosis and most commonly suggests consumptive thrombo-cytopenia due to DIC, bone marrow failure or immune-mediated mechanisms.

Evaluation of the coagulation cascade aids in the diagnosis of consumptive thrombocytopenia due to DIC. High-fibrin degradation products and D-dimer, low fibrinogen, prolonged prothrombin time, and partial thromboplastin time would be noted depending on the severity of DIC.

Bone marrow failure syndromes either due to infiltration, myelosuppressive treatment, or hemophagocytosis also present with severe thrombocytopenia, and usually other hematopoietic elements are affected, i.e., neutropenia, anemia, and reticulocytopenia.

Shortened platelet survival due to immune-mediated mechanisms, such as auto-immune ITP or alloimmune disorders due to HLA antibodies, posttransfusion pur-pura, or drug related, usually cause prominent severe thrombocytopenia. HIT is the exception that usually does not cause severe thrombocytopenia.

Thrombosis in the setting of thrombocytopenia usually occurs due to DIC, HIT, or anti-phospholipid syndrome. In the setting of coagulation cascade activation, natural anticoagulants may deplete faster when patients have underlying liver dis-ease, or acute ischemic liver injury, which results in peripheral small vessel throm-bosis and gangrene despite adequate arterial flow [47].

Management of Thrombocytopenia in Shock and Sepsis

Most patients who are critically ill present with thrombocytopenia as a part of their underlying disease. Understanding the physiological changes associated with dis-ease can help to define the projected course of platelet recovery and timely investi-gation and treatment when platelet recovery does not follow the anticipated course.

The principal treatment of ICU-associated thrombocytopenia is to treat the underlying cause. Appropriate antimicrobial therapy, source control, and organ sup-port in patients with sepsis are the essential steps of treating thrombocytopenia [20, 21, 24, 48]. Hemostatic treatment by transfusion and coagulation support, i.e., cryo-precipitate, fresh frozen plasma, and platelets, should be considered for patients with bleeding symptoms. Available data is not clear for prophylactic transfusion in critically ill patients, unless the underlying mechanism for thrombocytopenia is due to major surgery or trauma. The American Association of Blood Banks and the Society of Critical Care 2016 Surviving Sepsis Guidelines recommend prophylactic platelet transfusion below a threshold of 10 × 109/L [48–50]. Unfortunately, these recommendations are extrapolated from randomized trials evaluating prophylactic platelet transfusion in adult patients who developed thrombocytopenia due to che-motherapy exposure. In the setting of critically ill patients, platelet consumption and platelet dysfunction also contribute to bleeding risk [6, 7, 34]. Platelet


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dysfunction is usually aggravated by factors including uremia, liver failure, anti-platelet agents, and extracorporeal circuits. Additionally, response to platelet trans-fusion in terms of the posttransfusion platelet increment and the durability of platelet increase are known to be altered in critically ill patients [51]. Although the results vary considerably across patients, one-unit platelet transfusion results in a median increase in the platelet count of 15 × 109/L [51]. Correction of thrombocytopenia should always be pursued when there is a significant risk of bleeding; however, major hemorrhage can occur at any platelet count as a consequence of multiple organ failure, and transfusion associated risks should always be considered. Platelet transfusions are associated with increased risk of nosocomial infection and transfu-sion associated lung injury [49, 52, 53].

Upregulation of tissue factor expression on monocytes, and other cells in response to inflammatory mediators, i.e., endotoxin, triggers coagulation cascade activation in sepsis and DIC. Inhibition of coagulation cascade with heparin might have a role in breaking the consumption circuit in DIC and might avoid further thrombocyte consumption. Randomized trials investigating the role of heparin in sepsis indicate some clinical outcome improvement [54]. Though this meta-analysis suggests decreased mortality in patients with sepsis, septic shock, and disseminated intravascular coagulation, the overall impact remains uncertain [54]. Further multi-center clinical trials are investigating the safety outcomes of heparin use in sepsis.

Transfusion support in critically ill patients relies on physician judgement rather than data, and the effectiveness of platelet transfusion to reduce transfusion of other blood components, or improve overall outcome is obscure [17, 18, 51]. We are still in need of large randomized trials evaluating transfusion strategies to treat or pre-vent bleeding in critically ill thrombocytopenic patients. The guidelines for platelet transfusion summarized in Table 7.2 [6, 26, 49, 51, 55] depend on either low or very low quality of evidence.

Therapeutic platelet transfusions are indicated in patients with bleeding who have more than mild blood loss like epistaxis, hematuria, and hematemesis, at or above bleeding World Health Organization Grade 2. In ICU patients thrombocyto-penia is also associated with acquired mild-to-moderate platelet dysfunction [56–58] caused or aggravated by medications, i.e., antibiotics [59, 60] and analgesics, activation of platelets on extracorporeal circuits [61], or cleavage of platelet recep-tors by enzymes released in sepsis [7]. Therefore bleeding symptoms are much more relevant for transfusion decision-making than the actual platelet count. In patients who may have immune thrombocytopenia, drug-induced immune thrombo-cytopenia, or posttransfusion purpura, platelet transfusion should only be consid-ered for serious or life-threatening bleeding, as the survival of transfused platelets is remarkably low in patients who have ongoing immune-mediated platelet destruc-tion. Platelet transfusions should be avoided in patients who have low platelet counts with thrombosis, i.e., HIT [62] and TTP [63], as that might push the balance toward thrombosis. Platelet transfusions are considered to be useful in patients with platelet loss or consumption but might cause serious adverse events in patients with increased intravascular platelet activation, i.e., HIT or TTP. Therefore, successful treatment requires identifying the underlying cause of thrombocytopenia.


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In patients with hypoproliferative thrombocytopenia due to underlying bone marrow failure or chemotherapy exposure, but without major bleeding symptoms, prophylactic platelet transfusion is based on clinical judgment. Critically ill throm-bocytopenic patients who have nonimmune thrombocytopenia and spontaneous oropharyngeal mucous membrane bleeding have increased risk of bleeding into the central nervous system or retina and should receive platelet transfusion. For patients who have platelet counts above 10 × 109/L, prophylactic platelet transfusion should be considered for patients with active bleeding risks or before invasive procedures (Table 7.2).

Platelet count increment needs to be calculated after platelet transfusions to dis-tinguish platelet consumption versus refractoriness, as multiparous women and patients with a history of multiple transfusions could have anti-HLA antibodies, necessitating HLA-matched platelet transfusion. A unit apheresis platelet (or a pool of six platelet concentrates) should achieve an increment of 30,000–50,000/μL in an average adult; however, for critically ill patients, expected mean platelet count increase is approximately 15 × 109/L. Checking a platelet count 15–30 min after platelet transfusion, and calculating corrected count increment, provides valuable information if the patient should be further evaluated for platelet-reactive antibod-ies, i.e., anti-HLA class I antibodies or rarely antihuman platelet antigen antibodies. Corrected count increment or CCI is usually calculated with the following formula: CCI = (platelet count posttransfusion − platelet count pretransfusion) × BSA (m2)/number of platelets transfused × (1011). CCI below 5500–7000 is considered an inadequate response. Patients with platelet transfusion refractoriness require a mul-tidisciplinary approach, i.e., hematology and blood bank, to manage their need for HLA-matched platelets.

Table 7.2 Platelet transfusion recommendations in critically ill patient [21, 49–51]

Transfusion indication Threshold platelet count

Severe bleeding Maintain platelet count above 50 × 109/L

Prophylaxis in adults w/o bleeding symptoms 10 × 109/LProphylaxis in adults with mucocutaneous grade II bleeding symptoms

20 × 109/L

Prior to elective central venous catheterPrior to bronchoscopy with lavagePrior to urgent diagnostic lumbar puncture

20 × 109/L

Prior to elective diagnostic lumbar puncturePrior to chest tube insertion or paracentesisPrior to elective major surgery, excluding neurosurgery

50 × 109/L

Prior to neurosurgeryTraumatic brain injury, intracranial hemorrhagePrior to insertion of an intraventricular drain

100 × 109/L

Prior to paracentesisPrior to bone marrow biopsyProphylactic transfusion of nonthrombocytopenic patients before cardiopulmonary bypass surgery

Not routinely required, unless there is evidence of bleeding


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Management of thrombocytopenia in the critically ill is still often determined by expert opinion, and the guidelines summarized in Table 7.2 serve as suggestions until we have definitive data.

White Blood Cell Alterations in Sepsis

Increased production and activation of neutrophils and monocytes are important in the host’s response to infection [64]. In animals, intravenous injection of endotoxin produces a marked increase in number of circulating leukocytes [65]. In patients with sepsis, the white blood cell count rises, i.e., leukocytosis. Neutrophils play important roles in fighting infection through phagocytosis of infecting microorgan-isms as well as immune complexes [66]. Neutrophilia is produced by a combination of de-margination, increased bone marrow release, and increased production of neutrophils. When bone marrow reserves are mobilized, there is an increased num-ber of premature band forms released into the circulation producing a “left shift” in the peripheral blood white cell count. Although a neutrophilic leukocytosis is the appropriate response to many types of infections, neutropenia may develop in some patients and is associated with a poor prognosis [67–69]. This may represent an overwhelming immune suppression of marrow. Sepsis is also associated with acti-vation of monocytes. The monocytes/macrophage is the human equivalent of the invertebrate amoebocyte, the innate immune cell responsible for reaction to patho-gens as well as wound repair. The ability of the monocyte to upregulate synthesis and release of cytokines as well as expression of tissue factor provides critical cross- talk between inflammation and coagulation. Monocytes possess toll-like receptors that are a key component of the innate immune system. These pathogen-associated molecular pattern signaling receptors are a key to appropriate immune response [70].

Leukemoid reaction, defined as leukocyte counts in excess of 50,000, is an extreme response to infection.

Since the white blood cell is a key effector response to counter bacterial chal-lenge, it is appealing to postulate that granulocyte colony-stimulating factor (G-CSF) would improve outcome in severe infection. Although theoretically attrac-tive, especially in patients with sepsis and neutropenia, there is no evidence that this approach improves outcomes.

Immature granulocytes would be expected to differentiate a systemic inflamma-tory response related to infection versus one that is not. It has been shown that the immature granulocyte count does discriminate between infected and non-infected patients [71]. Although a differentiator of the presence or absence of an infection, the immature granulocyte count does not serve as a prognostic marker for mortality. It may, however, be useful as a rapid screening tool in patients with potential infec-tion. The “delta neutrophil index” measures the immature granulocyte fraction with an automated blood cell analyzer to create a delta that represents the difference between the mature PMN leucocytes and the total leucocyte count [72]. The delta


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neutrophil index expressed as a percentage has been shown to differentiate between controls, a systemic inflammatory response (SIRS) without infection, SIRS with infection, and severe sepsis (infection-induced organ dysfunction) better than C-reactive protein (CRP).

CD64 is an antigen expressed on neutrophils during an infectious or inflamma-tory state. In a bacterial infection, there is an increase in the density of CD64 antigen on neutrophils and an increase in the number of neutrophils expressing CD64. This is not typical for viral infections. CD64 expression may, however, also be seen in noninfectious inflammatory conditions such as sickle cell crisis or acute bouts of rheumatoid arthritis. Similar to the delta neutrophil index dis-cussed above, the percentage of CD64-positive neutrophils is highest in patients with sepsis, followed by SIRS in the absence of infection and lowest in normal controls [73].

It is now recognized that in some patients the pro-inflammatory response to severe sepsis is replaced over time with an anti-inflammatory response that can be identified by the presence of persistent lymphopenia [74]. This immunosuppressive phase is characterized by apoptosis-related loss of immune cells including CD4, CD8, and follicular dendritic cells [75, 76]. It is possible that pro-immune therapy would be anti-apoptotic, prevent lymphocyte death, and improve survival in severe sepsis. Animal data would support this possibility and indicate that immunomodula-tory therapy offers promise in future clinical research [77, 78]. Absolute lympho-cyte counts are easily measured during routine care.

Red Blood Cell and Blood Transfusion

Red Blood Cell Rheology in Sepsis

Alterations in RBC rheology may contribute to the microvascular injury and impaired oxygen supply seen in sepsis.

Major determinants of red blood cell (RBC) rheology are viscosity, aggrega-tion, deformability, and membrane physiology (X1). Viscosity is the extent to which a fluid resists flow. In very technical terms, it is the tangential stress on the flow of a liquid divided by the velocity gradient. It relates to internal friction defined by force per unit area of flow resistance. The major determinants of whole-blood viscosity are plasma viscosity, hematocrit, and RBC deformability and aggregation.

Shear rate signifies the rate of change in velocity as one layer of fluid passes over an adjacent layer. Rouleaux are stacks of red blood cells (RBCs) which tend to form because of the unique discoid shape of the red blood cell. Formation of rouleaux increases blood viscosity. Low shear rates, high hematocrits, and low-flow states promote rouleaux formation. In the presence of inflammatory acute-phase proteins, rouleaux of cells drive aggregation of RBCs. Erythrocyte sedimentation rate esti-mates aggregation tendency in RBCs.


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Deformability characterizes the RBC’s ability to undergo deformation during flow [79, 80]. RBC deformation when exposed to fluid forces is determined by membrane material properties cell geometry and cytoplasmic viscosity [81]. The RBC must deform to pass through the smaller capillaries and achieve oxygen transfer. Nitric oxide (NO) modulates RBC membrane properties and is released in abundance in severe sepsis and septic shock. NO, perhaps by an effect on the membrane calcium-ATPase channel, may decrease RBC deformability. Sepsis-induced production of reac-tive oxygen species has also been linked to decreased RBC deformability [82, 83].

Red Blood Cell Transfusion in Sepsis Hypoperfusion

In 1999 a large prospective randomized study of 838 stable intensive care unit patients assigned either to a hemoglobin target of 7–9 versus 10–12 g/dL was car-ried out [84]. Overall 30-day mortality was similar in the two groups with outcome better in the restrictive group and complications more frequent in the liberal group. Based on our personal observations at our own institution, there has been a steady increase in utilizing the 7 g/dL transfusion threshold in ICU patients in general.

A separate subgroup of ICU patients that deserves separate attention are those with septic shock or sepsis-induced hypoperfusion as manifested by lactate acidosis. Red blood cell transfusion has been shown to be a frequent intervention in patients with septic shock and anemia in the ICU [85–88]. Those who use a low threshold for transfusing patients with septic shock rationalize that blood transfusion would increase oxygen delivery (a given) and lead to increase oxygen consumption in those patients with an oxygen deficit due to tissue hypoperfusion. This is clearly contro-versial with some studies showing failure to increase oxygen consumption in septic patients with tissue hypoperfusion despite the increase in oxygen delivery, whereas others show increased oxygen consumption following blood transfusion, particu-larly in patients with elevated lactate or low superior vena cava O2 saturations [89–92]. Marik and Sibbald studied 23 critically ill patients with sepsis and failed to demonstrate a beneficial effect of red blood cell transfusion on measured systemic oxygen uptake [89]. Fernandes et al. studied 15 critically ill septic patients with Hgb levels <10 g/dL. Ten patients received one unit of blood, and five controls received albumin in the same volume. Increase in regional or global oxygen utilization could not be demonstrated [90]. Mazza and colleagues studied 46 patients with 74 transfu-sions and were able to show an association between blood transfusion and increase in ScvO2 and decrease in lactate [91]. In a surgical sepsis population, Steffles, Bender, and Levison were able to demonstrate augmentation of both DO2 and VO2 that could not be predicted by increased lactate levels. They postulated that patients with increased lactate levels may have peripheral oxygen utilization deficit that handicap improvement in VO2 with increase in DO2 [92]. One of the issues with transfusion of red blood cells relates to reduction in quality of the RBC during stor-age. During storage, changes in RBC morphology, changes in membrane surface characteristics, and decrease in RBC deformability are problematic [93].


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Some have advocated transfusion of fresh blood as opposed to stored blood to avoid the issues elucidated above, but no data exists to support that advantage. One database study using propensity-matched analysis in patients with severe sep-sis and septic shock did show an “association” between red blood cell transfusions and lower mortality [94]. Although the literature is conflicting as to the ability of increasing oxygen delivery to increase oxygen consumption, the predominance of high- quality literature and in particular the Holst study (see discussion to follow) showing no clinical outcome benefit of higher transfusion threshold in septic shock patients points to a preference for a more conservative transfusion in patients with severe sepsis and septic shock regardless of presence or absence of tissue hypoperfusion [95]. Although transfusion of RBCs would seem theoretically to be a potential solution for increasing tissue oxygen delivery, changes in septic patients’ RBCs induced by endogenous factors in the septic patients as well as effects of storage may ameliorate any potential positive effects in the microcirculation.

Blood Transfusion as Part of Early Goal-Directed Therapy for Septic Shock

In late 2001 Rivers et al. published a landmark paper, landmark in that it was a wake-up call as to our care of the septic shock patient. It was entitled “Early Goal- Directed Therapy in the Treatment of Severe Sepsis and Septic Shock” [96]. Over 260 patients in the emergency department (ED) with infection-induced hypotension (SBP < 90 mmHg after ≥20 cc/kg crystalloid IV bolus) and/or lactate ≥4 mmol/L were randomized to receive standard protocolized therapy or “early goal-directed therapy” (EGDT) as termed by the authors. Patients in both groups had central venous catheters placed and fluid resuscitation targeting a CVP of 8–12 mmHg, vasopressors titrated to a mean arterial pressure (MAP) of ≥65 mmHg, and a urine output of at least 0.5 cc/kg/h. The EGDT group had the same care as the control group plus ther-apy to raise the superior vena cava venous O2 saturation (ScvO2) to ≥70%, if neces-sary using dobutamine and/or blood. The in-hospital mortality was 30.5% in the EGDT group vs. 46.5% in the standard therapy group (p = 0.009). EGDT became part of many multifaceted sepsis performance improvement initiatives that demon-strated improved survival when compared to historical controls [97].

Surviving Sepsis Campaign Guidelines, Early Goal-Directed Therapy, ScvO2, and Blood Transfusion

The first surviving sepsis guidelines (SSC) were published in 2004 [98] and recom-mended that during the first 6 h of resuscitation in patients with sepsis-induced hypoperfusion (hypotension and/or lactic acidosis), resuscitation should target


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ScvO2 target of 70% using the EGDT methods of the Rivers trial. A mixed venous oxygen saturation (SvO2) of 65% or greater was offered as an alternative if a pulmo-nary artery catheter was present [99]. If fluid resuscitation, vasopressors as needed to achieve a MAP ≥ 65 mmHg, and normal oxygen saturation failed to raise the ScvO2 to 70%, then a transfusion of packed RBCs to raise the hematocrit to 30% and/or empiric dobutamine to raise the cardiac output was recommended in attempts to achieve that goal. The first revision of SSC guidelines occurred in 2008 [100] and again recommended the previous EGDT-delineated targets of CVP, MAP, urine out-put (UOP), and ScvO2. “Protocolized resuscitation” was used to describe the resus-citation recommendation, and the group to receive this resuscitation was specifically defined as persistent hypotension after fluid challenge and/or blood lactate concen-tration ≥4 mmol/L. This brought the SSC tissue hypoperfusion definitions in line with the original Rivers study. In the 2012 SSC guidelines [101], the term “proto-colized quantitative resuscitation” was used to describe the recommended treatment of septic patients with tissue hypoperfusion, keeping the targets the same as in 2008. Lactate clearance was suggested as an additional target after studies by Jones et al. [102] showed that achieving 10% lactate clearance during resuscitation of sepsis- induced tissue hypoperfusion was equivalent to targeting an ScvO2 of >70%. The recommendations for transfusion of blood or dobutamine were removed from the guidelines with the physician charged to normalize ScvO2 by whatever method they chose. The limitations for the use of CVP as a marker of intravascular volume status and fluid responsiveness were recognized, and dynamic targets were advised as a consideration for determination of volume responsiveness.

Following the publication of the ARISE, PRoCESS, and PROMISE trials that showed measurement of CVP and ScvO2 was not necessary for the successful resus-citation of septic shock [103–105]. The Centers for Medicare and Medicaid Services (CMS) published the CMS SEP-1 measures which did not require targeting or even measurement CVP and ScvO2, but these variables were still one option for satisfy-ing the reevaluation of intravascular volume and tissue perfusion following initial fluid resuscitation. If ScvO2 is chosen as a target for resuscitation of septic shock, what therapeutic interventions, if any, are needed beyond intravascular volume expansion and vasopressor agents? In septic shock patients, Jones et al., after aggressive administration of intravenous crystalloid to achieve a CVP of 8–12 mmHg and vasopressor agents to achieve an arterial pressure of 65 mmHg or greater in a stepwise resuscitation algorithm, found that very few patients were given packed red blood cell transfusion in an attempt to achieve ScvO2 goals (only 7% received packed red blood cell transfusion) [102]. In contrast, 64% of patients in the EGDT (ScvO2 targeted) arm in the Rivers study were treated with blood transfusions. The Rivers data suggested that packed red blood cell transfusions were part of the suc-cess of the EGDT arm, whereas the Jones trial (and other observational clinical studies) suggests that these additional therapies are rarely required to achieve ScvO2 goal, if utilized as a target.

The 2016 revision of the SSC guidelines has no recommendation for specific targets of resuscitation and emphasizes the importance of septic shock as a medical emergency with initial 30 mL/kg crystalloid to be given within 3 h of presentation


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with additional fluids guided by reassessment and the suggestion of dynamic (pulse pressure variation, stroke volume variation) over static (CVP measurement) to pre-dict fluid responsiveness [106]. Although not part of a recommendation, the body of the document does point to the fact that there were equal outcomes in the ScvO2 targeted and usual care groups of the ARISE, PRoCESS, and PROMISE trials. The only RBC transfusion recommendation is that for adults, in the absence of extenuat-ing circumstances such as myocardial ischemia, severe hypoxemia, or acute hemor-rhage, RBC transfusion occurs only when hemoglobin concentration decreases to <7.0 g/dL in. The rationale for this recommendation following acknowledgment of the lack of difference between the outcomes of the EGDT and usual care arms of the above three studies states “We judge the evidence to be high certainty that there is little difference in mortality, and, if there is, that it would favor lower hemoglobin thresholds.”

Summary

Hematologic manifestations of sepsis are leukocytosis, leukopenia, lymphopenia, anemia, thrombocytopenia, and subclinical or clinical disseminated intravascular coagulation. Leukocytosis is expected but leukopenia may be seen and carries a worse prognosis. Lymphopenia when persisting in the septic patient may imply immunodeficiency and risk for additional infections, ongoing apoptosis, and worse outcomes. Thresholds for platelet transfusion are based on need for procedures and active bleeding. When sepsis-induced tissue hypoperfusion and lactic acidosis exist, red cell transfusion may be entertained as a method to increase oxygen delivery to the tissues as an alternate or adjunct to increasing cardiac output. The pendulum for use of blood transfusion as part of the initial resuscitation protocol of sepsis-induced tissue hypoperfusion, although still somewhat controversial, has swung away from transfusion unless the Hgb is less than 7 g/dL or there is evidence of cardiac isch-emia or active hemorrhage. Subclinical DIC can be found in the majority of patients with severe sepsis, but clinical manifestations of DIC are uncommon.

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Chapter 8Hematologic Challenges in ICU Patients with Cardiovascular Disease

Annemarie Beth Docherty and Timothy Simon Walsh

Introduction

Cardiovascular disease (CVD) is the collective term for all diseases affecting the heart and blood vessels. Statistics from the British Heart Foundation (UK charity) show that approximately seven million people in the UK have coexisting CVD [1, 2]. In general non-cardiac critical care units, approximately 25–30% of all patients admitted will have coexisting cardiovascular disease, according to intensive care unit (ICU) casemix [3, 4]. CVD is the leading global cause of death, accounting for more than 17.3 million deaths in 2013 (31% of all global deaths), a number that is expected to grow to more than 23.6 million by 2030 [5]. Considerable geographical variation in mortality rates can occur within and between countries. For example, in 2014, in the UK, death rates from coronary heart disease were 45% higher in Scotland com-pared with the southeast of England. CVD accounted for 10% of all inpatient epi-sodes in the UK National Health Service (NHS) in men and 6.2% in women. Unsurprisingly, the economic burden of CVD is high: in 2010, the estimated global cost of CVD was $863 billion and is estimated to rise to $1044 billion by 2030 [5].

Anemia in Cardiovascular Disease

The myocardium has a limited anaerobic capacity and is dependent on a continuous supply of oxygen from the coronary circulation. At rest, the coronary blood flow is approximately 250 mL/min, representing 5% of cardiac output. The myocardium

A. B. Docherty (*) · T. S. Walsh Anaesthesia, Critical Care and Pain Medicine, School of Clinical Sciences, University of Edinburgh, Edinburgh, UKe-mail: [email protected]



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extracts 75% of the oxygen, which cannot increase significantly in response to increased oxygen demand, and the coronary sinus PO2 is subsequently very low (3 kPa) [6]. This oxygen extraction ratio (OER) is higher than for all other major organs, for which OERs of 25–30% are typical. In order to match the considerable increases in myocardial O2 consumption that occur during exercise (up to five times resting consumption), there must be substantial increases in coronary blood flow. Flow across the myocardium largely depends on the pressure gradient between the aortic root and the right atrium. The force from the contracting heart muscle is greatest in the left ventricular subendocardial layers where it approximates to intra-myocardial pressure, and significant left ventricular coronary flow can occur only during diastole. The right coronary flow is less affected by systole because of the smaller right ventricular muscle mass and lower chamber pressures during the car-diac cycle. Any increase in heart rate will result in a reduction in diastolic time and will reduce perfusion time; the ratio of systolic to diastolic time becomes closer to one as heart rate increases. Coronary blood flow is also controlled by the diameter of the coronary arteries. This is under nervous and humoral control as well as local vasorestrictors and vasoconstrictors in the endothelium. Hypoxia causes coronary vasodilatation directly and also releases adenosine and opens ATP-sensitive potas-sium channels [7]. It follows from these features of normal coronary physiology that any reduction in coronary flow and/or coronary blood oxygen content will decrease myocardial oxygen delivery, which could cause myocardial ischemia.

Anemia is associated with worse outcomes in patients with CVD, both in terms of severity of illness and mortality. Anemia is associated with poor outcome in isch-emic heart disease [8], chronic heart failure [9], rhythm disturbance, and mortality and major adverse cardiovascular events in acute coronary syndrome [10, 11]. This may be due to increased myocardial workload and adverse left ventricular and large artery remodeling. Anemia is also associated with worse postoperative mortality in patients with CVD [12], suggesting that patients with coexisting CVD are less toler-ant of anemia than patients without CVD. This is consistent with animal studies which showed that dogs with experimentally created coronary stenoses developed ischemic ECG changes at higher Hb concentrations compared to those with normal coronary arteries (stenoses 70–100 g/L vs normal 30–50 g/L) [13]. However, the evidence in humans is mainly from observational studies, and it is difficult to tease out whether the anemia is exacerbating the underlying condition or is a reflection of the severity of the underlying disease. It follows, therefore, that reversing anemia with RBC transfusion may not improve patient prognosis. These questions can only be answered with certainty by well-designed randomized trials in relevant patient populations.

There are additional reasons why patients with acute coronary syndrome (ACS) may have poorer outcomes if they are anemic. Reduction in the oxygen delivery to infarcted or ischemic myocardium may promote arrhythmias, worsen hypotension, and increase infarct size [14]. Patients with anemia may also have antiplatelet ther-apy withheld, due to concerns of the associated bleeding risks. For example, in the CADILLAC trial, a trial investigating the effectiveness of Abciximab (a platelet glycoprotein IIb/IIIa inhibitor), 18% of patients with anemia at the time of their

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ACS were no longer receiving aspirin at 1 year follow-up [15]. The prevalence of anemia among patients presenting with ACS is increasing, in part because of the aging population and the presence of coexisting morbidities. Anemia at presentation with ACS is associated with poorer short- and long-term outcomes [16], and bleed-ing events during treatment for ACS are associated with greater mortality and other cardiovascular events [17]. Some studies have found that hemoglobin decrement during hospitalization for ACS is an independent predictor of subsequent death or hospitalization with myocardial infarction (MI) [18, 19]. These associations high-light the importance of establishing whether blood transfusions to correct anemia can modify risk of adverse outcomes among anemic patients with ACS.

Anemia in Critically Ill Patients with CVD

Anemia causes an increase in cardiac output, achieved by an increase in heart rate and stroke volume and the reduction in vascular resistance associated with reduced blood viscosity (lower hematocrit) . In acute and critical illness, tachycardia reduces diastolic filling time and hypotension reduces the pressure gradient across the left ventricle. Both of these reduce blood flow through the coronary arteries. The use of catecholamines increases myocardial O2 demand, and global O2 demand is also increased. The myocardial oxygen supply is reduced in patients with anemia, and patients with coexisting cardiovascular disease with potentially atheroma-related flow-limiting disease have limited ability to compensate.

Myocardial Infarction

Myocardial infarction (MI) is defined according to the Third Universal Definition as evidence of myocardial necrosis in a clinical setting consistent with acute myocar-dial ischemia. This requires the presence of a rise and/or a fall pattern of cardiac biomarkers (usually Troponin I (TnI) or Troponin T (TnT)), with at least one value above the 99th percentile of the upper reference limit. This should occur with at least one of the following [20]:

• Symptoms of ischemia• Electrocardiographic (ECG) evidence of myocardial ischemia (new or presumed

new significant ST-segment-T-wave changes or new left bundle branch block or pathological Q wave changes in the ECG)

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality or identification of an intracoronary thrombus by angiography

MI can be further categorized according to its likely cause [20] (Table 8.1).Patients with myocardial necrosis (elevated troponin concentrations) in the

absence of symptoms or signs of myocardial ischemia are classified as having

8 Hematologic Challenges in ICU Patients with Cardiovascular Disease

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myocardial injury. Acute myocardial injury occurs where troponin concentrations display a dynamic rise and fall pattern, compared with chronic myocardial injury, where troponin concentrations remain elevated but unchanged on serial testing. Chronic myocardial injury may be found in patients with chronic heart failure, renal failure, and coronary artery disease in the community [21, 22]. Acute myocardial injury is common in critically ill patients with CVD and may be secondary to sepsis [23, 24], acute exacerbation of COPD [25], acute intracerebral pathology [26], or pulmonary embolism [27, 28].

Outcomes of Type II Myocardial Infarction and Myocardial Injury

Outcomes for patients with both type II MI and myocardial injury are poor, espe-cially in the critical care setting. There is currently no consensus on the optimal cardiac investigation, management, or treatment strategy for these conditions. For consecutive unselected hospital inpatients out with the critical care setting, patients with type II MI or myocardial injury have worse outcomes than patients who pres-ent with type I MI, with a third of patients dead at 1 year [29] and 60% of patients with type II and 75% of patients with myocardial injury dead at 5 years [30]. However, this reflects all-cause mortality, and it is not known whether therapeutic intervention can improve outcomes. Patients with type II MI were twice as likely as those with myocardial injury to be admitted with a type I MI during the subsequent year, suggesting that a proportion of patients with type II MI may benefit from fur-ther investigation and treatment for coronary artery disease.

Diagnosis of MI in Critical Illness

Diagnosis of MI in patients with critical illness is not straightforward. Many patients are unable to communicate any symptoms due to sedation and ventilation, strong analgesia, distracting injuries, and delirium. TnI elevation is common in critical ill-ness and in addition to cardiac causes has multiple non-cardiac etiologies as described above. ECGs are typically not performed routinely, and ECG interpretation is

Table 8.1 Types of myocardial infarction

Type I Spontaneous MI related to atherosclerotic plaque rupture, with intraluminal thrombus

Type II Secondary to ischemia, oxygen supply-demand imbalanceType III MI resulting in death when biomarker values are unavailableType IVa MI related to PCIType IVb MI related to stent thrombosisType V MI related to CABG


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difficult due to tachycardia, arrhythmias, and non-specific changes. Two groups have looked at ECGs taken routinely in heterogeneous critically ill patients [31–33]. They found that ECG interpretation by clinicians had poor agreement for the pres-ence of myocardial ischemia or infarction. This was improved to moderate agree-ment once the ECG was interpreted alongside the patient’s troponin values. Specific ECG changes such as bundle branch block had high reliability, compared to non-specific T-wave flattening.

Bedside imaging is limited to transthoracic echocardiography, which may miss small but important regional wall motion abnormalities. In critical care settings, echocardiography is frequently technically difficult, and an injury involving >20% of myocardial wall thickness may be required to detect a wall motion abnormality [34].

Diagnosis of MI in Critically Ill Patients with Coexisting CVD

Patients with coexisting CVD are at high risk of further myocardial injury during critical illness. Surgery and trauma induce an inflammatory state, with increase in the concentrations of cytokines such as TNF-alpha, interleukin-1, interleukin-6, and CRP. Patients are hypercoagulable due to increases in PAI-1, factor VIII, and plate-let reactivity and decreases in antithrombin III concentrations. Furthermore, patients have increased catecholamine and cortisol levels as a result of physiological stress. All of these may lead to coronary artery shear stress, plaque fissuring, and subse-quent acute coronary thrombosis, or type I MI [35]. Even in the absence of plaque rupture, increased oxygen demand and reduced oxygen delivery in the presence of stable atherosclerotic stenosis may result in type II myocardial infarction.

It is important to attempt to delineate the mechanism of raised TnI in critically ill patients with CVD, in order to identify patients where cardiac or coronary inves-tigations or therapies may be indicated. For the patient who presents with sub-massive pulmonary embolism, TnI elevation may be secondary to right ventricular strain or hypoxia, and coronary angiography is both unwarranted and an unneces-sary risk. For the patient who presents with community acquired pneumonia, chest pain, and ECG changes, TnI elevation may be due to hypoxia, tachycardia, or hypo-tension, with the acute illness representing a physiological stress test. In this con-text, it is appropriate to diagnose acute MI. These examples illustrate how the complexity of cases presenting to critical care, especially the interplay between pre-existing and complex acute disease, make the diagnosis of MI difficult in indi-vidual patients.

Management of MI in Critically Ill Patients with Coexisting CVD

If type I MI is suspected, then invasive coronary angiography should be considered. However, if TnI elevation is in the context of oxygen supply-demand imbalance, then the need for further investigation and treatment is uncertain [36]. A survey of 310


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intensivists regarding treatment strategies for critically ill patients with elevated tro-ponin and without typical symptoms of MI or ECG changes found that 76% would start aspirin or clopidogrel, 47.4% would start heparin, 48.9% would start high-dose statins, 68.7% would start beta-blockers, and 37.6% would use an ACE- inhibitor. 72.7% would request a cardiology consultation, and 51.3% would refer for an angio-gram once the patient was stable [37]. These responses indicate substantial clinical variation and uncertainty regarding best practice. In addition, patients with pre-exist-ing CVD are frequently already on secondary prevention therapies such as antiplate-let agents and statins. The risk to benefit ratio of continuing agents during a critical illness episode, which agents should be prioritized, and the optimum timing of restarting therapies during recovery are all areas of clinical uncertainty. Based on lack of clear evidence, the risks and benefits of primary and secondary treatment have to be assessed on an individual basis. For example, critically ill patients often have significant coagulation abnormalities. Approximately 25–34% of critically ill medical patients are thrombocytopenic [38], and patients with platelet counts of <50 × 109/L have a four- to fivefold increased risk of bleeding compared with patients with higher platelet counts [39]. In these patients, the risk of bleeding from heparin and antiplatelet medication may outweigh potential benefits to myocardial function.

Transfusion in Critically Ill Patients with CVD

Red blood cell transfusion may increase oxygen delivery to the myocardium, thereby reducing the risk of myocardial ischemia and necrosis. Current guidelines advocate a restrictive use of blood transfusions for general hospital inpatients including those who are critically unwell (Table 8.2) [41, 42, 44, 45]. These have highlighted the lack of evidence and uncertainty regarding best practice for patients with acute or chronic cardiovascular disease [41, 42, 44, 45]. The National Institute for Health and Care Excellence (NICE) blood transfusion guideline, published in November 2015, stated that the optimal transfusion threshold for patients with ongoing acute coronary syndrome was 80–100 g/L but made no specific recommen-dation for patients with chronic cardiovascular disease and highlighted the need for further research in this specific population [43].

Transfusion in Acute Coronary Syndrome

Until recently, the only data available exploring the association between anemia, transfusion practice, and clinical outcomes in ACS were observational cohort stud-ies. These provide contrasting and contradictory data but in meta-analysis suggest an association between blood transfusions and higher risk of mortality and reinfarc-tion [46]. However, as with all observational research exploring the association between anemia, transfusion, and clinical outcomes, these studies are potential


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subjects to confounding by indication [47, 48]. At best, these studies are hypothesis generating but indicate the need for randomized trials in the setting of ACS.

There are no completed large RCTs, but two pilot RCTs of RBC transfusion in acute coronary syndrome have been published. The CRIT pilot trial randomized 45 patients with ACS to either a liberal transfusion threshold (transfusion at hematocrit <30%) or a restrictive transfusion threshold (hematocrit <24%). Baseline hemato-crit was similar (liberal 26.9% vs restrictive 27.5%, p = 0.4). More patients in the liberal arm were transfused (100% vs 54%, p < 0.001), and the average number of units transfused per patient was higher in the liberal arm (2.5 vs 1.6, p = 0.07). The primary composite endpoint of in-hospital death, recurrent myocardial infarction, or congestive heart failure occurred in eight patients in the liberal arm and three in the conservative arm (38% vs 13%, p = 0.046) [49]. However, most of the excess events in the liberal group (eight versus two patients) were accounted for new or worsening heart failure, which could have been related to transfusion. There was no difference in deaths.

The MINT pilot trial (liberal Hb 100 g/L vs restrictive 80 g/L or symptoms of ischemia) found a trend for fewer major cardiac events and deaths in patients randomized to the liberal arm [50]. Baseline characteristics were similar between groups except age (liberal, 67.3; restrictive, 74.3). The mean number of units trans-fused was 1.6 in the liberal group and 0.6 in the restrictive group. The primary out-come (composite of death, myocardial infarction, or unscheduled revascularization up to 30 days) occurred in 6 patients (10.9%) in the liberal group and 14 (25.5%) in the restrictive group (risk difference = 15.0%; 95% confidence interval of difference 0.7–29.3%; p = 0.054 and adjusted for age p = 0.076). Death at 30 days was less frequent in liberal group (n = 1, 1.8%) compared to restrictive group (n = 7, 13.0%; p = 0.032).

Table 8.2 Guidelines for transfusion thresholds in all patients and specifically for patients with cardiovascular disease

Organization YearRecommendation (g/L) Recommendation for CVD

American Society of Anesthesiologists [40]

2006 60 60–100 g/L dependent on comorbidity and organ ischemia

The American College of Critical Care Medicine

2009 70 Higher for acute myocardial infarction or unstable myocardial ischemia

American Association of Blood Banks [41]

2012 70 Transfuse patients with symptoms of Hb < 80 g/L

British Committee for Standards in Haematology [42]

2012 70, target 70–90 Stable angina should have Hb > 70 g/L

National Institute for Health and Clinical Excellence (NICE) [43]

2015 70, target 70–90 ACS: Transfusion threshold of 80 g/L, target of 80–100 g/LChronic: Further research

Association of Anaesthetists of Great Britain and Ireland (AAGBI) [44]

2016 70 Uncertainty remains for patients with IHD, higher thresholds (80 g/L) may be appropriate


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The full MINT trial of RBC transfusion in ACS started recruiting early in 2017 and is aiming to recruit 3500 patients by 2021. The liberal arm will be transfused at a hemoglobin concentration of 100 g/L compared to 80 g/L (or symptoms of angina) for the restrictive arm. The primary outcome will be a composite outcome of all- cause mortality or nonfatal myocardial reinfarction. Until this trial reports, and despite the paucity of evidence, guidelines currently recommend a higher transfu-sion threshold of >80 g/L for patients with ACS. This threshold is higher than the value of 70 g/L suggested in guidelines for most other groups but is still close to the restrictive threshold used in these inconclusive pilot trials. Clinicians currently need to make decisions based on individual patient status, for example, whether patients are tachycardic and hypotensive or have evidence of ischemia.

Chronic Cardiac Disease

We conducted a systematic review and meta-analysis assessing the effect of restric-tive vs liberal red cell transfusion strategies on patient outcomes restricted to adult patients with coexisting cardiovascular disease, excluding patients undergoing car-diac surgery [51]. We were able to extract data on patients with CVD from 11 RCTs that compared restrictive and liberal strategies for 30-day mortality and 9 RCTs for new events of ACS.

We found no evidence of a difference in 30-day mortality between restrictive and liberal transfusion threshold groups. However, we found that a restrictive transfu-sion threshold was associated with a 78% increased risk of ACS in patients with cardiovascular disease with low heterogeneity between trials suggesting this increased risk is a consistent finding (RR 1.78, 95% CI 1.18–2.70, moderate quality of evidence as assessed by GRADE). There was no difference in the incidence of pulmonary edema between restrictive and liberal transfusion strategies, but hetero-geneity existed between trials, and the GRADE quality of evidence was judged as very low. It is possible that this outcome includes cases of transfusion associated circulatory overload (TACO), which is more likely with liberal strategies. There was no difference in hospital length of stay between restrictive and liberal transfusion strategies, and other outcomes were rare, with inadequate data for meta-analysis. There were limitations in the systematic review, notably the definition and diagnosis of ACS. In some trials ACS was diagnosed by the clinicians, who were not blinded to the transfusion arm, which increases the chance of ascertainment bias. Another limitation was the heterogeneity of the clinical setting of the trials, varying between orthopedics, critical care, and GI bleeding. The extent and duration of physiological stress and the duration of exposure to anemia also varied between settings, and this could have an impact on the risk-benefit balance for transfusion.

This review suggested that for anemic patients with CVD, the use of restrictive hemoglobin thresholds (Hb concentration 70–80 g/L) was associated with higher rates of ACS than liberal thresholds (90–100 g/L). No effects on mortality or other important outcomes were demonstrated. The currently available quality of evidence


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for all outcomes was low. These data support the use of a more liberal transfusion threshold (greater than 80 g/L) for patients with both acute and chronic cardiovas-cular disease, until adequately powered high-quality randomized trials have been undertaken in this patient population.

Cardiac Surgery

Cardiac surgery represents a major consumer of red blood cells in all healthcare systems. There is a physiological rationale that anemia may be harmful during car-diac surgery, when coronary blood flow may be compromised, the myocardium acutely injured by surgery, and global oxygen demands increased by the stress response to surgery. However, there are theoretical reasons for harmful effects from transfusion of allogeneic blood, including immune suppression and infection and the pro-inflammatory and procoagulant effects of stored red blood cells [52].

Observational cohort studies mostly show associations between anemia and a range of adverse outcomes following cardiac surgery, especially infection and mor-tality. However, associations also exist between blood transfusions and these out-comes, even after attempts to adjust for hemoglobin concentrations [53]. This observational research is unable to delineate the relative risk to benefit ratio of ane-mia and blood transfusion, especially as other issues such as patient case mix and the red cell product could modify the association.

Several RCTs have explored the effectiveness of liberal versus restrictive trans-fusion practice among anemic patients undergoing cardiac surgery. A systematic review and meta-analysis by Patel and colleagues reviewed all studies published to May 2015, identifying six RCTs involving 3352 patients [54]. Meta-analysis found a pooled fixed effects mortality odds ratio (liberal versus restrictive transfusion threshold) of 0.70 (95% CI 0.49–1.02; p = 0.060), indicating a trend toward better outcomes with more liberal practice. This contrasted with the direction of effect in RCTs in the non-cardiac surgery setting supporting the hypothesis that patients undergoing cardiac surgery may benefit from a more liberal practice; however, data were inconclusive. Important differences between the trials included the timing of intervention (during cardiopulmonary bypass (CPB), on ICU post-CPB, or through-out the perioperative period) and the hemoglobin thresholds used. These issues may be important, especially in relation to the acute hemodilution that occurs during CPB.

The two largest trials involved 502 [55] and 2007 [56] patients. Hajjar and col-leagues randomized all consecutive patients undergoing CPB surgery in a single Brazilian center to a transfusion threshold of hematocrit 30% or 24% throughout the perioperative period. No difference in the 30-day composite of mortality and major morbidity was observed (10% vs 11%), or mortality alone (5% vs 6%). Murphy and colleagues randomized patients in 17 UK hospitals to a restrictive (Hb 75 g/L) or liberal (Hb 90 g/L) transfusion strategy post-surgery in the ICU if their hemoglobin concentration was 90 g/L or less. They found no difference in the composite out-


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come of serious infection or ischemic events within 3 months post-randomization (35.1% vs 33.0%), with no heterogeneity across pre-defined patient subgroups. However, more deaths occurred in the restrictive threshold group (4.2% vs 2.6%; hazard ratio, 1.64; 95% CI, 1.00–2.67; p = 0.045). As this was a secondary outcome, its significance was uncertain, but the finding made a major contribution to the effect observed in the meta-analysis [54].

Two further studies have been published since 2015. Koch and colleagues ran-domized 722 patients undergoing cardiac surgery in two US hospitals to a transfu-sion threshold of hematocrit 24% or 28% throughout hospitalization. This trial was stopped at the second interim analysis because a pre-defined futility boundary was crossed. There was no difference in the composite outcome of mortality and mor-bidity (16% vs 19%). These data supported the safety of a restrictive transfusion practice. Most recently, Mazer and colleagues randomized 5243 adults undergoing cardiac surgery with a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of six or more (on a scale from 0 to 47) to a restrictive red cell transfusion threshold (Hb < 75 g/L) or a liberal red cell transfusion threshold (Hb < 95 g/L) [57].

The intervention lasted from induction of anesthesia throughout hospitalization. They found no difference in the primary composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis (11.4% vs 12.5%); mortality was also similar (3.0% vs 3.6%). There were no differences between the groups in any of the secondary outcomes or for any pre-defined sub-groups including patients with worse preoperative left ventricular function, renal dysfunction, or diabetes mellitus. The non-inferiority design of this trial provides high-quality evidence for the safety of this restrictive strategy in cardiac surgery.

Clinical trial evidence therefore provides clarity about current best practice for patients undergoing cardiac surgery. Despite the association between anemia and adverse outcomes in this population, red blood cell transfusions are only indicated when the hemoglobin concentration is 75 g/L or less during the perioperative period and subsequent hospitalization. More liberal transfusion practices confer no clinical benefit to the patient and increases red cell use.

Conclusions

Coexisting cardiovascular disease is prevalent among patients admitted to ICU. Critical illness places significant strain on the vulnerable myocardium, and both atheromatous plaque rupture and supply-demand oxygen imbalance may result in myocardial infarction. Clinical trials have shown that red blood cell transfusions are only indicated when the hemoglobin concentration is ≤75 g/L for patients undergoing cardiac surgery. However, there is biological plausibility, supported by work from pilot trials and systematic reviews, that more liberal transfusion strate-gies may be beneficial in patients with both acute and chronic cardiovascular dis-ease. We would recommend a more liberal transfusion strategy of ≥80 g/L until data from high-quality RCTs in these populations are available.


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42. Retter A, Wyncoll D, Pearse R, Carson D, McKechnie S, Stanworth S, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol. 2013;160(4):445–64.

43. National Institute for Health and Clinical Excellence, 2015. Transfusion. Department of Health. Available http://www.nice.org.uk/guidance/ng24/evidence/full-guidance-2177160733.

44. Klein AA, Arnold P, Bingham RM, Brohi K, Clark R, Collis R, et al. AAGBI guidelines: the use of blood components and their alternatives 2016. Anaesthesia. 2016;71:829–42.

45. Norfolk D. Handbook of transfusion medicine. Norwich: TSO; 2013. 46. Chatterjee S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of blood transfu-

sion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis. JAMA Intern Med. 2013;173(2):132–9.

47. Middelburg RA, van de Watering LM, van der Bom JG. Blood transfusions: good or bad? Confounding by indication, an underestimated problem in clinical transfusion research. Transfusion. 2010;50(6):1181–3.

48. Carson JL, Hebert PC. Here we go again--blood transfusion kills patients?: comment on “Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis”. JAMA Intern Med. 2013;173(2):139–41.

49. Cooper HA, Rao SV, Greenberg MD, Rumsey MP, McKenzie M, Alcorn KW, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol. 2011;108(8):1108–11.

50. Carson JL, Brooks MM, Abbott JD, Chaitman B, Kelsey SF, Triulzi DJ, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013;165(6):964–71.e1.

51. Docherty AB, O’Donnell R, Brunskill S, Trivella M, Doree C, Holst L, et al. Effect of restric-tive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis. BMJ. 2016;352:i1351.

52. Chen D, Serrano K, Devine D. Introducing the red cell storage lesion. ISBT Sci Ser. 2016;11(S1):26–33.

53. Loor G, Rajeswaran J, Li L, Sabik JF 3rd, Blackstone EH, McCrae KR, et al. The least of 3 evils: exposure to red blood cell transfusion, anemia, or both? J Thorac Cardiovasc Surg. 2013;146(6):1480–7.e6.

54. Patel NN, Avlonitis VS, Jones HE, Reeves BC, Sterne JA, Murphy GJ. Indications for red blood cell transfusion in cardiac surgery: a systematic review and meta-analysis. Lancet Haematol. 2015;2(12):e543–53.

55. Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559–67.

56. Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372(11):997–1008.

57. Mazer CD, Whitlock RP, Fergusson DA, Hall J, Belley-Cote E, Connolly K, et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med. 2017;377(22):2133–44.


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Chapter 9Hematologic Challenges in ICU Patients with Liver Disease and Gastrointestinal Hemorrhage

Jeannie Callum, Harry L. A. Janssen, and Walter Dzik

Introduction

Considering the high prevalence of liver disease and cirrhosis in the hospitalized population, it is remarkable how little we know about how to manage the coagula-tion and cytopenias seen in these patients. Patients with liver disease and gastroin-testinal disorders account for 15% of patients transfused with red blood cells, 20% of patients transfused with plasma, and 15% of patients transfused with platelets in the intensive care [1]. Due to the prevalence of these disorders, one would expect large randomized controlled trials comparing different transfusion strategies in the bleeding patient and in patients prior to invasive bedside and operative procedures. Studies have been done to clarify the role of red cell transfusions in the patient with gastrointestinal hemorrhage, finding a restrictive strategy as effective, or better, than a liberal transfusion approach [2, 3]. Unfortunately, large, prospective, randomized trials for plasma and platelet transfusion in the ICU patient with liver failure and gastrointestinal hemorrhage have not been done, requiring a detailed review of the

J. Callum (*) Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON, Canadae-mail: [email protected]

H. L. A. Janssen Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada

Hepatology, University Health Network, Toronto, ON, Canada

W. Dzik Department of Pathology, Harvard University, Boston, MA, USA

Pathology, Massachusetts General Hospital, Boston, MA, USA



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retrospective and observation data published to date. Before we delve into the clini-cal studies, it is necessary to review the variety of hemostatic disturbances found in advanced liver disease.

Hemostatic Disturbances in Patients with Liver Disease

Vascular Disturbance

The physiology of cirrhosis leads to prominent portal-systemic venous shunting through the azygous venous system leading to engorged gastric and esophageal varices. The treatment of variceal bleeding has been dramatically improved through the use of endoscopic variceal ligation, pharmacologic therapies, and other local measures. If coagulopathy contributes to the severity of the hemorrhage, it is cer-tainly a more minor player than the bleeding that results from the rupture of chroni-cally dilated varices. Hence, prompt local measures are paramount to hemorrhage control and minimizing complications and transfusion requirements. The nutritional deficiencies that accompany chronic advanced liver disease may also lead to friable vessels and further impair local vascular hemostasis [4, 5].

Coagulation Disturbance

Our understanding of the coagulation disturbance in patients with liver disease has undergone a paradigm shift from the historic understanding that patients had a hemostatic disorder based purely on insufficient production of clotting factors to a more modern view based on “rebalanced” hemostasis [6]. The classic outdated dogma was that a patient with liver disease and elevated test results for coagulation (most widely taught was an INR above 1.5) who was either bleeding or planned for an invasive procedure should be transfused with plasma to treat or prevent bleeding. Similarly, we continue to teach and propagate in guidelines [7] a need for platelet transfusions for platelet counts below 50 × 109/L despite no published randomized trials. This older view of the coagulation status of liver disease patients has been effectively discredited by extensive basic science and clinical research. The histori-cal theory has been replaced by the theory of the “rebalanced” hemostasis, whereby numerous alternations in the both procoagulant and anticoagulant pathways result in maintained hemostasis, albeit with less physiologic reserve and therefore a more precarious balance between bleeding and thrombosis (Table 9.1). Because standard clinical laboratory tests of coagulation, such as the INR and partial thromboplastin time (PTT), fail to consider the contribution of natural anticoagulant proteins and only assess procoagulant proteins, these tests are unable to recognize the rebalanced hemostasis of liver disease and for years have falsely suggested that liver disease

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was only a bleeding disorder. However, clinically, it is recognized that liver disease is also a risk factor for thromboembolic complications, including deep vein, pulmo-nary, and portal vein thrombosis [8, 9], and experts continue to recommend appro-priate thromboembolic prophylaxis despite elevations in routine laboratory test results of coagulation [10]. Thus, patients with liver disease and an elevated INR are not “auto-anticoagulated.”

The liver parenchyma produces all of the procoagulant factors, with the notable exceptions of factor VIII and von Willebrand factor (vWF). Procoagulant factor levels drop in proportion to the severity of the patient’s liver disease, as stratified by Child-Pugh class [11]. The notable exception is the fibrinogen level which is either preserved or elevated in patients with liver disease [12]. To further complicate mat-ters, patients with liver disease produce abnormal and hypofunctional fibrinogen proteins due to increased sialic acid residues leading to impaired polymerization [13]. Factor VIII and vWF in contrast are elevated in patients with liver disease, with possible theories including reduced clearance from decreased expression of low-density lipoprotein receptor-related protein [14], increased release due to gut- derived lipopolysaccharide [15], and decreased degradation due to reduced activity of ADAMTS13 metalloproteinase [16]. A study found that samples from patients with liver disease and platelet counts as low as 60 × 109/L had thrombin generation equivalent to control patients with normal platelet counts, likely due to high vWF levels in those with liver disease [17]. Similarly, most of the natural anticoagulant proteins (antithrombin III, protein C, protein S) are synthesized by the hepatocytes and progressively fall with increasing severity of the liver impairment [18]. The sum of the above alterations is “rebalanced” hemostasis despite abnormal traditional test results for hemostasis.

Another very important finding of the research studies of the coagulation distur-bance in liver disease is the concept that every patient appears different from baseline lab tests. Some are hypocoagulable, others are normal, and some are even hyperco-agulable, calling for the development of testing assays in clinical coagulation

Table 9.1 Factors contributing to the balance between procoagulant and anticoagulant forces in patients with liver disease

Factors Procoagulant Anticoagulant

Platelet High vWFHigh factor VIIILow ADAMTS13

ThrombocytopeniaPlatelet dysfunction

Coagulation factors

High factor VIIILow protein CLow protein SLow antithrombin III

Low coagulation factors (except factor VIII)

Fibrinogen High fibrinogen (early) DysfibrinogenemiaFibrinolytic pathway

Low plasminogenHigh plasminogen activator inhibitor

Low antiplasminLow tissue factor pathway inhibitorHigh tPA

Heparinoids High natural heparinoids

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laboratories to help direct our therapeutic strategies. Essentially at the current time, we are managing liver disease patients with a one-size-fits-all approach without an understanding of their individual risk of bleeding or alternatively thrombosis.

Traditional coagulation test results have been incorporated into liver disease prognostic scores [19, 20] and scores used as guidelines for liver transplantation [21]. Although traditional coagulation tests predict survival and outcome after liver transplantation, one should not assume that the impact on survival is a result of hemorrhage. Abnormal test results may simply reflect hepatic reserve (coagulation factor and thrombopoietin synthetic reserve) and the degree of portal hypertension (thrombocytopenia).

Thrombocytopenia and Platelet Dysfunction

Thrombocytopenia is common in liver disease, including severe thrombocytopenia (<50 × 109/L) occurring in 13% of patients [22]. The etiology is thought to be mul-tifactorial including splenic sequestration from portal hypertension, impaired pro-duction of thrombopoietin (TPO) by hepatocytes [23], and bone marrow suppression from alcohol and specific antiviral therapies, such as peg-interferon. In addition, one must consider that thrombocytopenia in patients with enlarged spleens is par-tially attributable to pooling of platelets in the spleen. In fact a remarkable 50–90% of platelets are sequestered in the spleen in a patient with splenomegaly [24] and can be mobilized in response to the hemodynamic stress of hemorrhage. Hence, a plate-let count of 45 × 109/L in a patient with splenomegaly from chronic liver disease should not be viewed as severe as the same count in a patient with chemotherapy- induced thrombocytopenia. The relationship between platelet count and spleen size is poor and calls into question the dominant role of portal hypertension as the pri-mary cause of thrombocytopenia [25]. The thrombocytopenia is believed to be par-tially offset by the very high vWF level, leading to partial restoration of platelet adhesion [6].

Thrombocytopenia is predictive of outcomes in some liver cirrhosis models [26] and of the risk of hepatocellular carcinoma [27]. Thrombocytopenia in patients with severe liver disease is predictive of the risk of subsequent hemorrhage, with a five-fold increase in the risk of hemorrhage (98% gastrointestinal) compared to patients with a normal platelet count [22]. In this report, the median nadir platelet count in patients who subsequently bled was surprisingly high at 76 × 109/L, suggesting it is not the thrombocytopenia alone causing the bleeding but an association of thrombo-cytopenia with higher portal pressures leading to higher rates of esophageal and gastric varices.

In addition to the drop in platelet count, there is also a concern regarding platelet dysfunction in patients with liver disease with multiple factors contributing to impaired platelet aggregation [28]. The level of D-dimers is elevated in patients with cirrhosis and progressively rises with the severity of disease as stratified by Child-Pugh class [29] and may impair platelet function [30]. The impact of platelet

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dysfunction on the risk of bleeding is thought to be a minor contribution to the risk of bleeding in patients with cirrhosis [31].

Fibrinolysis

The liver is also the primary site of synthesis of both pro-fibrinolytic and antifibri-nolytic proteins, with the balance believed to be slightly tipped in favor of hyperfi-brinolysis [32]. In liver disease, plasminogen, α2-antiplasmin, thrombin-activatable fibrinolysis inhibitor (TAFI), and factor XIII are reduced, presumably due to decreased synthesis. The exceptions are both tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) which are synthesized by endothelial cells and are normal or increased in liver disease due to reduced clearance by the liver [33]. tPA is released from endothelial cells in response to injury and hemody-namic stress, and in liver disease clearance is impaired [34], and accumulation of tPA is thought to trigger hyperfibrinolysis. Lastly, movement of ascitic fluid into the circulation is hypothesized to contribute to hyperfibrinolysis [35].

This area of the hemostatic system in liver disease has not been extensively stud-ied, but most studies suggest a degree of hyperfibrinolysis [32], without clarifying the impact on clinical outcomes such as the risk of gastrointestinal bleeding or the risk of bleeding with surgical procedures. For a comprehensive review on the impact of liver disease on the fibrinolytic pathway, the reader is directed to a review by Leebeek and Rijken [32].

A study of the fibrinolytic status of patients with liver disease found a wide vari-ability in patient results, suggesting a need for a rapid, easy to perform laboratory test to guide the use of antifibrinolytic drugs [36]. Unfortunately, neither rotational thromboelastometry (ROTEM) nor thromboelastography (TEG) is sufficiently sen-sitive to hyperfibrinolysis, and better assays will need to be developed [37].

Standard Laboratory Assays

There are only four widely available tests for clinicians faced with a patient with liver disease – the INR, PTT, fibrinogen level, and platelet count. There are unfortu-nately limitations for all of these tests in patients with liver disease.

There are several levels of evidence that make us question the role of the INR in the management of patients with liver disease. First and foremost, the degree of INR elevation does not correlate with the risk of bleeding at the time of surgery or a procedure [38]. Second, the INR is based on the International Sensitivity Index (ISI), an index developed for patients stably anticoagulated on vitamin K antago-nists. Further highlighting the limitation of the INR in patients with liver disease, there is substantial variability between labs for patients with cirrhosis [39]. A sub-committee of the International Society on Thrombosis and Haemostasis


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recommended in 2010 that the INR calibrated for vitamin K antagonists (ISIvka) should not be used indiscriminately for patients with liver disease and that an INR calibrated against a population of patients with cirrhosis should be utilized (ISIliver) [39]. Despite this recommendation, patient population-specific INRs have not been adopted. Third, both the INR and the PTT are only sensitive to the coagulation enzymes and do not reflect the concurrent drop in the natural anticoagulants. This is thought to be attributed to the lack of thrombomodulin in the test system. Thrombomodulin is a transmembrane protein on endothelial cells that downregu-lates thrombin generation. In the absence of thrombomodulin in the assay, protein C is not fully activated resulting in falsely elevated coagulation test results in patients with liver disease. Lastly, the PTT may be shortened by the high factor VIII levels seen in patients with liver disease. The accuracy of fibrinogen testing has not been widely studied but appears to be valid in the majority of patients with good correla-tion between the functional assays (Clauss fibrinogen) and antigenic assays [40]. The platelet count is also only a measure of platelet number, and not function, and there is limited literature to suggest the impact of impaired function and number is compensated for by an increase in the vWF level [41].

Research Assays

The following assays have been used in research studies to further elucidate whether patients with elevated coagulation test results are actually at risk for bleeding. None of these tests are in routine, widespread clinical practice to guide decisionmaking in patients with liver disease that are either to undergo an invasive procedure or are bleeding. The results of these studies, however, further call into question the histori-cal dogma that patients with elevated coagulation test results are at risk for hemor-rhage and challenge the use of traditional tests as a guide for transfusion decisions.

1. Thrombin generation test (TGT): The TGT measures the total amount of thrombin generated and is thought to be a superior measure of the balance between the procoagulant and anticoagulant pathways. Indeed in a clinical study of patients with acute liver failure with a median INR of 3.4, thrombin genera-tion by this assay, which includes thrombomodulin, was preserved [42]. The lack of correlation between the INR/PTT and TGT in patients with liver disease has been confirmed by several reports [43, 44]. This test is not available in most centers, is very complex, and has not been standardized.

2. Rotational thromboelastometry (ROTEM): In contrast to the TGT, ROTEM is becoming widely available due to its use in perioperative and trauma settings. ROTEM is a point-of-care device that measures coagulation on whole blood and is believed to reflect the sum total of platelet and coagulation competency. For example, a patient with thrombocytopenia may still have a preserved ability to clot due to an increase in their fibrinogen or vWF to “compensate” for the plate-let deficit. Studies to date have failed to confirm a correlation between the TGT

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and ROTEM, suggesting results of ROTEM may not reflect the true coagulation balance in liver disease [45]. Given the very preliminary data published on the use of ROTEM to predict bleeding risk and utility in guiding blood component therapy in liver disease, routine use of ROTEM in these patients should only be done in the setting of controlled clinical studies.

3. Thromboelastography (TEG): TEG is a very similar technology to ROTEM that has undergone evaluation in the perioperative setting to guide blood compo-nent therapy, including for patients undergoing liver transplantation for liver fail-ure [46]. In liver disease, a small RCT has compared standard laboratory testing (platelet count and INR) to TEG-guided blood component therapy before bed-side and operative procedures [47]. Patients randomized to receive transfusion triggered by results of standard testing all received either platelets or plasma, as compared with only 17% of the TEG group. Despite the substantial reduction in blood component therapy, there was no difference in the bleeding rate. Of course, one could argue that none of the patients received any benefit from the transfu-sions in either treatment arm, but the study does raise solid concerns with the current protocols used to trigger transfusions in response to traditional laboratory tests. A small study of 40 patients undergoing liver resection monitored in the perioperative period with both conventional coagulation testing and TEG was performed [48]. Despite abnormal results of the INR and PTT, the TEG param-eters were hypercoagulable preoperatively and normalized postoperatively. Obviously, we are in the dark as to which assay is a more accurate reflection of the coagulation status of the patients. Similar to standard coagulation assays, both TEG and ROTEM have limitations. In particular, each lacks activation of protein C in the test system, and each lacks sensitivity to the levels of vWF [49, 50]. In addition, some reports have raised concern that patients with cirrhosis with prolonged standard coagulation test results, but a contrasting hypercoagu-lable pattern on TEG, are potentially at risk for thrombotic complications [51].

Pharmacologic Therapies

Vitamin K

There is a common practice of administering vitamin K to reverse the INR and PTT in patients with liver disease. In the setting of vitamin K deficiency, under- carboxylated precursors of the vitamin K-dependent factors (II, VII, IX, X, protein C, protein S) are produced and referred to as “proteins induced by vitamin K absence” (PIVKA). Vitamin K deficiency can be detected by the INR but more accurately by the measurement of PIVKA levels (not available in most hospital laboratories). A study of 89 patients with inactive hepatitis B infection, chronic viral hepatitis, cirrhosis, and hepatocellular carcinoma (and 39 healthy controls) admin-istered 10 mg of subcutaneous vitamin K was conducted [52]. At baseline before


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vitamin K administration, only the patients with cirrhosis and hepatocellular carci-noma had reduced factor VII levels (approximately 50% with INR at 1.6-fold above normal) and elevated levels of PIVKA levels. After vitamin K, there was minimal improvement in INR, PTT, and factor levels. There was a reduction in the level of PIVKA proteins after vitamin K, although the relevance of this modest change with-out corresponding increases in factor levels remains to be determined. A retrospec-tive single center study of patients with cirrhosis identified 130 patients treated with vitamin K and 146 patients not treated with vitamin K [53]. Administration of vita-min K was not associated with a decrease in either the INR or the incidence of bleeding.

In patients at risk for vitamin K deficiency based on history (alcoholism [54], poor intake of vitamin K-rich foods, and antibiotic exposure), it seems reasonable to administer vitamin K (preferably intravenously to ensure effectiveness as oral and subcutaneous have variable absorption) [55]. The routine application of vitamin K for all elevated coagulation test results in patients with liver failure is not justified based on the evidence to date.

1-Deamino-8-D-Arginine Vasopressin (DDAVP)

DDAVP is known to increase factor VIII and vWF in patients with congenital hemostatic disorders and therefore was logically studied in liver disease to see whether the same effect was observed. In a study of ten patients with cirrhosis, there was no increase in the factor VIII level and a minor increase in vWF level isolated to patients with less severe disease (Child-Pugh B vs. C) [56]. In a small study (n = 36) evaluating DDAVP prior to dental extraction in patients with cir-rhosis and platelet counts between 30 and 50 × 109/L and/or INR of 2–3, patients were randomized to either a classic platelet/plasma strategy or DDAVP. They found no difference in bleeding [57]. Unfortunately, there was no control arm of this trial, and therefore it remains to be determined if anything is needed before dental extraction in patients with cirrhosis. Preliminary clinical studies in patients with variceal bleeding [58] and undergoing liver transplantation [59, 60] also sug-gest questionable efficacy in improving hemostasis with DDAVP in patients with liver disease.

Recombinant Factor VIIa

Recombinant factor VIIa has been studied in multiple clinical situations in patients with liver disease including at time of hepatectomy [61], to facilitate procedures in ICU patients [62], management of variceal bleeding [63], and liver transplantation [64, 65]. There appears to be no significant impact on clinically important outcomes, such as mortality and other complications. Given the extreme costs of recombinant

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factor VIIa and the concern regarding thromboembolic complications in RCTs [66], it should be rarely, if ever, used outside of a clinical trial for patients with liver disease and bleeding.

Antifibrinolytic Agents

Antifibrinolytic agents have the potential for decreasing blood loss at the time of a surgical procedure and at the time of hemorrhage in patients with liver failure. In gastrointestinal bleeding of all etiologies including a subset of patients with variceal hemorrhage, a meta-analysis found that tranexamic acid reduced mortality com-pared with placebo (41 of 829 versus 68 of 825 patients; RR 0.61, 95% CI 0.42–0.89) [67]. A definitive trial of 12,000 patients with gastrointestinal bleeding is underway (HALT-IT trial; clinical trial.gov NCT0165812) [68]. The trial is pow-ered to detect a mortality benefit from tranexamic acid in this setting. Patients with all types of upper and lower gastrointestinal bleeding are eligible for this trial, including variceal hemorrhage patients. One expects that approximately a quarter of patients will have variceal bleeding to allow for subgroup analysis regarding the effectiveness in this important patient population. This trial will also provide clarity on the risk of thromboembolic complications from tranexamic acid in this setting. Currently, tranexamic acid is rarely used in clinical practice. Indeed, in a study of 1313 patients admitted with cirrhosis to hospital, 30% were transfused for bleeding/periprocedure, but only 5% of patients were administered antifibrinolytics [69]. If found to be effective in the management of bleeding patients with cirrhosis in the HALT-IT trial, this would be a huge advancement for the care of these patients.

Trials of the use of antifibrinolytics in liver transplantation find these agents effective at reducing transfusion requirements without increasing the risk of throm-botic complications [65, 70]. A randomized trial of 137 patients undergoing liver transplantation found aprotinin to be superior to placebo in reducing transfusion requirements [71]. In a small RCT of 45 patients undergoing liver transplantation, tranexamic acid was found to be superior to placebo in terms of transfusion require-ments [72]. A retrospective, case-controlled study of 367 matched pairs treated with and without tranexamic acid at the time of liver transplantation found a reduction in transfusion requirements without increasing the rate of thromboembolic complica-tions [73]. No difference between aprotinin and tranexamic acid in three random-ized trials of 52 patients [74], 127 patients [75], and 400 patients [76] undergoing liver transplantation was found. Tranexamic acid was found to be potentially more effective than epsilon-aminocaproic acid in a small randomized trial in patients undergoing liver transplantation [77]. A systematic review in liver transplantation found no increase in thromboembolic complications with the prophylactic use of antifibrinolytics [70]. Similar benefits in terms of transfusion requirements were found for both aprotinin and tranexamic acid for patients undergoing liver resection in a systematic review [78]. Studies on the use of antifibrinolytics in patients with liver disease outside of gastrointestinal bleeding, liver transplantation, and liver


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resection have not been done and are needed to clarify their role for control of bleeding at other sites and for prophylaxis before procedures.

Thrombopoietin Receptor Agonists

After trials utilizing thrombopoietin (TPO) receptor antagonists in patients with severe immune thrombocytopenia showed impressive responses, it was logical that such agents were studied in patients with thrombocytopenia from liver failure. Patients with severe thrombocytopenia planned for elective procedures or to com-mence therapy with antivirals appeared to be optimal candidates for such therapy. Indeed, 7% of patients with hepatitis C infection are ineligible for antiviral therapy due to severe thrombocytopenia [79], although this figure may further decrease with the introduction of less toxic direct antiviral agents.

In a trial of 292 patients with liver disease and platelet count below 50 × 109/L, participants were randomized to eltrombopag 75 mg orally for 14 days, or placebo, before an invasive procedure [80]. A platelet transfusion was avoided in 72% of eltrombopag-treated patients versus 19% of placebo-treated patients (p < 0.001), and there were no differences in the rate of hemorrhagic complications between the two groups. Unfortunately after 292 patients had been randomized, of a planned 500 patients, the trial was stopped early due to an excess of thromboembolic complica-tions in the eltrombopag-treated patients (OR 3.04, 95% CI 0.62–14.82), with all thrombotic events in the eltrombopag group in the portal venous system. In a report, 74 patients with platelet counts between 20 and 70 × 109/L were randomly assigned to one of three doses of eltrombopag or placebo [81]. Three-quarters of the eltrombopag- treated patients achieved a platelet count in excess of 100 × 109/L, compared to none of the placebo-treated patients. There was a clear increase in response with increasing doses. There were no thromboembolic complications observed. A study with the thrombopoietin receptor agonist, romiplostim, enrolled patients with liver disease and platelet count below 50 × 109/L prior to elective sur-gery [82]. A dose of 2 μg/kg subcutaneously on a weekly schedule was administered to a target platelet count of 70 × 109/L. Overall, 94% achieved the target platelet response by surgery with no untoward bleeding or thrombotic complications. Another study reported on 130 patients with cirrhosis and platelet counts between 10 and 58 × 109/L treated with avatrombopag for 7 days prior to procedures or pla-cebo [83]. Platelet count rise to >50 and 20 × 109/L above baseline was achieved by half of those treated with avatrombopag and less than 10% of the placebo-treated patients. No concerns regarding thromboembolic complications were observed.

The data on thrombopoietin agonists are encouraging, but clearly more data are needed to fully understand the risk of thrombotic complications. It is possible that these agents are safer than platelet transfusions which are not risk free and carry a risk of bacterial contamination, transfusion-related acute lung injury, and volume overload. Although these agents should still be considered experimental, off-label use would be justified in patients refractory to platelet transfusions, during severe platelet shortages, or for patients with religious objections to transfusion.

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Pharmacologic and Interventional Strategies for the Prevention and Management of Bleeding Esophageal Varices

Gastrointestinal hemorrhage is the leading cause of mortality in liver disease, with half of patients with cirrhosis and esophageal varices experiencing hemorrhage due to rupture, of whom one-third will die of hemorrhage [84]. Size of the varices is the primary factor for risk of subsequent hemorrhage [85]. Patients with cirrhosis should undergo baseline screening endoscopy and then every 2 years if no or small (<5 mm) varices are detected (every 3 years if ongoing liver injury is absent) [86]. Patients with medium and large varices should undergo either endoscopic variceal ligation, nonselective beta-blockade, or carvedilol treatment, with choice based on patient preference [86]. Prophylactic treatment can reduce the risk of bleeding by 50% [87].

For patients that unfortunately fail preventative strategies, a multimodal approach is taken and includes transfusion, vasoactive drugs (such as somatostatin, octreo-tide, or other agent), endoscopy for endoscopic variceal ligation within 12 h (or sclerotherapy where ligation is technically not feasible), and transjugular intrahe-patic portosystemic shunt for select patients [87]. Less commonly, patients bleed from other gastrointestinal processes, including Mallory-Weiss tear, gastric varices, portal hypertensive gastropathy, and ectopic varices [84].

Prevention of Bleeding with Transfusion Support

Prophylactic Platelet Transfusions Prior to Bedside or Surgical Procedures

Approximately 5% of all platelet transfusions are administered in the ICU [88], of which 5% are transfused for a “gastrointestinal” admitting diagnosis [89]. The American Association for the Study of Liver Diseases (AASLD) position paper on the management of patients scheduled for liver biopsy states two (conflicting) rec-ommendations for platelet transfusions [90]:

1. The decision to perform liver biopsy in the setting of abnormal laboratory param-eters of hemostasis should continue to be reached as the result of local practice(s) and consideration of the risks and benefits of liver biopsy because there is no specific PT-INR and/or platelet count cutoff at or above which potentially adverse bleeding can be reliably predicted (Class I, Level C).

2. Platelet transfusion should be considered when levels are less than 50–60 × 109/L (this applies whether one is attempting biopsy transcutaneously or transve-nously) (Class I, Level C).

The lack of consistency in the above recommendations can be explained by the conflicting data from clinical studies. First, rarely do patients undergoing a procedure bleed, irrespective of their platelet count. This makes it nearly impossible to complete


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an RCT due to the low frequency of adverse events. In a large retrospective study of 6613 image-guided liver biopsies, there were 34 (0.5%) hemorrhagic complications [91]. The following were statistically associated with bleeding in this report: more than two biopsy passes, female gender, and platelet count of less than 50 × 109/L. There were only 92 patients with platelet counts less than 50 × 109/L, of whom only 2 (2.2%) bled, when compared to patients with platelet counts in excess of 50 × 109/L of whom 0.5% bled. Similarly, a study of 2740 liver biopsies reported 16 (0.58%) bleeding complications, with one-quarter of these in patients with platelet counts below 60 × 109/L [92]. Bleeding risk was associated with a low platelet count (5.9% vs. 0.5%, p < 0.001), but it is unknown if the risk is directly from thrombocytopenia or if the low platelet count is simply a marker for other factors (increased venous pressure, poor vascular integrity, clot fragility, or increased clot lysis) that increase the risk of bleeding. In particular, it is unknown if a platelet transfusion could correct the clotting impairment to prevent bleeding. In contrast, in a study of 852 patients with cirrhosis undergoing a variety of procedures, 0 of 89 patients with platelet counts below 50 × 109/L bled, compared to 10 of 763 with higher platelet counts [93]. Other studies have been performed in this patient population and again found no increased risk of bleeding associated with the baseline platelet count [94, 95].

Second, even if pre-procedure platelet transfusions could reduce the chance of bleeding at the time of an invasive procedure, the actual rate of procedure-related bleeding is so low that the number-needed-to-treat is very high, making the inter-vention very unlikely to be either cost-effective or with a favorable risk-benefit ratio. Third, studies have raised the concern regarding thromboembolic complica-tions from platelet transfusions, and therefore it is unlikely that platelet transfusions are given without any risk [96–99]. In fact, there is a reasonable concern that the increased venous pressure resulting from a pre-procedure platelet transfusion may increase the risk of bleeding at the time of percutaneous liver biopsy or central line placement. Fourth, platelet sequestration in patients with hypersplenism may reduce the posttransfusion increment and the effectiveness of platelet transfusions despite still incurring the volume toxicity. Over 20% of platelet transfusions are ineffectual (rise of <5 × 109/L), with preexisting liver disease being an associated risk factor [89]. In a study of 26 patients undergoing endoscopic variceal ligation, platelet transfusion prior to the procedure resulted in an increment of 13 × 109/L, without change to either the thrombin generation time or TEG results [100]. Given the cur-rent state of the literature on procedures in patients with liver disease and thrombo-cytopenia, the only logical conclusion is that prophylactic platelet transfusions should only be rarely applied and that therapeutic platelet transfusions should be given for the uncommon patient with hemorrhagic consequences. With the current clinical guidelines suggesting to prophylactically transfuse platelets for counts less than 50 × 109/L, we are undoubtedly overtransfusing the vast majority of patients. The American Association of Blood Banks (AABB) guidelines provide global rec-ommendations for platelet thresholds for all patient types before procedures but do not provide specific recommendations for patients with liver failure [7]. The AABB recommends a threshold of 20 × 109/L for central line placement and 50 × 109/L for major non-neuroaxial procedures (quality of the evidence, very low; strength of the recommendation, weak; no specific recommendations for liver biopsy or paracente-

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sis). A systematic review of studies evaluating platelet thresholds for central line placement (in all patient types and not just liver disease) identified no RCTs and 20 studies reporting on outcomes of patients with platelet counts pre-procedure of less than 50 × 109/L [101]. No major bleeding events occurred in patients with platelet counts below 50 × 109/L, and this has led many authors [102–104] and the AABB [7] to choose 20 × 109/L as the threshold for platelet transfusion, although the opti-mal threshold may be below 20 × 109/L.

Platelet Transfusions to Treat Active Hemorrhage in Patients with Liver Disease

There is very little published on evaluating different platelet thresholds in the man-agement of bleeding in patients with liver disease (or any other patient population). It is believed that bleeding in liver disease is almost exclusively gastrointestinal from high portal pressures and the resulting varices, rather than due to the low plate-let count [105]. The higher the portal pressures and the larger the varix diameter, the greater the risk of gastrointestinal bleeding [105]. Indeed, patients with liver failure rarely bleed at other sites, such as an intracranial hemorrhage (1.5% of bleeding in patients with liver failure) [22]. Hence the management of patients with isolated gastrointestinal bleeding should be focused on local therapies to stop the bleeding (prompt endoscopic therapy with ligation) [105].

It is also likely prudent to prevent and treat any concurrent illnesses that may contribute to the bleeding risk. Renal failure is associated with platelet dysfunction and should be appropriately managed. Bacterial infection is known to trigger the release of heparinoids from endothelial dysfunction, which resolves with antibiotics [106]. Bacterial endotoxin is also thought to impair platelet function [107]. Hence, prompt treatment with antibiotics is indicated when infection is suspected or confirmed.

The appropriate platelet transfusion threshold for patients with liver disease and hemorrhage has not been studied. Experts commonly recommend maintaining the platelet count above 50 × 109/L, but this is based on very-low-quality evidence [108].

Plasma Transfusion for Patients with Liver Disease

Prophylactic Plasma Transfusion for Patients with Liver Disease Before Bedside and Surgical Procedures

Overall, 42% of all plasma transfused is in the ICU [109], and 24% of plasma is transfused to patients with liver disease, of which the vast majority is likely unnec-essary [110]. In a large series of 1313 consecutive patients admitted with cirrhosis from 85 hospitals in the United Kingdom, 11% of plasma was transfused to patients


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with an INR below 1.5 where there would be no anticipated benefit [69]. It is unclear what is driving this inexplicable practice, whether it is knowledge gaps, delays in access to coagulation test results, or inappropriate utilization of massive hemor-rhage protocols with formula-driven resuscitation. Several large retrospective stud-ies have documented variable plasma transfusion practice across centers and concerns regarding overuse [111, 112].

In addition, several studies have documented a minimal change in the INR when plasma is administered to patients with an INR below 1.8 [113–115]. Administering plasma before procedures is not without consequences, including delays in procedures for the infusion and transfusion adverse events, particularly transfusion- associated circulatory overload [116] and increases in venous pres-sures increasing the risk of hemorrhage. Most importantly, there is no evidence from systematic reviews that the practice reduces the incidence of hemorrhagic complications at the time of procedures [101]. Several authors have published on the inutility of current practice and call for a change in clinical management [117–119]. In addition, a liver transplant can be done with minimal plasma trans-fusion, calling into question the need for plasma for more minor procedures [120, 121].

In a study of 1234 non-cardiac surgery patients with INR > 1.5, of whom 11% were prophylactically transfused with plasma before the procedure, there was no reduction in the incidence of bleeding with plasma transfusions, and perioperative outcomes, including mortality, were inferior in the plasma-treated group [119].

Certainly for minor bedside procedures with bleeding rates below 1% (paracen-tesis, thoracentesis, central line placement), plasma should only be transfused after the procedure for the rare patient who has a bleeding complication. In addition, plasma should never be transfused for an asymptomatic elevation of the coagulation tests. For patients undergoing more major procedures, the current standard of care is not to transfuse plasma prophylactically [119], as can be seen from the retrospective review detailed above, and this approach appears to confer better outcomes for patients.

Plasma Transfusion for Active Hemorrhage in Patients with Liver Disease

There are no interventional trials to guide decisions about plasma transfusion in bleeding patients with liver disease. This leaves us with guidance from experts in the field based on their own clinical experience [122] and retrospective reviews of “real-world” plasma transfusion practice [69]. A review of one of the largest retro-spective series of blood use in patients with cirrhosis [69] involved 1313 patients from 85 hospitals of whom 34% of patients were transfused plasma (61% of trans-fusions for bleeding and 39% for prophylaxis). In this study involving 1313 patients from 85 hospitals, 34% of patients were transfused with plasma, with 61% of trans-fusions for bleeding and 39% for prophylaxis. Disturbingly, but perhaps

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highlighting an area of clinical medicine ripe for change, 42% of patients had nor-mal INR levels (or worse not even measured) before the infusion of the plasma. This overuse of plasma has been highlighted in other multicenter studies [123] and has been the focus of “Choosing Wisely” campaigns [124–126].

The AABB published guidelines for plasma transfusion in 2010 [122]. Due to the lack of evidence, the guideline group was unable to make an evidence-based recommendation regarding if or when plasma should be transfused to non-trauma, bleeding patients in the absence of massive hemorrhage. They did however make a recommendation against the use of plasma in patients with abnormal test results in the absence of bleeding or procedures.

A retrospective review of 1493 ICU patients found 211(12%) had cirrhosis [127], with 17% of patients developing new major bleeding during their ICU stay. They compared patients that experienced new major bleeding compared to no major bleeding and found ICU admission platelet count, fibrinogen level, and PTT were statistically more deranged in the major bleeding group. Patients who experienced major bleeding were more likely to have a history of varices, large varices, and half were bleeding on admission. It is unclear in a retrospective review to determine if the bleeding was triggered by the coagulopathy, whether the coagulopathy was a marker of more severe portal hypertension or whether the bleeding resulting in derangement of laboratory test results due to consumption at sites of hemorrhage.

Specifically in patients with gastrointestinal hemorrhage, the data from prospec-tive clinical trials find the use of blood components (plasma, platelets, and cryopre-cipitate) to be unnecessary in the vast majority of patients, with approximately 95% only requiring red blood cell transfusion [2, 3].

Given the complete lack of clinical studies and the lack of correlation between the INR and the coagulation status of the patient with liver disease, one cannot make a recommendation for when to give plasma based on the INR. One can make a rec-ommendation, as the AABB did [122], of when not to give plasma. Certainly if the INR is below 1.8 due to liver disease and the patient is bleeding, plasma transfusion is very unlikely to change the INR or mitigate the rate of hemorrhage. In the absence of data, plasma transfusion decisions should be individualized, and the clinician should consider the rate and location of hemorrhage, whether local hemostatic mea-sures or prompt surgical intervention alone would be sufficient, whether there is evidence of coagulopathy due to bleeding at multiple sites, and the rate of change in the coagulation test results over time. Refrain from transfusing plasma for all patients with INR levels in excess of 1.5 in the setting of liver disease, as in the vast majority of the time, minimal benefit is expected.

Prothrombin Complex Concentrates in Patients with Liver Disease

Prothrombin complex concentrates are lyophilized coagulation factor concentrates (PCCs) of the vitamin K-dependent factors (factors II, VII, IX, and X, protein C, protein S) and antithrombin III that are utilized extensively for the reversal of


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warfarin therapy in patients with serious bleeding or in need of emergency surgery. Prior to infusion they are resuspended in a small volume of sterile diluent, resulting in a low volume product of 40–80 mL depending on the dose but certainly much lower volume than 4 units of plasma at 1000 mL. This smaller volume certainly is appealing for patients with liver disease with concerns regarding transfusion caus-ing increases in portal pressures, resulting in aggravation of bleeding from lesions in the gastrointestinal tract. In addition, infusion risks are lower, particularly the risk of transfusion-associated circulatory overload. Although there are potential theo-retical benefits, many studies have raised concerns regarding the thrombotic risks of PCCs [128, 129].

There are no definitive studies evaluating the use of PCCs in patients with liver disease. Studies are needed because PCCs contain no fibrinogen, factor V, factor IX, factor XI, or factor XIII, all of which are made in the liver. An ongoing study called the PROTON study [130] involving 70 patients scheduled for liver transplantation with “severe coagulopathy” (an INR in excess of 1.5) will randomize patients to PCCs or placebo immediately before surgery. The primary endpoint is the volume of red cell transfusion during and up to 24 h after surgery. Obviously, if the INR fails to predict who bleeds at the time of surgery, utilizing the INR as the primary inclu-sion criteria for the study may be problematic.

There are only small retrospective studies evaluating the utility of PCCs in liver disease. In a retrospective study of 45 patients treated with plasma, PCCs, or recom-binant factor VIIa before procedures, the authors suggested bleeding was more prevalent in the plasma group and thrombosis more in the other two groups, although the numbers were too small to draw any conclusions [62]. Similarly, a retrospective cohort study of 30 patients treated with PCCs with liver disease before procedures or to manage bleeding found a reduction in the INR in most patients, although 2 of 9 patients treated for active hemorrhage died of bleeding [131]. Lastly, in a small, retrospective cohort study of 25 patients with liver disease undergoing procedures or bleeding, the therapy reduced the INR without any adverse events [132]. Obviously, these small retrospective studies provide little evidence to support the use of PCCs to mitigate the blood loss risk with procedures or to manage actively bleeding patients. Hence, the use of PCCs in patients with liver disease is experimental and should only be done in a prospective study with appropriate con-sent of the patient and a control population.

Red Blood Cell Transfusion Support in Patients with Liver Disease

Red blood cell transfusion is one area of transfusion management that is based on higher-quality evidence. Randomized controlled trials confirm that a restrictive strategy (<70 g/L) is at least as good and possibly superior to a liberal transfusion strategy (<90 g/L) [2, 3]. Patients in the liberal transfusion strategy have a higher

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rate of rebleeding and mortality [3], presumably due to a rise in portal pressures posttransfusion. In the study by Villanueva et al. [3], 31% had cirrhosis (74% Child- Pugh B/C), and 24% had variceal hemorrhage, and therefore the results are general-izable to liver disease patients with bleeding. The major limitations to this study are as follows: (a) key patient populations were excluded (massively bleeding patients, patients with acute coronary syndromes) and (b) all patients underwent therapeutic endoscopy within 6 h. Hence, this restrictive strategy may not be appropriate for all patient subgroups and may only be safe in centers able to perform rapid therapeutic endoscopy. The finding of increased rebleeding in the liberal transfusion arm raises the possibility of new strategies for transfusions which might reduce a sudden increase in portal pressures (e.g., single-unit transfusions, slow rate of infusion, and pre-transfusion diuretics).

Thromboprophylaxis and Therapeutic Anticoagulation in Patients with Liver Disease

The incidence of thrombosis for patients on prophylactic dose anticoagulants is approximately 2%, and the incidence of bleeding on these agents is 3% [133, 134]. A case-control study involving 99,444 patients with venous thromboembolism and 496,872 controls found that patients with liver disease had an increased risk of venous thromboembolism [135].

A systematic review of the published literature (seven trials, only one RCT) found thromboprophylaxis to be safe with no increase in the risk of bleeding, but surprisingly no decrease in the risk of thrombosis [136]. In a retrospective case series of 600 patients published after the systematic review, of which half of the patients were prescribed venous thromboprophylaxis, no difference in the incidence of thrombosis or bleeding was found [134]. In the single, randomized, non-blinded trial included in the systematic review which included 70 outpatients, those patients allocated to low molecular weight heparin had a lower rate of portal vein thrombosis (9% vs. 28%, p = 0.048). Experts and guidelines recommend that thromboprophylaxis should not be withheld unless there is active bleeding, although this is not based on high-quality evidence [137, 138]. To complicate matters, the ideal choice of antico-agulant is unclear for patients with liver disease. Vitamin K antagonists may be more difficult to administer to patients with chronic liver disease due to their low factor VII levels, with its short half-life. Other agents, such as low molecular weight heparins or the new direct oral anticoagulant drugs, may be theoretically easier to administer and in theory may be more effective and safer.

For patients with a thrombosis, there is little clarity on the safety and the optimal agent for patients with liver disease. There are safety concerns with vitamin K antagonist, as patients with liver disease have been excluded from randomized tri-als [139]. In addition, the optimal INR target for a patient with liver disease is unknown if the patient has a baseline elevation in their INR. Anticoagulation in


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liver disease has been most extensively studied in patients with portal vein throm-bosis. In a systematic review and meta-analysis of eight studies (353 patients), patients treated with either warfarin or low molecular weight heparin (vs. no ther-apy) had higher rates of recanalization, without increasing the rates of minor or major bleeding [140]. There are only small preliminary studies on the efficacy and safety of the direct oral anticoagulants, as compared to vitamin K antagonists [141].

Recommendations for the Prevention and Management of Bleeding in Patients with Liver Disease

Given the unfortunate lack of high-quality clinical studies in patients with liver disease to allow for evidence-based clinical care, one can only make some prelimi-nary recommendations based on expert opinion and low quality of evidence (with the notable exception of higher-quality evidence for red cell transfusion):

(a) Bleeding from esophageal varices should be prevented through the evidence- based use of endoscopic screening, use of pharmacologic agents to reduce por-tal pressures, and endoscopic variceal ligation.

(b) Bleeding from esophageal varices should be promptly managed with timely endoscopic variceal ligation and pharmaceutical agents.

(c) Prevent and treat conditions that aggravate the coagulation disturbance in liver disease (bacterial infections, renal failure).

(d) Standard laboratory tests and emerging technologies for the assessment of the coagulation status in patients with liver disease do not accurately reflect the coagulation competence of these patients; hence, their results should be used with caution when making transfusion decisions.

(e) Red cell transfusions should be administered with a restrictive approach (<70 g/L) with attention paid to avoid increasing portal pressures and precipitat-ing rebleeding and transfusion-associated circulatory overload.

(f) Platelet transfusions are often considered if the platelet count is below 20 × 109/L for procedures with low risk of hemorrhage (e.g., paracentesis, central catheter placement) and below 50 × 109/L for operative procedures with higher risk for bleeding, but the evidence for this practice is poor.

(g) There is likely no benefit from plasma for patients with liver disease with INR levels below 1.8 before procedures or at the time of hemorrhage.

(h) There is no benefit from plasma for patients with liver disease with high INR levels (any level) in the absence of bleeding or procedure.

(i) It is unknown if there is any benefit from plasma transfusion for bleeding patients or patients scheduled for invasive procedures with INR levels above 1.8.

(j) Vitamin K 10 mg with slow (>20 min) IV infusion should only be considered in patients with clinical risk factors for vitamin K deficiency (poor oral intake, alcoholism, and antibiotic therapy).

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(k) Don’t withhold thromboprophylaxis or therapeutic anticoagulation unless there is a clear contraindication (i.e., do not assume that patients with elevated INRs are auto-anticoagulated).

(l) The following therapies are unproven/experimental for the management of bleeding in patients with liver disease: tranexamic acid, DDAVP, thrombopoi-etin agonists, recombinant factor VIIa, and PCCs.

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73. Badenoch A, Sharma A, Gower S, Selzner M, Srinivas C, Wasowicz M, et al. The effective-ness and safety of tranexamic acid in orthotopic liver transplantation clinical practice: a pro-pensity score matched cohort study. Transplantation. 2017;101(7):1658–65.

74. Ickx BE, van der Linden PJ, Melot C, Wijns W, de Pauw L, Vandestadt J, et al. Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation. Transfusion. 2006;46(4):595–605.

75. Dalmau A, Sabate A, Koo M, Bartolome C, Rafecas A, Figueras J, et al. The prophylactic use of tranexamic acid and aprotinin in orthotopic liver transplantation: a comparative study. Liver Transpl. 2004;10(2):279–84.

76. Massicotte L, Denault AY, Beaulieu D, Thibeault L, Hevesi Z, Roy A. Aprotinin versus tranexamic acid during liver transplantation: impact on blood product requirements and sur-vival. Transplantation. 2011;91(11):1273–8.

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78. Gurusamy KS, Li J, Sharma D, Davidson BR. Pharmacological interventions to decrease blood loss and blood transfusion requirements for liver resection. Cochrane Database Syst Rev. 2009(4):CD008085.

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81. McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357(22):2227–36.

82. Moussa MM, Mowafy N. Preoperative use of romiplostim in thrombocytopenic patients with chronic hepatitis C and liver cirrhosis. J Gastroenterol Hepatol. 2013;28(2):335–41.

83. Terrault NA, Hassanein T, Howell CD, Joshi S, Lake J, Sher L, et al. Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure. J Hepatol. 2014;61(6):1253–9.

84. Ertel AE, Chang AL, Kim Y, Shah SA. Management of gastrointestinal bleeding in patients with cirrhosis. Curr Probl Surg. 2016;53(8):366–95.

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86. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrho-sis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017;65(1):310–35.

87. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hyperten-sion: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120(3):726–48.

88. Charlton A, Wallis J, Robertson J, Watson D, Iqbal A, Tinegate H. Where did platelets go in 2012? A survey of platelet transfusion practice in the North of England. Transfus Med. 2014;24(4):213–8.

89. Ning S, Barty R, Liu Y, Heddle NM, Rochwerg B, Arnold DM. Platelet transfusion practices in the ICU: data from a large transfusion registry. Chest. 2016;150(3):516–23.

90. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. American Association for the Study of Liver D. Liver biopsy. Hepatology. 2009;49(3):1017–44.

91. Boyum JH, Atwell TD, Schmit GD, Poterucha JJ, Schleck CD, Harmsen WS, et al. Incidence and risk factors for adverse events related to image-guided liver biopsy. Mayo Clin Proc. 2016;91(3):329–35.

92. Seeff LB, Everson GT, Morgan TR, Curto TM, Lee WM, Ghany MG, et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(10):877–83.

93. Napolitano G, Iacobellis A, Merla A, Niro G, Valvano MR, Terracciano F, et al. Bleeding after invasive procedures is rare and unpredicted by platelet counts in cirrhotic patients with thrombocytopenia. Eur J Intern Med. 2017;38:79–82.

94. Shah A, Amarapurkar D, Dharod M, Chandnani M, Baijal R, Kumar P, et al. Coagulopathy in cirrhosis: a prospective study to correlate conventional tests of coagu-lation and bleeding following invasive procedures in cirrhotics. Indian J Gastroenterol. 2015;34(5):359–64.

95. Thakrar SV, Mallett SV. Thrombocytopenia in cirrhosis: impact of fibrinogen on bleeding risk. World J Hepatol. 2017;9(6):318–25.

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97. Schmidt AE, Refaai MA, Blumberg N. Platelet transfusion and thrombosis: more questions than answers. Semin Thromb Hemost. 2016;42(2):118–24.

98. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605–13.

99. Zakko L, Rustagi T, Douglas M, Laine L. No benefit from platelet transfusion for gas-trointestinal bleeding in patients taking antiplatelet agents. Clin Gastroenterol Hepatol. 2017;15(1):46–52.

100. Tripodi A, Primignani M, Chantarangkul V, Lemma L, Jovani M, Rebulla P, et al. Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion. Liver Int. 2013;33(3):362–7.

101. van de Weerdt EK, Biemond BJ, Baake B, Vermin B, Binnekade JM, van Lienden KP, et al. Central venous catheter placement in coagulopathic patients: risk factors and incidence of bleeding complications. Transfusion. 2017;57(10):2512–25.

102. Barrera R, Mina B, Huang Y, Groeger JS. Acute complications of central line placement in profoundly thrombocytopenic cancer patients. Cancer. 1996;78(9):2025–30.

103. Tomoyose T, Ohama M, Yamanoha A, Masuzaki H, Okudaira T, Tokumine J. Real-time ultrasound-guided central venous catheterization reduces the need for prophylactic platelet transfusion in thrombocytopenic patients with hematological malignancy. Transfus Apher Sci. 2013;49(2):367–9.

104. Zeidler K, Arn K, Senn O, Schanz U, Stussi G. Optimal preprocedural platelet transfu-sion threshold for central venous catheter insertions in patients with thrombocytopenia. Transfusion. 2011;51(11):2269–76.

105. Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, et al. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;64(11):1680–704.

106. Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. J Hepatol. 2002;37(4):463–70.

107. Kujovich JL. Coagulopathy in liver disease: a balancing act. Hematology Am Soc Hematol Educ Program. 2015;2015:243–9.

108. Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G, Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party. Recommendations for the trans-fusion of plasma and platelets. Blood Transfus. 2009;7(2):132–50.

109. Triulzi D, Gottschall J, Murphy E, Wu Y, Ness P, Kor D, et al. A multicenter study of plasma use in the United States. Transfusion. 2015;55(6):1313–9. quiz 2

110. Pahuja S, Sethi N, Singh S, Sharma S, Jain M, Kushwaha S. Concurrent audit of fresh frozen plasma: experience of a tertiary care hospital. Hematology. 2012;17(5):306–10.

111. Walsh TS, Stanworth SJ, Prescott RJ, Lee RJ, Watson DM, Wyncoll D, et al. Prevalence, management, and outcomes of critically ill patients with prothrombin time prolongation in United Kingdom intensive care units. Crit Care Med. 2010;38(10):1939–46.

112. Dara SI, Rana R, Afessa B, Moore SB, Gajic O. Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy. Crit Care Med. 2005;33(11):2667–71.

113. Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Am J Gastroenterol. 2003;98(6):1391–4.

114. Holland LL, Foster TM, Marlar RA, Brooks JP. Fresh frozen plasma is ineffective for correct-ing minimally elevated international normalized ratios. Transfusion. 2005;45(7):1234–5.

115. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on pro-thrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion. 2006;46(8):1279–85.

116. Gorlinger K, Saner FH. Prophylactic plasma and platelet transfusion in the critically ill patient: just useless and expensive or even harmful? BMC Anesthesiol. 2015;15:86.

117. Roberts LN, Bernal W. Management of bleeding and thrombosis in critically ill patients with liver disease. Semin Thromb Hemost. 2015;41(5):520–6.

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119. Jia Q, Brown MJ, Clifford L, Wilson GA, Truty MJ, Stubbs JR, et al. Prophylactic plasma transfusion for surgical patients with abnormal preoperative coagulation tests: a single- institution propensity-adjusted cohort study. Lancet Haematol. 2016;3(3):e139–48.

120. Massicotte L, Denault AY, Beaulieu D, Thibeault L, Hevesi Z, Nozza A, et al. Transfusion rate for 500 consecutive liver transplantations: experience of one liver transplantation center. Transplantation. 2012;93(12):1276–81.

121. Massicotte L, Beaulieu D, Thibeault L, Roy JD, Marleau D, Lapointe R, et al. Coagulation defects do not predict blood product requirements during liver transplantation. Transplantation. 2008;85(7):956–62.

122. Roback JD, Caldwell S, Carson J, Davenport R, Drew MJ, Eder A, et al. Evidence-based practice guidelines for plasma transfusion. Transfusion. 2010;50(6):1227–39.

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Chapter 10Hematological Challenges in Intensive Care Unit Patients with Neurological Disease

Alejandro Vargas and Thomas P. Bleck

Introduction

Hematologic complications are common challenges in a neurological or neurosci-ences intensive care unit (NICU) due to the extent of neurological conditions encountered. This chapter will focus on common disease states encountered in the NICU and the hematologic complications in each of these diseases, such as anemia, coagulopathy, thrombocytosis, and leukocytosis.

Traumatic Brain Injury

Traumatic brain injury (TBI) can be encountered on a day-to-day basis from a slip and fall, motor vehicle accidents, sports, or combat. The degree of TBI varies with severity, if consciousness was altered, or if the injury was open or closed. TBI from any cause is a leading cause of death and disability in the United States [1]. In the span of a decade, the incidence of TBI increased from 1.4 million people in the United states to 2.5 million, and hospitalizations increased from 235,000 to 284,630 [2, 3]. If it is severe enough to warrant an intensive care unit (ICU) admission, then other peripheral consequences may arise. Anemia has been recognized in relation to traumatic brain injury but has not been well characterized and is roughly estimated to occur in approximately 50% of admissions [4]. The definition of anemia, either by hemoglobin concentration or hematocrit, is important to distinguish. At least one

A. Vargas, MD (*) • T. P. Bleck, MD Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USAe-mail: [email protected]; [email protected]




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hematocrit of <30% was seen during the ICU stay of TBI patients in 40–50% of patients in multiple retrospective evaluations [5–7]. A hemoglobin concentration of <8 g/dL occurred in 22% of TBI patients, though this same study noted hypoten-sion, hyperglycemia, and hypoalbuminemia were more likely independent predic-tors of an unfavorable outcome [8].

A retrospective study of 81 patients with severe TBI (defined as Glasgow Coma Scale [GCS] score of ≤8) who excluded patients who died in the first 24 h, had delayed transport, had rapid improvement in symptoms, or did not have evidence of a hemorrhagic lesion (such as subdural hemorrhage [SDH] or traumatic subarach-noid hemorrhage [SAH]) followed 11 secondary brain injury factors to determine their importance (acidosis, coagulopathy, hypotension, hypoxia, hypocapnia, hyper-capnia, hypothermia, hyperthermia, hyperglycemia, intracranial hypertension, sei-zure) [9]. They concluded that hypotension and hypothermia had the most significant impact on morbidity and mortality, though hypoxia and acidosis were also associ-ated with poor outcomes [9].

Where the ideal hemoglobin should be maintained is crucial for patient care and outcomes but has not been well established with evidence. The Transfusion Requirements in Critical Care (TRICC) trial randomized 838 patients admitted to the ICU without evidence of active bleeding to a restrictive transfusion goal (7–9 g/dL) versus a liberal transfusion goal (10–12 g/dL) and noted that a restrictive trans-fusion goal is at least as effective and possibly superior in survival compared to a liberal transfusion goal [10]. A subgroup analysis of TRICC focusing on patients who sustained a closed head injury noted no difference in mortality, length of stay, and organ failure between a restrictive and liberal transfusion protocol in these patients [11]. Maintaining a hematocrit >30% has long been recommended with theoretical benefit of maintaining optimal oxygen carrying capacity but with little supporting evidence; however, a retrospective analysis of 174 patients demon-strated no impact of persistence of hematocrit <30% on long-term outcomes [12]. Given the well-known harmful effects of transfusion, such as lung injury, fever, infection, and thromboembolic events, and the association with increased in hospi-tal mortality rates, the importance of definitive data emerged [13]. The largest ret-rospective analysis of this subject included 1565 adult (>16 years of age) patients who did not expire in the first 24 h of admission, comparing a restrictive (hemoglo-bin >7 g/dL) versus a liberal (hemoglobin >10 g/dL) transfusion protocol, and they demonstrated a significant difference in fever burden, but no difference in ICU length of stay, ventilator delays, incidence of lung injury, thromboembolic events, and mortality, with an estimated savings of $115,000 annually in direct and indirect costs [14].

Coagulopathy and thrombocytopenia may also be encountered in TBI. The inci-dence of coagulopathy varies significantly, and a meta-analysis of 82 articles over 40 years estimated one out of three civilian TBI patients displays signs of coagu-lopathy [15]. This may be >60% when TBI is severe but could be as rare as <1% in mild TBI [16, 17]. If bleeding is a concern, then platelets may be culprit. The exact mechanism of coagulopathy (either hypercoagulability or bleeding diathesis),

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thrombocytopenia, or platelet dysfunction after TBI is still speculative [18]. A ret-rospective study noted that thrombocytopenia predicted traumatic intracranial hemorrhage (ICH) progression at counts of <175,000/mm3 and a ninefold risk of death with counts <100,000/mm3 [19]. Another prospective study demonstrated that bleeding tendency can occur in the setting of a normal platelet count, and platelet dysfunction is implicated [20]. Functional assays may be used for early diagnosis of a hypo- or hypercoagulable state after TBI, and this may be in turn used to guide treatment [21].

Coagulopathy may be defined by thrombocytopenia, internal normalized ratio (INR), or activated partial thromboplastin time (aPTT). Coagulopathy has been noted to be more common with increasing severity of injury [22]. TBI patients with coagulopathy (which this study found an incidence of 42%) had more signs of tissue hypoperfusion as indicated by increased lactate levels and metabolic acidosis [23]. Whatever degree of severity or character of TBI, when coagulopathy is present, it portends worse prognosis [24–26]. A recent review suggests, given the lack of stan-dardization of definitions and the knowledge gap on pathogenesis, that even mild TBI can be associated with clinically significant coagulopathy due to platelet dys-function [27]. A retrospective study noted that coagulopathy was found to be an early predictor of mortality after penetrating TBI [28]. The most recent and exten-sive literature review pools all the reports of coagulopathy in TBI, noting the signifi-cant data reported, but there exists a gap in knowledge in contributions of platelet dysfunction and endothelium abnormalities, as well as different phenotypes and manifestations, and lastly the different effects of older patients presenting with falls with their more frequent use of antiplatelets and anticoagulants in the management and treatment of these TBI patients [29].

Leukocytosis may also be seen in TBI, though an association with outcome has not been well established. In a retrospective study of 279 blunt trauma patients, a statistically significant difference in leukocytosis existed between two groups dichotomized (with significant injury and without significant injury), but the white blood cell (WBC) level could not be used to rule in or rule out severe injury [30]. Another retrospective study of 805 patients found that WBC count is not a useful addition as a diagnostic indicator of major trauma [31]. Another biomarker, inter-leukin-6 (IL-6), is noted to be in higher concentrations in cerebrospinal fluid (CSF), and this may play a role in initiating the acute-phase response [32]. Other biomarkers such as neurofilament heavy chain protein (NF-H), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1), neuron spe-cific enolase (NSE), myelin basic protein (MBP), and tau have been shown to be elevated in the acute phase of severe head trauma, though their clinical implica-tions are not known, and the downstream effects of these pathways are also uncer-tain [33]. The identification of biomarkers which would correlate with these hematological derangements paired with further understanding the mechanisms of the development of anemia or coagulopathy would provide significant targets for preventive treatment, rather than consequentially treating abnormalities once they are already triggered.

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Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) may be traumatic or spontaneous, and a substan-tial percentage are due to ruptured aneurysms. This section will focus on the hema-tological challenges faced in aneurysmal SAH (aSAH), as traumatic SAH patients were covered in the TBI section above. Anemia is commonly found in SAH patients, and when a cutoff of <30% hematocrit is used, 47% of patients were found to be anemic [34]. When a cutoff of <11 g/dL hemoglobin is used, it is present in 80% of patients [35]. Poor outcomes were just suggested by these studies, and thus little data existed until a retrospective study of 103 patients and a prospective registry of 611 patients collected outcomes at 14 days/discharge and at 3 months and noted that patients who were independent had higher peak and nadir levels and thus overall higher hemoglobin levels correlating this higher level with improved outcome (increased independence, less cerebral infarction, less poor outcomes, and less death) [36, 37]. Short-term outcome analyses may be confounded, however, by the mixture of patients treated with coiling and clipping, since coiled patients tend to have less blood loss and better short-term outcome, even though their long-term outcomes are similar to clipped patients. Mechanistically, impaired oxygen delivery and cerebral blood flow (CBF) mediated by anemia would predispose to delayed cerebral ischemia (DCI) [38]. A higher hemoglobin level may not be without con-sequence as well, and a higher level may increase blood viscosity, lead to autoregu-latory vasoconstriction and thus reduce CBF [38, 39].

Red blood cell (RBC) transfusion is an option to increase arterial oxygen content and theoretically compensate for mechanisms that may lead to DCI. An observa-tional study of eight patients with aSAH and hemoglobin <10 g/dL obtained (15)O-positron emission tomography (PET) before and after transfusion of one unit of RBCs, and this resulted in a significant rise in cerebral oxygen delivery without lowering global CBF [40]. On the other hand, a retrospective review of 441 patients demonstrated those who received intraoperative RBC transfusion were at increased risk for worse outcomes and postoperative RBC transfusion placed patients at a higher risk of angiographically confirmed vasospasm [41]. Other observations sup-port this and mechanistically involve altered nitrous oxide (NO) metabolism and transfusion products in exacerbating cerebral ischemia or inducing vasoconstriction or RBC deformability due to storage and ischemia in microcirculation leading to DCI and worse outcomes [42–44]. The risk and incidence of cardiac dysfunction during admission for SAH patients makes a restrictive goal for transfusion contra-indicated, and thus data from the TRICC trial cannot be applied to this patient popu-lation [45]. Most recently, a retrospective study of 261 SAH patients who received an RBC transfusion had statistically significant increase of angiographic vasospasm (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1–2.3, p = 0.025), but not of severe angiographic spasm, DCI, or delayed infarction [46]. However, when exam-ining the time course of transfusion, transfusion is often found to follow the devel-opment of clinical signs of DCI, indicating that transfusion was the consequence, not the cause, of neurologic deterioration [47].


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Anemia predicts a poorer outcome from aSAH regardless of the occurrence of DCI, however [48]. The Aneurysmal SubArachnoid Hemorrhage-Red Blood Cell Transfusion and Outcome (SAHaRA) trial will dichotomize patients into a liberal (hemoglobin <10 g/dL) versus restrictive (hemoglobin <8 g/dL) transfusion strat-egy to specifically address SAH patients and obtain prospective data [49].

Coagulopathy is less described in SAH. As early as 1970, 30 patients were described as having abnormal coagulation and fibrinolytic studies, notably that fibrinogen values >400 mg/dL were associated with low probability of survival, and laboratory values suggested a procoagulable state and activation of fibrinolytic mechanisms [50]. This was later further supported with a prospective study of 76 patients demonstrating strong activation of the coagulation and fibrinolytic system, notably increase of plasmatic thrombin-antithrombin complex seemed to parallel clinical status, and high levels of D-dimer were associated with poor outcomes [51]. A systematic review found that patients with DCI had higher levels of von Willebrand factor and platelet activating factor in plasma 5–9 days after aSAH, membrane tis-sue factor in cerebrospinal fluid 5–9 days after aSAH, and D-dimer in plasma 11–14 days after aSAH, compared to patients without DCI [52]. Lastly, small evi-dence exists on the role of thrombocytopenia and SAH. Relative thrombocytopenia (platelets <150,000/mm3) was associated with symptomatic vasospasm with an OR 5.1–6.9 between days 5 and 9 [53].

Systemic inflammatory response syndrome (SIRS) may develop after aSAH, and it was associated with poor outcome, but not with angiographic vasospasm, delayed ischemic neurologic deficit, or cerebral infarction among 413 patients [54]. Another retrospective review of 224 patients found four independent predictors of vaso-spasm, including peak serum leukocyte count (OR 1.09, 95% CI 1.02–1.16), and specifically if leukocyte count was >15 × 109/L the risk was higher (OR 3.33, 95% CI 1.74–6.38) [55]. A retrospective study of 55 patients found that on day 3 after aSAH, leukocytosis (OR 5.18, 95% CI 1.03–26.13, p < 0.046) and anemia (OR 4.12, 95% CI 1.12–15.16, p < 0.032) correlated with the occurrence of delayed cerebral ischemia [56]. A prospective study of 246 patients demonstrated that leu-kocytosis had a significant association with DCI and poorer Glasgow Outcome Scale (GOS) score [57].

Ischemic Stroke

A prospective study of 250 patients demonstrated an increased risk of death at 6 months among patients who were diagnosed with anemia (defined as hemoglobin <12 g/dL for women, <13 g/dL for men) with an OR of 4.1 (95% CI 1.1–8.2) [58]. Another prospective study of 859 patients demonstrated, after adjustment for patient characteristics, admission anemia had an adjusted OR for all-cause death at 1 month of 1.90 (85% CI 1.05–3.43) and at 1 year of 1.72 (95% CI 1.00–2.93) and combined disability or nursing facility care or death at 1 month of 2.09 (95% CI 1.13–3.84) and 1 year of 1.83 (95% CI 1.02–3.27); however anemia did not have a linear


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correlation, and increased risk existed at both extremes of hemoglobin level [59]. Given that stroke severity was strongly predictive of stroke-related mortality, comorbidities may be more apparent in less severe strokes. A retrospective cohort of 1306 stroke admissions demonstrated that among less severe stroke (National Institutes of Health Stroke Scale [NIHSS] <10), admission anemia was indepen-dently associated with in-hospital mortality and discharge to hospice (OR 4.17, 95% CI 1.47–11.90) [60]. A prospective study of 107 patients noted that patients with hemoglobin <11 g/dL more often achieved a modified Rankin Scale (mRS) score of 4–5 than patients with hemoglobin >11 g/dL (p = 0.0167) [61]. A case-control study in a Taiwanese population included 51,093 stroke patients matched with 153,279 randomly selected controls and found an adjusted OR of prior iron deficiency anemia diagnosis in stroke cases to be 1.45 (95% CI 1.34–1.58) when compared to their control population [62]. A retrospective study of 1733 AIS patients from a single center in Japan demonstrated that anemia was independently associated with a 3-month mortality (OR 2.81, 95% CI 1.46–5.43) [63]. Finally, a pooled population from a meta-analysis demonstrated that anemia on admission was found to be associated with an increased risk of mortality in ischemic stroke (OR 1.97, 95% CI 1.57–2.47) [64]. Notably, earlier studies demonstrated the higher the hematocrit level, the stronger association with reduced reperfusion, greater infarct size, and in women may represent an independent risk factor for mortality [65, 66].

Transfusion has been investigated less than anemia, and little prospective data exist for the general population of stroke patients. A retrospective analysis of 109 patients further noted that almost all patients developed substantial anemia during their hospital stay and that patients receiving RBC transfusion did not show any advantage in outcome [67]. Current guidelines do not support any specific level of treatment of anemia with transfusion, either in the acute management, primary pre-vention, or secondary prevention of ischemic stroke for the general population [68–70].

Sickle cell disease patients require different management approaches. Stroke is a major complication of sickle cell disease, with a prevalence of 11% by age 20 and with a significant burden of white matter hyperintensities and silent ischemia [71, 72]. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) demonstrated that maintaining the hemoglobin S concentration to <30% would reduce the risk of stroke by 70% [73]. This was later demonstrated in another study that the risk of stroke was reduced from 10% annually to 1% annually [74].

Hypercoagulable states are a rare cause of AIS. These hypercoagulable syn-dromes primarily affect veins, though reports of arterial thrombosis exist in protein S deficiency, protein C deficiency, antithrombin III deficiency, factor V Leiden mutation, prothrombin gene mutations, hyperhomocysteinemia, dysfibrinogenemia, plasminogen deficiency, and antiphospholipid antibody syndrome [75]. Despite these, due to their rarity, guidelines currently state that screening for thrombophilic states in patients with a history of ischemic stroke or TIA has an unknown benefit (class IIb, Level of Evidence C) and that anticoagulation might be considered in patients who are found to have these states (class IIb, Level of Evidence C) [70].


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Similarly, hypercoagulability has been recognized as a result of cancer [75]. Trousseau’s syndrome, manifesting as stroke and then revealing an underlying malignancy, is an important consideration [76, 77]. A suspicion of an underlying malignancy should be considered in patients with older age, history of smoking, elevated C-reactive protein, elevated fibrinogen levels, and elevated D-dimer; the most common cancer implicated was lung cancer [78]. This was correlated with ultrasound as well, noting a high prevalence of embolic signal on transcranial Doppler in patients with cancer and those without conventional stroke mechanisms when compared to those without stroke (57.9% vs 33.3%, p = 0.034), and also not-ing higher levels of D-dimer (OR 1.082 per 1 mcg/mL increase, 95% CI 1.1014–1.154) and adenocarcinoma (OR 3.829, 95% CI 1.23–13.052) were independently associated with the presence of embolic signal [79].

Essential thrombocythemia was also a risk factor for ischemic stroke, both in a watershed distribution and in a small-vessel disease distribution, in a retrospective analysis [80, 81]. Seven patients out of 2185 first-ever AIS patients presented with immune thrombocytopenia, and three of them were of undetermined etiology, sug-gesting a relationship [82]. A retrospective study of 9230 patients showed that both low and high platelet counts were associated with a higher 30-day mortality (p ≤ 0.0335) and 90-day mortality (p ≤ 0.048), but not initial stroke severity, degree of disability, or length of stay [83].

The association with outcomes in AIS and leukocytosis was observed as well, and along with erythrocyte sedimentation rate (ESR), it was thought to be related with a poor prognosis [84]. Leukocytosis and neutrophilia were associated with the volume of infarcted tissue in AIS [85]. Elevated leukocyte count in the very early phase of AIS is a significant independent predictor of poor initial stroke severity (p < 0.001), pool clinical outcome at 72 h (p < 0.001), and disability at discharge (p < 0.001) [86]. The degree of leukocytosis was recently implicated in outcome, and every 1 × 10−9/L increase was found to be an independent predictor of stroke severity (OR 1.09, 95% CI 1.07–1.10, p < 0.0001), disability at discharge (OR 1.04, 95% CI 1.02–1.06, p = 0.0005), and 30-day mortality (hazard ratio [HR] 1.07, 95% CI 1.05–1.08, p < 0.0001), as well as noting an elevated WBC count is associated with increased mortality in AIS (p = 0.001) [87].

Antiplatelets and Anticoagulants

Antiplatelets and anticoagulants are widely encountered in neurological diseases, notably in ischemic stroke prevention. Primary or secondary ICH could be compli-cations encountered in the ICU setting with patients on these medications. Two-thirds of ICH could be primary (non-traumatic), due to cerebral small-vessel disease [88]. A recent review noted that the increased use of antiplatelets along with a popu-lation increasing in age demonstrated increased risk of ICH with antiplatelet use, and increased risk of death after ICH [89]. The PATCH trial demonstrated, contrary to hypothesis, that platelet transfusion increases the risk of death or dependence in


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ICH patients on antiplatelet medications [90]. Guidelines recommend against plate-let administration and could only be considered in the setting prior to a neurosurgi-cal procedure [91]. Desmopressin (DDAVP) could be considered in ICH associated with aspirin/cyclo-oxygenase (COX)-1 inhibitors or adenosine diphosphate (ADP) receptor inhibitors, but low-quality evidence exists [91].

Anticoagulation carries a more grim prognosis in ICH, with about half of patients showing symptom progression in the first 24 h, fluid-blood levels being seen in the first 12 h, and death or dependence as outcomes in 76% of patients [89]. The worse prognosis seems to be associated with vitamin K antagonists (VKA). Evidence reviewed and recommended by the Neurocritical Care Society and Society of Critical Care Medicine states discontinuing VKA, administration of vitamin K, and administration of three-factor or four-factor prothrombin complex concentrate (PCC) for VKA-associated ICH [91]. When PCC is not available, then fresh frozen plasma (FFP) is recommended [91]. Heparin-associated ICH may also be encoun-tered, with heparin itself or low-molecular-weight heparin (LMWH) . Protamine sulfate administration is recommended in these instances [91].

Outcomes in patients with novel or direct oral anticoagulants (DOACs) are not as grim as warfarin-associated ICH, and these patients do have better outcomes in observational studies, but further prospective data is necessary, as well as data on direct reversal agents for these medications [89]. For oral direct factor Xa inhibi-tors, data recommends discontinuation of medication, activated charcoal if last dose was within 2 h, and administering four-factor PCC or activated PCC if hemor-rhage occurred within 3–5 half-lives of last exposure or in the context of liver failure [91]. For direct thrombin inhibitors (DTI), discontinuation of medication, activated charcoal if last dose was within 2 h, and administration of idarucizumab for dabigatran or four-factor PCC/activated PCC if another DTI was culprit are recommended [91].

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74. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5–11.

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78. Selvik HA, Thomassen L, Bjerkreim AT, Næss H. Cancer-associated stroke: the Bergen NORSTROKE study. Cerebrovasc Dis Extra. 2015;5(3):107–13.

79. Seok JM, Kim SG, Kim JW, Chung CS, Kim GM, Lee KH, et al. Coagulopathy and embolic signal in cancer patients with ischemic stroke. Ann Neurol. 2010;68(2):213–9.

80. Pósfai É, Marton I, Szőke A, Borbényi Z, Vécsei L, Csomor A, et al. Stroke in essential throm-bocythemia. J Neurol Sci. 2014;336(1–2):260–2.

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82. Park HK, Lee SH. Ischemic stroke associated with immune thrombocytopenia: lesion patterns and characteristics. Neurol Sci. 2014;35(11):1801–6.

83. Furlan JC, Fang J, Silver FL. Outcomes after acute ischemic stroke in patients with thrombo-cytopenia or thrombocytosis. J Neurol Sci. 2016;362:198–203.

84. Nikanfar M, Shaafi S, Hashemilar M, Oskouii DS, Goldust M. Evaluating role of leukocytosis and high sedimentation rate as prognostic factors in acute ischemic cerebral strokes. Pak J Biol Sci. 2012;15(8):386–90.

85. Buck BH, Liebeskind DS, Saver JL, Bang OY, Yun SW, Starkman S, et al. Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke. 2008;39(2):355–60.

86. Nardi K, Milia P, Eusebi P, Paciaroni M, Caso V, Agnelli G. Admission leukocytosis in acute cerebral ischemia: influence on early outcome. J Stroke Cerebrovasc Dis. 2012;21(8):819–24.


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87. Furlan JC, Vergouwen MD, Fang J, Silver FL. White blood cell count is an independent predic-tor of outcomes after acute ischaemic stroke. Eur J Neurol. 2014;21(2):215–22.

88. Al-Shahi Salman R, Labovitz DL, Stapf C. Spontaneous intracerebral haemorrhage. BMJ. 2009;339:b2586.

89. An SJ, Kim TJ, Yoon BW. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: an update. J Stroke. 2017;19(1):3–10.

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Chapter 11Hematologic Challenges in the Critically Ill: Obstetrics

Nadav Levy and Carolyn F. Weiniger

Coagulation Changes in the Pregnant Woman

Pregnancy is a hypercoagulable state characterized by substantial rise in coagula-tion factor concentrations, a twofold increase in fibrinogen levels, a reduction in natural anticoagulants concentrations, and diminished fibrinolytic activity [1, 2]. The increase in coagulation activity is correlated with gestational age and reaches its peak at the time of delivery [3].

Identification of the Pregnant Woman at Risk for Hematologic Complications

Pregnant women may present with a variety of hematologic challenges, most com-monly in the postpartum period with hemorrhage related to uterine atony, adherent placenta, delivery-related trauma, or disseminated intravascular coagulation. Prior to delivery, pregnant women may present most commonly with trauma-related inju-ries [4]. Other bleeding conditions such as antepartum hemorrhage related to bleed-ing diathesis, idiopathic thrombocytopenia, HELLP syndrome with preeclampsia, and liver cirrhosis and hypercoagulable conditions such as thromboembolism may

N. Levy, MD Division of Anesthesia, Intensive Care and Pain Medicine, Tel-Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel

C. F. Weiniger, MB ChB (*) Division of Anesthesia, Intensive Care and Pain Medicine, Tel-Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel

Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel


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also present a hematologic challenge for the pregnant patient. Sickle-cell crisis is a relatively rare yet important challenge.

Antepartum Hematologic Crises

Trauma in pregnant women occurs in less than 10% of pregnancies, and although most frequently associated with minor injuries [4], it is the leading non-obstetrical cause of maternal death during pregnancy [5]. Motor vehicle accidents, assaults, and falls are the most common causes of trauma in pregnancy, all associated with a signifi-cant hemorrhage risk [6]. Trauma in pregnancy should be managed as for nonpregnant cases, along the Advance Trauma Life Support guidelines. The primary goal is stabili-zation and management of the mother. Fetal well-being may assist assessment of the mother; however this is not a primary management goal [6, 7]. As with other traumas, the current management recommendations may include 1:1:1 transfusion ratio of packed red blood cells, fresh frozen plasma, and platelets and has been associated with improved survival [8]. Individualized “goal-directed” patient blood management in trauma, based on point-of-care viscoelastic tests, may be used in some centers. However, further studies are needed to identify the optimal strategy of fixed transfusion ratios and point-of-care management, particularly in the obstetric population [9, 10].

An obstetrician may be required to assist in the evaluation, and in cases of abrup-tion and hysterotomy, a laparotomy should be performed with a surgeon present to assist with management of other possible concurrent injuries [6]. Aside from inju-ries associated with the mechanism, placental abruption is a major risk for pregnant women and should be suspected in both major and minor traumas [6]. Thrombotic risk is increased in fractures in pregnant women, and fractures have an associated increased placental abruption risk [11]. Blood transfusion is more likely in pregnant women who sustain fractures versus pregnant women without injury during preg-nancy, and 18% of women with fractures have concurrent placental abruption [11].

Sickle-cell disease Sickle-cell hemoglobinopathies may constitute a critical mater-nal condition during pregnancy, particularly when associated with preeclampsia and during delivery. Hemoglobin (Hb) SS is the most prevalent variant of sickle-cell disease (SCD), yet other variations exist, albeit usually associated with less severe morbidities. Pregnancy-related morbidity such as stroke, infection, eclampsia, hem-orrhage, and organ failure is higher, as reported among 1526 women with SCD in the United States [12]. There are a number of hematologic aspects to SCD beyond the multi-organ disease resulting from the sickle-cell-shaped red blood cell mem-brane that impacts capillary circulation [12–14]. Vaso-occlusive crisis (VOC), caused by organ vaso-occlusion in the presence of impaired microcirculation [15], is triggered by acidosis, hypoxia, and infection [14] and is the most common SCD- related cause of hospitalization during pregnancy [14–17]. Thrombotic events asso-ciated with pregnancy and SCD include deep vein thrombosis, embolus, and stroke, and a low index of suspicion is required when faced with a pregnant woman with

N. Levy and C. F. Weiniger

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SCD and suspicious signs. One important differential diagnosis in SCD for pulmo-nary embolus is acute chest syndrome, manifesting with similar symptoms, and it may also be confused with pneumonia. Management includes hydration, oxygen, and antibiotics, and blood transfusion may be required to manage severe hypoxia [14]. SCD raises the mortality risk (relative risk 5.98; 95% confidence interval [CI], 1.94–18.44) [18] versus women without SCD.

Venous Thromboembolism

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mor-tality. Assessment of thromboembolism risk is recommended for every woman pre-senting for prenatal care. Clear guidelines for VTE prophylaxis are available, based primarily on low molecular weight heparin (LMWH) or unfractionated heparin (UFH), varying in dosage and duration according to the patient’s history and under-lying condition [19]. Advanced planning and structured communication should be practiced when preparing patients receiving VTE prophylaxis for delivery. Information regarding the antithrombotic drug, the dosage, and the time of the last dose is crucial for the anesthetic and obstetric management [20].

Antepartum Evaluation

Adequate preventive measures should be taken in the presence of known risk factors for PPH (Table 11.1) and for women with anemia or an anticipated decline to receive blood components such as Jehovah’s witnesses. Guidelines from the National Institute for Health and Care Excellence (NICE) recommend that pregnant women should be offered screening for anemia and should receive iron supplementation [21, 22]. The British Committee for Standards in Haematology (http://www.b-s-h.org.uk/guide-lines/guidelines/management-of-iron-deficiency-in-pregnancy/) has produced guide-lines on the investigation and management of anemia in pregnancy. Hemoglobin (Hb) levels outside the normal UK range for pregnancy (110 g/l at first contact and 105 g/l at 28 weeks) should be investigated and iron supplementation considered if indicated.

Hemorrhage in Pregnancy

Antepartum Hemorrhage

Placental abruption, placenta previa, or vasa previa should be considered in any case of antepartum vaginal bleeding. Pregnancy should be suspected in women of child-bearing age who present with an acute abdomen, as hemorrhage may be concealed.

11 Hematologic Challenges in the Critically Ill: Obstetrics

http://www.b-s-h.org.uk/guidelines/guidelines/management-of-iron-deficiency-in-pregnancy/

http://www.b-s-h.org.uk/guidelines/guidelines/management-of-iron-deficiency-in-pregnancy/

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Obstetric management is determined according to volume of blood loss and mater-nal/fetal clinical picture and vital signs [23]. Emergency delivery and immediate hemorrhage management may be required. An obstetric hemorrhage protocol may guide all components of the management planned in an emergency scenario. Coagulopathy risk is increased with the severity of placental detachment, and early administration of FFP is recommended by some guidelines [22], although there is potential to dilute fibrinogen as donor plasma may have lower fibrinogen levels from mostly male donors [24].

Postpartum Hemorrhage (PPH)

The American Congress of Obstetricians and Gynecologists defined postpartum hemorrhage (PPH) as the “cumulative blood loss of >=1000 ml or blood loss accom-panied by signs and symptoms of hypovolemia within 24 hours following the birth process” [25]. PPH is a leading cause of maternal morbidity and mortality

Table 11.1 Risk factors for postpartum hemorrhage

Preexisting conditions

Age > 40 years Anemia Asian and African ethnicity Coagulopathies Grand multiparity Hypertension Obesity Over-distended uterus (macrosomia, twins)Obstetric conditions

Preeclampsia Previous PPH Previous cesarean deliveries Peripartum factors Prolonged or rapid labor Instrumental delivery Episiotomy Infection Induction of laborPlacental conditions

Abnormal placentation (invasive/previa) Abruption Retained placentaPostpartum conditions

Atony Birth canal trauma

Key: PPH postpartum hemorrhage


203

worldwide, with an estimated incidence of 5–15% of deliveries [21, 26, 27]. Uterine atony (failure of the uterus to contract postpartum) is the most common cause, accounting for 70–80% of PPH cases. Other major causes of PPH are presented in Table 11.1 [28].

Anticipation of Postpartum Hemorrhage

Most cases of PPH occur unexpectedly, mandating the anesthetic and obstetric teams to be familiar with the risk factors and presentation of PPH. Women with known risk factors for PPH should be referred to deliver in a facility with immediate access to blood and blood components [29]. Since anemic patients are more prone to hemodynamic compromise in case of hemorrhage, anemia diagnosed in the pre-natal follow-up should be corrected using iron supplements [30]. Women with known bleeding diathesis should receive prophylactic treatment or factor replace-ment therapy in the perinatal period. This may depend on the specific factor defi-ciency (homozygote vs. heterozygote) and history of bleeding. Hemorrhage is often far greater than estimated and, as for antepartum hemorrhage, on many occasions, may be concealed [31].

Diagnosis of Postpartum Hemorrhage

Early recognition and diagnosis of PPH and rapid correction of hypovolemia are crucial to mitigate hypovolemic shock and development of coagulopathies. Neuraxial block, with its associated sympathetic block used during anesthesia for cesarean delivery, may magnify the physiologic response, or hypotension may be wrongly attributed to the anesthesia, if ongoing blood loss is overlooked.

Visual Estimate the visual estimation of blood lost during vaginal or cesarean delivery is often inaccurate [31], and methods to improve accurate blood loss assess-ment have not been found to expedite the diagnosis [32].

Maternal Vital Signs may be normal even with hemorrhage up to 30% of the blood volume [33]. A number of obstetric early warning systems are described, designed to warn of impending instability as vital signs become deranged (Table 11.2) [34]. The obstetric shock index (pulse rate divided by systolic blood pressure) if used may facilitate early recognition of PPH [35].

Adjuvant Diagnostic Modalities the fetal heart rate monitor may be a useful sign of maternal well-being [6]. Noninvasive hemodynamic monitors, based on bio-impedance analysis or Doppler velocimetry, have yet to be validated in obstetrics but may effect on the diagnosis of PPH and the decision-making process in the future.


204

Transthoracic echocardiography (TTE) can be used for early assessment of vol-ume status and as a monitor for resuscitation. Simple TTE-based, hemodynamic evaluation protocols (e.g., the RUSH exam) can be adjusted for obstetric population and serve as an additional tool in the management of acute hemorrhage [36, 37].

Laboratory Testing serum fibrinogen levels are normally elevated in pregnancy (350–600 mg/dl during the third trimester) [38], and therefore the threshold fibrinogen level for replacement administration during PPH should reflect this [39, 40]. During PPH, fibrinogen levels <400 mg/dl may be seen, and these are considered abnormal [41, 42]. Point-of-care tests including viscoelastic hemostatic assays, such as throm-boelastogram (TEG®) and thromboelastometry (ROTEM®) [43], can provide a faster coagulation analysis and flag the need for specific components such as fibrinogen.

Management of Postpartum Hemorrhage

ACOG recommends that all departments have a specific PPH protocol to guide treatment and hold regular drills to optimize team management [44]. Early recog-nition is vital to enable early implementation of management strategies. Several national PPH guidelines present treatment strategies including patient blood management and have been recently summarized [39]. The rapid management approach as for any unstable patient is the ABC approach, including supplemen-tary oxygen, and maneuvers to adapt for pregnancy that avoid acid aspiration and aortocaval compression. The critically ill pregnant/postpartum woman may be acutely unstable and require intensive ventilatory and cardiovascular support.

Table 11.2 Maternal early warning criteria

Parameter Value

Systolic BP (mm Hg) <90 or >160Diastolic BP (mm Hg) >100Heart rate (beats per min) <50 or >120Respiratory rate (breaths per min) <10 or >30Oxygen saturation, room air, % <95Oliguria, mL/h., for ≥2 h <35Maternal agitation, confusion, unresponsiveness

Reproduced with permission and without modification from Arora et al. [34]Key: BP blood pressure


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Patient Blood Management

Adequate intravenous access may include insertion of large bore cannula, and the antecubital fossa may be a suitable site, or neck veins, rather than femoral veins. A heating rapid infusor should be used, and invasive arterial blood pressure monitor-ing may be required.

Massive transfusion protocols (MTPs) are associated with improved outcomes for bleeding trauma patients [45]. MTPs typically recommend blood management strategies and transfusion ratios [46]. However, although many hospitals may have MTP, compliance with their use for management of trauma and other hemorrhages may be low, for example, Cotton et al. [47] and Bawazeer et al. [48] reported non- compliance rates of 34% and 47%, respectively. National guidelines recommend a 1:1:1 transfusion ratio for packed red blood cells (PRBCs), fresh frozen plasma (FFP), and platelets, based on these trauma guidelines [39]. Furthermore trauma transfusion ratios and MTPs may be unsuitable for PPH management due to the unique physiological blood component adaptations in pregnancy [46]. Point-of-care testing may be more suitable to guide replacement, as described previously, for example, fibrinogen is needed early in PPH.

Many units have a PPH protocol. A study of US academic centers revealed that 67% of centers have a PPH protocol [49]. However, the presence of a MTP may not necessarily be associated with the presence of a PPH protocol [49]. Importantly, similar to trauma hemorrhage, PPH managed using an MTP is asso-ciated with decreased mortality, as reported in a 3-year study of 77 women undergoing cesarean delivery for placenta accreta or increta in 19 medical cen-ters [50]. Furthermore Shields et al. [51] and Rizvi et al. [52] noted that compli-ance with a PPH protocol during peripartum hemorrhage results in faster cessation of bleeding and transfusion of less PRBC units. Butwick et al. noted that activation of an MTP can contribute to timely administration of cross-matched blood components [53]. Large volumes of crystalloid solutions are associated with dilutional coagulopathy, ARDS, and abdominal compartment syndrome. “Crystalloid minimization” is therefore recommended for trauma and hemorrhagic shock management [54]. Initial fluid resuscitation with isotonic crystalloids is recommended by WHO guidelines for PPH management [55]. More specifically, some guidelines suggest an infusion of up to 2–3.5 L of warmed crystalloid solution if clinically required until blood is available [22]. Colloids have dose-dependent effects on fibrin polymerization and platelet aggregation, aggravating coagulopathy, and should generally be avoided during uncontrolled hemorrhage [56].


206

Pharmacology for Postpartum Hemorrhage

Prophylactic administration of uterotonics reduce the PPH risk. Oxytocin is usually the first-line uterotonic and low dose infusion appears sufficient for a suitable effect (Fig. 11.1) [57]. Methylergonovine may be associated with reduced PPH risk com-pared to carboprost [58].

Tranexamic acid may reduce hemorrhage if given safely within 3 h among women with PPH; however prophylactic use has not been shown to reduce PPH at this time [59].

Vasopressor support should be initiated as required to support maternal hemodynamics.

Surgical Interventions for Postpartum Hemorrhage

A stepwise parallel surgical/obstetric and blood management approach should be adopted for PPH management, according to the bleeding etiology and severity (Fig. 11.2). Bleeding from genital tract laceration, uterine rupture, and placenta accreta or due to retained placenta prompts immediate operative intervention. The first intervention in case of uterine atony is to achieve tamponade via uterine mas-sage. A balloon tamponade can be considered as the next step and may act as a bridge until invasive interventions. Selective arterial embolization has a high suc-cess rate and relatively low morbidity and can be a diagnostic or curative procedure that may preclude surgical interventions. Angiographic embolization may be pos-sible if the patient can be transferred and relies on the facility and personnel capa-bilities. Some institutions may have a hybrid operating room available that will facilitate surgical and angiographic therapies. Transfer of a woman with PPH from hospital to hospital for embolization is possible if hemodynamic condition allows. Surgical interventions range from uterine compression sutures to vessel ligation and hysterectomy that may be required as a last resort [39, 60].

The use of a cell saver is supported by the American College of Obstetrics and Gynecology and by the UK’s National Institute for Health and Care recommenda-tions [61, 62].

Emergency Drills

As efficient protocols and teamwork are crucial for correct and timely treatment of PPH, emergency drills should be considered in every delivery facility. Multidisciplinary simulation-based team training is potentially effective in the pre-vention of errors and may aid in correcting and adapting protocols to the local set-ting, thus improving patient safety [44, 63]. Multidisciplinary drills of obstetricians,


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Postoperative Considerations

General anesthesia with intubation may have been performed to protect airway and ventilation in case of hemodynamic instability [21]. Once adequate resuscitation and control of the bleeding are achieved, reassessment should be performed to determine the need for further blood component administration. After massive hem-orrhage management, an intensive care unit bed is appropriate to assess further hemodynamic stability and to wean from inotrope and ventilation support as needed. In their review of all pregnancy-related ICU admissions in France over a 4-year period, Chantry et al. reported that despite PPH being a leading diagnosis for ICU admissions, women with PPH have relatively low case fatality rates and relatively

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Fig. 11.2 Management of postpartum hemorrhage. (Adapted with permission from Obstetrics: normal and problem pregnancies 7th edition; Gabbe S, Niebyl J, Simpson J et al. IV: Intravenous)


209

short ICU stays [66]. Respiratory (transfusion-related lung injury) or hemodynamic (transfusion-associated circulatory overload) complications associated with alloge-neic blood component administration are not common in the obstetric population [67, 68]. In cases of severe lung injury, further ventilation support may be required [69]. The volume status of critically ill women with hematologic disease should be monitored closely. Autotransfusion likely adds to the circulating volume that may be overloaded after hemorrhage replacement in PPH or renal dysfunction in pre-eclampsia [70].

Special consideration should be given to postpartum women with hypertensive disease of pregnancy. Hypertensive disease of pregnancy generated 30% of 2927 obstetric ICU admissions according to a Maryland State Inpatient Database 1999–2008 [71]. Some women may develop hypertension only after delivery (including HELLP syndrome) [72]. This initial presentation may be a seizure without prior hypertension or visual disturbance [73]. Women with preeclampsia may have liver ischemia which may cause liver capsule hemorrhage. Rupture of liver capsule has a high maternal mortality rate [74]. A rare complication of preeclampsia is renal fail-ure requiring dialysis. In a Canadian cohort of almost 2 million pregnancies, 1:10000 pregnancies required dialysis associated with acute kidney injury [75]. Risk factors for renal failure in pregnancy include diabetes, pre-pregnancy hypertension, chronic renal disease, and SLE [75].

The decision for extubation at the end of surgery will be based upon the likeli-hood of re-bleed, need for additional surgical procedures such as angiography, and presence of airway edema.

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2. Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114:409–14. 3. Thornton P, Douglas J. Coagulation in pregnancy. Best Pract Res Clin Obstet Gynaecol.

2010;24:339–52. 4. El Kady D. Perinatal outcomes of traumatic injuries during pregnancy. Clin Obstet Gynecol.

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14. Pregnancy. G-tGMoscdi: Management of sickle cell disease in pregnancy, London: Royal College of Obstetricians and Gynaecologists 2011.

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19. Friedman AM, D’Alton ME. Venous thromboembolism bundle: risk assessment and prophy-laxis for obstetric patients. Semin Perinatol. 2016;40:87–92.

20. Leffert L, Butwick A, Carvalho B, Arendt K, Bates SM, Friedman A, Horlocker T, Houle T, Landau R, Dubois H, Fernando R, Houle T, Kopp S, Montgomery D, Pellegrini J, Smiley R, Toledo P. The Society for Obstetric Anesthesia and Perinatology Consensus Statement on the anesthetic management of pregnant and postpartum women receiving thromboprophylaxis or higher dose anticoagulants. Anesth Analg 2018;126(3):928–44.

21. Sentilhes L, Vayssiere C, Deneux-Tharaux C, Aya AG, Bayoumeu F, Bonnet MP, Djoudi R, Dolley P, Dreyfus M, Ducroux-Schouwey C, Dupont C, Francois A, Gallot D, Haumonte JB, Huissoud C, Kayem G, Keita H, Langer B, Mignon A, Morel O, Parant O, Pelage JP, Phan E, Rossignol M, Tessier V, Mercier FJ, Goffinet F. Postpartum hemorrhage: guidelines for clini-cal practice from the French College of Gynaecologists and Obstetricians (CNGOF): in col-laboration with the French Society of Anesthesiology and Intensive Care (SFAR). Eur J Obstet Gynecol Reprod Biol. 2016;198:12–21.

22. Prevention and management of postpartum haemorrhage: Green-top guideline no. 52. BJOG 2017; 124: e106-e149.

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24. Collis RE, Collins PW. Haemostatic management of obstetric haemorrhage. Anaesthesia. 2015;70(Suppl 1):78–86, e27–8.

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26. Abdul-Kadir R, McLintock C, Ducloy AS, El-Refaey H, England A, Federici AB, Grotegut CA, Halimeh S, Herman JH, Hofer S, James AH, Kouides PA, Paidas MJ, Peyvandi F, Winikoff R. Evaluation and management of postpartum hemorrhage: consensus from an international expert panel. Transfusion. 2014;54:1756–68.

27. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, Gulmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2:e323–33.

28. Main EK, Goffman D, Scavone BM, Low LK, Bingham D, Fontaine PL, Gorlin JB, Lagrew DC, Levy BS. National partnership for maternal safety: consensus bundle on obstetric hemor-rhage. Anesth Analg. 2015;121:142–8.

29. National Blood Authority. Patient Blood Management Guidelines: Module 5 - Obstetrics and Maternity. © National Blood Authority, 2015. ISBN 978-0-9924971-2-5. https://www.blood.gov.au/system/files/documents/20180426-Module5-WEB.pdf.

30. Leduc D, Senikas V, Lalonde AB. CLINICAL PRACTICE OBSTETRICS COMMITTEE. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage: No. 235 October 2009 (Replaces No. 88, April 2000). Int J Gynaecol Obstet 2010; 108: 258–267.


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32. Hancock A, Weeks AD, Lavender DT. Is accurate and reliable blood loss estimation the ‘cru-cial step’ in early detection of postpartum haemorrhage: an integrative review of the literature. BMC Pregnancy Childbirth. 2015;15:230.

33. Gutierrez G, Reines HD, Wulf-Gutierrez ME. Clinical review: hemorrhagic shock. Crit Care. 2004;8:373–81.

34. Arora KS, Shields LE, Grobman WA, D’Alton ME, Lappen JR, Mercer BM. Triggers, bun-dles, protocols, and checklists--what every maternal care provider needs to know. Am J Obstet Gynecol. 2016;214:444–51.

35. Le Bas A, Chandraharan E, Addei A, Arulkumaran S. Use of the “obstetric shock index” as an adjunct in identifying significant blood loss in patients with massive postpartum hemorrhage. Int J Gynaecol Obstet. 2014;124:253–5.

36. Dennis AT. Transthoracic echocardiography in obstetric anaesthesia and obstetric critical ill-ness. Int J Obstet Anesth. 2011;20:160–8.

37. Perera P, Mailhot T, Riley D, Mandavia D. The RUSH exam: rapid ultrasound in SHock in the evaluation of the critically lll. Emerg Med Clin North Am. 2010;28:29–56. vii

38. Liu XH, Jiang YM, Shi H, Yue XA, Wang YF, Yang H. Prospective, sequential, longitudinal study of coagulation changes during pregnancy in Chinese women. Int J Gynaecol Obstet. 2009;105:240–3.

39. Shaylor R, Weiniger CF, Austin N, Tzabazis A, Shander A, Goodnough LT, Butwick AJ. National and international guidelines for patient blood management in obstetrics: a quali-tative review. Anesth Analg. 2017;124:216–32.

40. de Lloyd L, Bovington R, Kaye A, Collis RE, Rayment R, Sanders J, Rees A, Collins PW. Standard haemostatic tests following major obstetric haemorrhage. Int J Obstet Anesth. 2011;20:135–41.

41. Cortet M, Deneux-Tharaux C, Dupont C, Colin C, Rudigoz RC, Bouvier-Colle MH, Huissoud C. Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth. 2012;108:984–9.

42. Green L, Knight M, Seeney F, Hopkinson C, Collins PW, Collis RE, Simpson NA, Weeks A, Stanworth SJ. The haematological features and transfusion management of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based study. Br J Haematol. 2016;172:616–24.

43. Ekelund K, Hanke G, Stensballe J, Wikkelsoe A, Albrechtsen CK, Afshari A. Hemostatic resuscitation in postpartum hemorrhage - a supplement to surgery. Acta Obstet Gynecol Scand. 2015;94:680–92.

44. No PB. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017;130:e168–86. 45. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel

KJ, Bulger EM, Callcut RA, Cohen MJ, Cotton BA, Fabian TC, Inaba K, Kerby JD, Muskat P, O’Keeffe T, Rizoli S, Robinson BR, Scalea TM, Schreiber MA, Stein DM, Weinberg JA, Callum JL, Hess JR, Matijevic N, Miller CN, Pittet JF, Hoyt DB, Pearson GD, Leroux B, van Belle G. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471–82.

46. Bonnet MP, Deneux-Tharaux C, Bouvier-Colle MH. Critical care and transfusion manage-ment in maternal deaths from postpartum haemorrhage. Eur J Obstet Gynecol Reprod Biol. 2011;158:183–8.

47. Cotton BA, Dossett LA, Au BK, Nunez TC, Robertson AM, Young PP. Room for (perfor-mance) improvement: provider-related factors associated with poor outcomes in massive transfusion. J Trauma. 2009;67:1004–12.

48. Bawazeer M, Ahmed N, Izadi H, McFarlan A, Nathens A, Pavenski K. Compliance with a massive transfusion protocol (MTP) impacts patient outcome. Injury. 2015;46:21–8.

49. Kacmar RM, Mhyre JM, Scavone BM, Fuller AJ, Toledo P. The use of postpartum hem-orrhage protocols in United States academic obstetric anesthesia units. Anesth Analg. 2014;119:906–10.


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56. Klein AA, Arnold P, Bingham RM, Brohi K, Clark R, Collis R, Gill R, McSporran W, Moor P, Rao Baikady R, Richards T, Shinde S, Stanworth S, Walsh TS. AAGBI guidelines: the use of blood components and their alternatives 2016. Anaesthesia. 2016;71:829–42.

57. Duffield A, McKenzie C, Carvalho B, Ramachandran B, Yin V, El-Sayed YY, Riley ET, Butwick AJ. Effect of a high-rate versus a low-rate oxytocin infusion for maintaining uterine contractility during elective cesarean delivery: a prospective randomized clinical trial. Anesth Analg. 2017;124:857–62.

58. Butwick AJ, Carvalho B, Blumenfeld YJ, El-Sayed YY, Nelson LM, Bateman BT. Second-line uterotonics and the risk of hemorrhage-related morbidity. Am J Obstet Gynecol. 2015;212:642.e1–7.

59. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105–16.

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Chapter 12Hematologic Challenges in ICU Patients with Malignancy

Michael Gale, Vikram Dhawan, and Stephen M. Pastores

Introduction

Over the past two decades, significant strides have been made in the early detection and management of patients with hematologic and solid malignancies [1]. These have been largely achieved with the use of more intensive chemotherapeutic regi-mens, hematopoietic stem cell transplantation, and novel immunotherapeutic agents including monoclonal antibodies [2]. Nevertheless, patients with cancer will remain at risk for acute life-threatening illnesses associated with the underlying malignancy or complications of antineoplastic therapy that will require intensive care unit (ICU) admission.

Thrombotic and hemorrhagic complications are a common cause of morbidity and mortality in patients with cancer and associated with a high economic burden. In particular, thrombotic events are the second leading cause of death in cancer patients. Patients with malignancy are more likely to develop thrombotic events dur-ing the course of their illness compared to those without malignancy. It is now widely held that oncogenes activate blood coagulation as an integral feature of neo-plastic transformation, whereby cancer cells support clot formation and clotting proteins support cancer growth and dissemination [3]. The mechanisms underlying the cancer-mediated hypercoagulability include direct activation of procoagulant pathways by cancer cells (mediated by aberrant tumor cell tissue factor (TF) expres-sion, release of tumor cell derived, TF-expressing microparticles, cancer procoagu-lant, and other cell surface proteases) and indirect systemic effects of cancer on platelets, endothelial cells, and leukocytes. Recent studies have demonstrated that a complex coagulopathy develops in patients with cancer characterized by activation

M. Gale, MD · V. Dhawan, MD · S. M. Pastores, MD (*) Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USAe-mail: [email protected]; [email protected]; [email protected]





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of clotting mechanisms to different extents. The manifestations of this coagulopathy may range from a subclinical asymptomatic hypercoagulable state to overt throm-bosis of the large vessels and further to systemic disseminated intravascular coagu-lation (DIC) with severe bleeding [4].

Several factors contribute to thrombotic risk in cancer patients including patient-related (higher in females, older age, and African-Americans), cancer-related (pri-mary site of cancer and cancer stage), treatment-related (surgery, chemotherapy, hormonal therapy, and use of erythropoiesis-stimulating agents), and elevated levels of thrombotic biomarkers such as tissue factor (TF) expression by tumor cells and circulating TF, D-dimer, prechemotherapy white blood cell (>11,000/mm3) and platelet (>350,000/mm3) counts, soluble P-selectin, and C-reactive protein. This chapter will focus on the common hematologic challenges that ICU clinicians are likely to encounter when caring for patients with hematologic and solid malignan-cies including patients undergoing hematopoietic stem cell transplantation (HSCT) (Table 12.1).

Table 12.1 Hematologic issues in critically ill patients with cancer

Thrombotic complications

Venous thromboembolism: deep venous thrombosis, pulmonary embolism, splanchnic vein thrombosisArterial thrombosis: acute cerebrovascular accident, acute coronary syndrome, visceral and peripheral artery thromboembolismCatheter-related thrombosisThrombotic microangiopathies (TMAs) Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Post-hematopoietic stem cell TMAImmune thrombocytopenic purpura (ITP)Heparin-induced thrombocytopeniaVeno-occlusive diseaseHemorrhagic complications

ThrombocytopeniaThrombocytopathiesUremic platelet dysfunctionCoagulation abnormalities Disseminated intravascular coagulation (DIC) Acquired FVIII inhibitors (acquired hemophilia A) Acquired factor X deficiencyThrombocytosisHematologic issues associated with antineoplastic therapy

Leukopenia, anemia, and thrombocytopeniaRed cell aplasiaAcquired hemophilia ACryoglobulinemia inhibitors

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Thrombotic Complications

Thromboembolic events in patients with cancer can involve both the venous and arterial systems [5]. Venous thromboembolism (VTE), including deep vein throm-bosis (DVT), pulmonary embolism (PE), and splanchnic vein thrombosis, is more common and may precede or coincide with a diagnosis of cancer. Arterial throm-botic events, such as stroke and myocardial infarction, are also more commonly seen in patients with cancer than in the general population.

Venous Thromboembolism

Approximately 20% of all VTE are associated with cancer [6, 7]. Patients with can-cer are four to seven times more likely to develop VTE than patients without cancer [8]. Gastrointestinal, pancreatic, and colorectal malignancies in particular are asso-ciated with increased risk for VTE [5]. Several studies have showed that the inci-dence of VTE is associated with the duration of the underlying malignancy. The highest rate of VTE is seen in the initial period after cancer diagnosis, and mortality from VTE is highest 1 year after cancer diagnosis [9]. Chemotherapy increases the risk of VTE and recurrent VTE sixfold and twofold, respectively, in patients with cancer [10]. It is estimated that the annual incidence of VTE in cancer patients undergoing chemotherapy is about 11% [11]. Chemotherapeutic agents associated with increased risk for VTE include bevacizumab, lenalidomide, thalidomide, and the tyrosine kinase inhibitors sunitinib and sorafenib [5].

Management of Cancer-Associated Thrombosis

Patients with malignancy have a higher rate of VTE recurrence than noncancer patients, and major bleeding is particularly high in cancer patients with VTE receiv-ing anticoagulant therapy [12, 13]. VTE recurrence and bleeding rates also appear to correlate with cancer stage [12, 14]. Risk factors commonly acquired in the ICU including mechanical ventilation, pharmacologic sedation, immobilization, vaso-pressor use, and central venous catheters place these cancer patients even more at higher risk of VTE. Management of VTE in the ICU is complicated because many cancer patients have high risk of bleeding from coagulopathy, thrombocytopenia, concomitant major surgery, or gastrointestinal bleeding.

The most recent antithrombotic guidelines recommend anticoagulation with low molecular weight heparin (LMWH) over vitamin K antagonists (e.g., warfarin) for VTE treatment in cancer patients (Table 12.2) [15–18]. LMWH is associated with a lower risk of heparin-induced thrombocytopenia (HIT) and simple dosing (once-daily, weight-based subcutaneous injection). A statistically significant reduction in

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Table 12.2 Summary of major guidelines for initial management, long-term management, and duration of VTE in patients with malignancy

NCCN 2017 ACCP 2016 ASCO 2015

Initial treatment

Acute management: at diagnosis or during diagnostic evaluationLMWH (preferred) Dalteparin (200 units/kg

SC daily) Enoxaparin (1 mg/kg SC

every 12 h) Fondaparinux (5 mg

[<50 kg], 7.5 mg [50–100 kg], 10 mg [>100 kg] SC daily)

Unfractionated heparin IV (80 units/kg load and then 18 units/kg/h, target aPTT of 2–2.5× control or per hospital standard operating procedures)Unfractionated heparin SC 333 units/kg load and then 250 units/kg every 12 h

For VTE associated with cancer, LMWH is recommended over VKA (Grade 2B) or any direct oral anticoagulants (all Grade 2C)

LMWH is recommended for the initial 5 to 10 days of treatment of established DVT and PE

Long-term treatment

LMWH (category 1) is preferred for the first 6 months as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer

In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), as long-term (first 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C)

LMWH is recommended for long-term secondary prophylaxis

Duration of therapy

Minimum time of 3 monthsFor non-catheter-associated DVT or PE recommend indefinite anticoagulation while cancer is active, under treatment, or if risk factors for recurrence persistFor catheter-associated thrombosis, anticoagulate as long as catheter is in place. Recommended total duration of therapy is at least 3 months

In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who(i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B); for those who(ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B)

At least 6 months

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mortality risk has been demonstrated with LMWH at 3 months of follow-up. The reason for this survival benefit is unknown. Studies of the efficacy of LMWH in the treatment of malignancy-associated VTE have reported a survival benefit not only because of resolution of the thrombus but also because of an antineoplastic effect [19]. In the ICU, weight-based intravenous unfractionated heparin or subcutaneous LMWH (e.g., enoxaparin) is commonly used in the hemodynamically stable patient with PE. In patients with PE accompanied by shock and/or significant right ven-tricular dysfunction or failure, systemic thrombolytic therapy with intravenous tis-sue plasminogen activator (tPA) or catheter-directed thrombolysis may be considered if there are no contraindications. Most of the thrombolytic therapy trials for VTE exclude patients with cancer because of a perceived higher risk of bleeding; thus data is limited to small single-center, retrospective series with insufficient statistical power and patient selection bias. Current guidelines recommend that thrombolytic therapy be restricted to patients with life- or limb-threatening thromboembolic events [16–18].

The optimal duration of anticoagulation is not known as this has not been for-mally assessed beyond 6 months. In current practice, the consensus is to continue LMWH anticoagulation for at least 6 months and then reassess the need for continu-ing anticoagulation. In those with ongoing risk factors, such as metastatic or pro-gressive disease or ongoing systemic chemotherapy, continuing LMWH anticoagulation beyond the initial 6 months may be indicated to prevent recurrence. Conversely, in those without ongoing risk factors, the risk of recurrent VTE is likely to be sufficiently low to justify stopping anticoagulation [20].

In recent years, direct oral anticoagulants (DOACs) have been shown to be as effective and safe as warfarin for the treatment of VTE in cancer patients [21]. Four DOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) have received regula-tory approval for the treatment of VTE. Until very recently, robust data on the effi-cacy and safety of DOACs in cancer patients with VTE was not available. The Hokusai VTE Cancer trial, which involved patients with predominantly advanced cancer and acute symptomatic or incidental VTE, showed that treatment with a fixed once-daily dose of oral edoxaban for up to 12 months was noninferior to treat-ment with subcutaneous dalteparin with respect to the composite outcome of recur-rent VTE or major bleeding [22]. However, the rate of major bleeding was significantly higher with edoxaban than with dalteparin mainly due to the higher rate of upper gastrointestinal bleeding with edoxaban, especially among patients with gastrointestinal cancer. The frequency of severe major bleeding, however, was similar.

Impaired renal function is very common in patients with malignancy who are admitted to the ICU. LMWH is partially cleared by renal excretion and metabolism; therefore drug accumulation is expected with long-term management in those with significant renal insufficiency. Thus, these patients have a much higher risk of bleed-ing with LMWH therapy.


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Manufacturer-recommended dose reduction in renal impairment exists for enoxaparin but not for other LMWH preparations [23]. Most experts and guidelines recommend LMWH dose adjustment based on anti-factor Xa activity in patients with a creatinine clearance (CrCl) of 30 mL/min. Anti-Xa monitoring (peak and trough) is recommended in the latest National Comprehensive Cancer Network (NCCN) guidelines [17] for patients with severe renal dysfunction, although limited data is available to support the clinical relevance of anti-Xa levels. LMWHs are contraindicated in patients with HIT. In patients with a history of HIT, a direct thrombin inhibitor and fondaparinux are safer alternatives.

Inferior vena cava (IVC) filters should only be used temporarily in patients with acute thrombosis who have absolute contraindications to anticoagulation. A pro-spective randomized study of 200 patients (including 56 patients with cancer) showed that patients who received IVC filters had short-term protection from PE but higher rates of DVT and filter-site thrombosis compared to those randomized to no filters (20.8 vs. 11.6%, OR 1.87, 95% CI 1.10–1.38) [20]. There was no short- or long-term survival benefit from IVC filter placement. Non-randomized cohort stud-ies have also found that IVC filters were associated with increased metastases and reduced survival in cancer patients [24]. Complications associated with IVC filters include recurrent VTE up to 32%, and cases of fatal PE have been reported [25]. Insertion problems occur in 4–11% of patients, and long-term adverse effects, such as thrombosis proximally or distally to the filter, occur in 4–32% of patients [25]. Retrievable IVC filters should be used whenever possible with a plan to retrieve the filter when appropriate [20].

Incidental VTE, defined as VTE discovered on computed tomography (CT) scans ordered for reasons other than suspected VTE (i.e., cancer staging or restag-ing), has been reported to be a major contributor to the burden of cancer-associated VTE [20]. The incidence of unsuspected PE in cancer patients ranges from 1 to 5%. Although management of these events remains controversial, retrospective studies have found similar risks of mortality and recurrent VTE between patients with symptomatic and incidental PE [20]. Because of the high risk of future symptomatic VTE in these patients, many clinicians are reluctant to manage these cases without anticoagulation. However, there is evidence that patients with isolated, incidental subsegmental PE may not need anticoagulation [20]. It is recommended that patients with incidental DVT and PE receive therapeutic anticoagulation if there are no con-traindications [26].

Catheter-related thrombosis is associated with a low risk for thrombosis recur-rence and post-thrombotic syndrome [27]. Conservative treatment is recommended with removal of the catheter if there is evidence of concomitant DVT or catheter-related sepsis.

VTE is commonly diagnosed in patients with malignancy and thrombocytope-nia. Possible etiologies of the thrombocytopenia in cancer patients are heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura, immune thrombocytopenia, or chemotherapy effect. In >75% of patients with platelet counts <50 × 109/L, the thrombocytopenia was due to chemotherapy [9]. Thrombocytopenia increases the risk of bleeding in the setting of therapeutic anticoagulation for VTE.

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In patients with acute cancer-associated VTE and platelet count >50 × 109/L, full-dose enoxaparin (1 mg/kg twice daily) without platelet transfusion is appropri-ate [17]. The general consensus is that the risk of spontaneous bleeding is very low with platelet counts >50 × 109/L. For patients with a platelet count of 25–50 × 109/L, reducing the dose of enoxaparin to 50% of the therapeutic dose (0.5 mg/kg twice daily) is recommended. For patients with a platelet count of <25 × 109/L, temporar-ily holding enoxaparin is suggested, and placement of a retrievable IVC filter may be considered [9]. For patients at high risk for recurrent VTE and anticipated pro-longed thrombocytopenia, transfusion of platelets to maintain platelet count >25 × 109/L to allow for continuation of enoxaparin may be appropriate.

Recurrent VTE despite appropriate anticoagulation is common among cancer patients. In the initial month following the diagnosis of VTE, the risk of recurrent thrombosis is highest [28]. Approximately 10–17% of patients with cancer-associ-ated thrombosis treated with a VKA and 6–9% of patients treated with LMWH will have recurrent VTE during follow-up [29]. Once recurrent VTE is confirmed, it is essential that HIT be excluded in patients who were first exposed to LMWH or UFH within the past 10–14 days and also to confirm drug compliance.

Patients with a recurrent VTE event who are being treated with VKAs should be switched to LMWH monotherapy (e.g., enoxaparin) or continue VKA after a bridg-ing period with LMWH (or UFH). Patients with recurrent VTE who are being treated with LMWH should have their dose increased by 25% (or increased to thera-peutic, weight-adjusted doses if they are receiving lower doses). Other therapeutic options, including the insertion of an IVC filter or switching to a different antico-agulant (e.g., fondaparinux or VKA), have been proposed [15–17].

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial showed that among patients with acute proximal DVT, the addition of pharmacomechanical catheter-directed thrombolysis (catheter-mediated or device-mediated intrathrombus delivery of recombinant tis-sue plasminogen activator and thrombus aspiration or maceration, with or without stenting) to anticoagulation compared to anticoagulation alone did not result in a lower risk of post-thrombotic syndrome but did result in a higher risk of major bleeding [30]. There was also no significant difference in recurrent VTE over the 24-month follow-up period (12% in the pharmacomechanical thrombolysis group and 8% in the control group; P = 0.09). Although the data is limited, catheter-directed thrombolysis may be considered in cancer patients with acute iliofemoral DVT, low expected bleeding risk, and good functional status, if DVT-related sequelae are likely to cause decrease in functional status and quality of life.

Arterial Thromboembolism

Compared to the large number of studies on VTE, there are limited reports on the pathogenesis, incidence, management, and outcomes of arterial thrombotic events in patients with cancer. Prior studies have shown an increased risk of


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cerebrovascular accidents and cardiac ischemia in patients with breast cancer, cervi-cal cancer treated with radiotherapy, head and neck cancer, lung cancer, and remote Hodgkin lymphoma [9, 31]. Chemotherapeutic agents reported to be associated with arterial thromboembolism include cisplatin, 5-flurouracil, gemcitabine, beva-cizumab, L-asparaginase, sorafenib, and sunitinib. Clinicians should have a low threshold for performing transesophageal echocardiography because of the high prevalence of nonbacterial thrombotic endocarditis in cancer patients. CT angiogra-phy of the chest and abdomen may be needed to detect a vascular source. When a thrombotic arterial ischemic event is suspected, further testing is necessary to exclude the presence of antiphospholipid antibody or tumor-induced blood vessel compression. Management of limb-threatening ischemia includes anticoagulation with UFH or LMWH and antiplatelet agents, reversal of shock if present, and dis-continuation of chemotherapy. Emergent surgical intervention is indicated if an embolic event is highly suspected. In some cases, arteriography is necessary to determine whether percutaneous revascularization, embolectomy, catheter-based thrombolysis, or surgical bypass is required.

Thrombotic Microangiopathies

Thrombotic microangiopathy (TMA) is a well-described complication of cancer treatment including HSCT. The incidence of TMA has increased in the last few decades, as a result of better awareness of this complication in cancer patients on one hand but also of a larger array of therapeutic compounds including anti-vascular endothelium growth factor (VEGF) agents [32]. It is therefore mandatory to recog-nize these conditions since they have a significant impact on patient management and prognosis.

The thrombotic microangiopathies include thrombotic thrombocytopenic pur-pura (TTP), hemolytic uremic syndrome (HUS) and hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) syndrome, which should be distin-guished from similar disease processes such as immune thrombocytopenia (ITP), disseminated intravascular coagulation (DIC), and heparin-induced thrombocytope-nia (HIT) [33, 34].

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)

Thrombotic thrombocytopenic purpura (TTP) is a systemic disease characterized by platelet aggregation into widespread platelet thrombi and resulting occlusion of the microvasculature. Acquired TTP is characterized by a deficiency (<10% activ-ity) of the von Willebrand factor cleaving enzyme ADAMTS13. The classic

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“pentad” of fever, hemolytic anemia, thrombocytopenia, renal impairment, and neu-rologic manifestations is not universal, stressing the importance of a high clinical vigilance in recognizing and treating this disorder. A more accurate definition for TTP is a microangiopathic hemolytic anemia (MAHA) and thrombocytopenia with-out other explanations [33].

TTP and HUS exist on a spectrum. HUS is best described under the practical and inclusive term of TMA. Although HUS shares the definition of a MAHA with thrombocytopenia and microvascular thrombosis, HUS additionally includes prom-inent renal dysfunction or failure. HUS is primarily described in children and often associated with Shiga toxin-producing bacteria [33]. HUS has been reported as a complication of chemotherapy with gemcitabine, mitomycin, and cisplatin.

The treatment of choice for TTP is plasma exchange with fresh-frozen plasma. At least five plasma exchanges are usually performed in the first 10 days. Corticosteroids (prednisone 1 mg/kg per day) are also commonly used as adjunctive therapy. In patients with TTP refractory to plasma exchange, rituximab, an anti-CD 20 monoclonal antibody, has been shown to be effective [33]. In the absence of life-threatening hemorrhage or intracranial bleeding, it is prudent to avoid platelet trans-fusions, which can exacerbate microvascular thrombosis. Aspirin may provoke hemorrhagic complications in patients with severe thrombocytopenia [34]. Anticomplement therapy including eculizumab, a C5 inhibitor, has shown very promising results in several case reports and small case series. Given the increased risk for meningococcal infection, meningococcal vaccine is required prior to start-ing eculizumab.

Transplant-Associated Thrombotic Microangiopathy

HSCT-associated TMA is now considered a distinct entity from TTP and is charac-terized by microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunc-tion, and neurological symptoms. Risk factors include histocompatibility leukocyte antigen mismatch, high-dose chemotherapy conditioning and exposure to immuno-suppressive regimens, graft-versus-host disease (GVHD) and infections [35]. The reported incidence of TA-TMA is 0–64% following allogeneic HSCT depending on diagnostic criteria used, with mortality rate as high as 100% in published case series. It usually presents between 20 days and 100 days after HSCT and most com-monly involves the kidneys but can also involve the lungs, GI tract, brain, and heart. The pathogenesis of TA-TMA involves arteriolar thrombi associated with intimal swelling and fibrinoid necrosis of the vessel wall [36]. First-line treatment is sup-portive and includes withdrawal or minimization of offending agents (e.g., calcineu-rin inhibitors such as cyclosporine and tacrolimus), treatment of coexisting infections and GVHD, and aggressive management of hypertension. Unlike in TTP, plasma exchange is not as beneficial. Eculizumab has been useful in some cases as well as rituximab and defibrotide.


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Immune Thrombocytopenic Purpura (ITP)

Immune thrombocytopenic purpura (ITP) is an acquired immune-mediated syn-drome characterized by an isolated thrombocytopenia and increased risk of bleed-ing. It is classified into primary ITP, a diagnosis of exclusion with no inciting cause, or secondary ITP, an underlying condition or medication drives the immunologic response leading to platelet degradation [37]. It can be associated with chronic lym-phocytic leukemia, Hodgkin lymphoma, and various types of non-Hodgkin lym-phoma. Diagnosis of ITP with lymphomas is challenging because of many factors that can affect platelet counts in these patients. Treatment includes the use of corti-costeroids and IV immunoglobulin (IVIg) [37]. Platelet transfusions should only be administered in patients with ITP who have severe hemorrhage.


Heparin-induced thrombocytopenia (HIT) is an adverse immune-mediated drug reaction that is associated with a high risk of venous and arterial thrombosis. Heparin exposure leads to the formation of IgG antibodies that recognize multimo-lecular complexes of platelet factor 4 (PF4) and heparin that form on the surface of platelets. These complexes bind to the Fc_IIa (IgG) receptors of platelets, resulting in platelet activation and release of procoagulant, platelet-derived microparticles. The end result is marked generation of thrombin and the formation of venous and arterial thromboses that are the clinical hallmark of HIT [38].

The overall risk of HIT is estimated to be 0.2% in heparin-exposed patients. Other studies estimate the risk to be as high as 1–5%. Data on the incidence and prevalence of HIT in cancer patients is limited. Prandoni et al. speculated that HIT may develop more frequently in cancer patients than in patients without cancer [5 of 335 (1.5%) vs. 14 of 1998 (0.7%), respectively] [12]. Cancer patients may be at higher risk of HIT due to increased exposure to heparin in situations that are more common in cancer patients than in the general population including treat-ment of VTE, inpatient thromboprophylaxis, and heparin flushes for vascular catheters [39].

Opatrny et al. reported that patients with cancer suffer significantly more HIT-related complications than those without cancer. Combined venous and arterial thrombotic events, venous thrombotic events, and limb loss due to amputation occurred more in patients with underlying malignancy [40].

Management involves discontinuation and avoidance of all heparin products, avoidance or postponement of an oral vitamin K antagonist until platelet count recovery, initiation of a nonheparin anticoagulant such as argatroban, and more recently the use of DOACs [41]. Accurate diagnosis and prompt commencement of therapy for HIT are paramount.

HIT can be especially challenging to diagnose in cancer patients due to many potential confounders, particularly those that contribute to thrombocytopenia or thrombosis, and their impact on the 4T score calculation. Cancer patients commonly

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have thrombocytopenia due to myelophthisis or myelosuppression from chemo-therapy/radiation, DIC, and thrombotic microangiopathies.

The current standard of care for the evaluation of HIT is to perform testing to detect heparin-platelet factor 4 antibodies (H-PF4 ab) in whom the pretest clinical probability using the 4T scoring is estimated to be intermediate to high (4T score ≥4) [42].

The 4Ts is a pretest scoring system for HIT that was developed to improve and standardize clinical diagnosis [42]. It incorporates four typical features of HIT: (1) magnitude of thrombocytopenia, (2) timing of thrombocytopenia with respect to heparin exposure, (3) thrombosis or other sequelae of HIT, and (4) likelihood of other causes of thrombocytopenia. The system yields an integer score between 0 and 8 with scores of 0–3, 4–5, and 6–8 classified as low, intermediate, and high pretest probability for HIT, respectively. The 4Ts is widely used in clinical practice, and several single-center experiences with the model have been reported. However, the generalizability of these studies to other settings and patient populations is uncertain [42]. Wong et al. suggest that cancer patients may need higher cutoff values for the 4T score. Conventional H-PF4 antibody testing seems to perform similarly for the diagnosis of HIT when compared to published data from noncancer patients [39].

Veno-occlusive Disease

Hepatic veno-occlusive disease (VOD) is a common complication of the chemother-apy and radiotherapy conditioning used in preparation for HSCT. Also known as sinu-soidal obstruction syndrome, hepatic VOD results from damage to the endothelial cells of the hepatic sinusoids. It affects approximately 14% of patients who undergo HSCT. In severe cases, it can cause multiorgan failure, leading to death in up to 80% of cases. VOD has an unpredictable course that makes early diagnosis and treatment crucial. However, currently accepted therapies are inadequate, and many approaches have demonstrated unacceptable levels of toxicity. Defibrotide, a derivative of single-stranded deoxyribonucleotides, has been shown to restore the thrombofibrinolytic balance and heal the endothelium through multiple mechanisms of action [43].

Hemorrhagic Disorders

Thrombocytopenia

Thrombocytopenia is present in about 10% of patients with solid tumors and in a higher proportion in patients with hematological malignancies before any chemo-therapy is initiated [44]. Platelets are reduced due to three mechanisms: (1) decreased platelet production, (2) increased consumption or destruction, and (3) splenic sequestration. A detailed history is essential in patients with cancer to differentiate the various causes of thrombocytopenias and should include their medical condi-tions, comorbidities, and medication history.


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Hematopoietic stem cells in the bone marrow differentiate with the help of thrombopoietin and other cytokines such as IL-6 and IL-2 [45, 46]. Once mega-karyocytes are differentiated (in the stem cell compartment of the bone), they migrate to bone sinusoids for final platelet production. This process is achieved with the help of stromal-derived factor-1α (SDF-1 α) and fibroblast growth factor-4 (FGF-4). Any process which prevents maturation of hematopoietic stem cells to megakaryocytes or the migration of megakaryocytes to bone sinusoids can affect platelet production. This may include bone marrow infiltration as it may occur with hematological and solid tumors (especially the lung, breast, and prostate) or a result of chemotherapy.

Platelet destruction and sequestration are much more common than decreased production as the cause of thrombocytopenia. Most commonly, immune-mediated thrombocytopenia either due to drugs or autoantibodies is present. Platelet con-sumption due to ongoing clotting such as disseminated intravascular coagulation (DIC) and thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) plays an important role. Normally one third of platelets are sequestered in the spleen, and as spleen size increases, so does the sequestration, in the process lower-ing peripheral platelet count. This is mostly seen with myeloproliferative disorders and less likely with lymphomas or chronic lymphocytic lymphoma.

Thrombocytopathies

Although platelet counts may be low, platelet dysfunction may occur in malignan-cies such as myelodysplastic syndrome in which fewer alpha (α) granules and tubu-lar system abnormalities are seen [47]. Various morphological, biochemical, and functional platelet defects have been reported, but most notable are defective aggre-gation in response to agonists (adenosine diphosphate) and severely reduced α-granules [48]. Membrane glycoproteins and receptor abnormalities such as glyco-protein IIb–IIIa-associated receptors have also been observed.

It is important to examine the peripheral blood smear to differentiate between the various causes of thrombocytopathy. The automatic cytometers may spuriously detect low platelet counts due to clumping, whereas a peripheral smear may provide true counts. The presence of schistocytes or microspherocytes is suggestive of microangiopathic process such as hemolytic-uremic syndrome (HUS) or throm-botic thrombocytopenic purpura (TTP).

Acquired von Willebrand syndrome (AvWS) is seen in hematologic disorders including monoclonal gammopathy of undetermined significance (MGUS), multi-ple myeloma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and essen-tial thrombocythemia [49]. Laboratory testing reveals a prolongation of the activated partial thromboplastin time due to low factor VIII levels and decreased levels of plasma vWF antigen (vWF:Ag) and ristocetin cofactor activity (vWF:RCo). Bleeding time is prolonged. The ability of vWF to bind to collagen is significantly decreased. Decreased high molecular weight vWF multimers and/or a high ratio of

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vWF propeptide to vWF:Ag (ratio > 3) may be present. Treatment of the underlying malignancy helps in correction of AvWS in a significant number of cases including multiple myeloma where remission of AvWS occurs in 35–70% of cases. Symptomatic treatment of bleeding includes the use of deamino-8-D-arginine vaso-pressin (desmopressin acetate [DDAVP]), factor VIII/vWF concentrate and intrave-nous immunoglobulin (IVIg), activated factor VIIa, and plasmapheresis [50]. Depending on the underlying condition, the efficacy of desmopressin has been reported to be only about 30%.

Uremic Platelet Dysfunction

Renal failure is common in patients with cancer who are critically ill. Uremia result-ing from renal failure can lead to platelet dysfunction. Platelet dysfunction in these patients is multifactorial and involves both platelet dysfunction and platelet-endo-thelium interaction. Decrease in platelet aggregation and adhesion due to dysfunc-tional GP IIb/IIIa receptor interaction with fibrinogen and vWF plays a significant role in uremic bleeding in cancer patients. Other factors contributing to platelet dysfunction are altered release of adenosine diphosphate (ADP) and serotonin, ure-mic toxins, anemia, and increased nitric oxide (NO) production [51]. There is cur-rently no specific laboratory test to detect “bleeding tendency” in uremic patients. Patients should be treated only when they are actively bleeding or require an inva-sive surgical procedure. Desmopressin is commonly used in a dose of 0.3 mcg/kg given IV or subcutaneously. Desmopressin can also be given intranasally at a simi-lar dose of 3 mcg/kg with the effect seen within 1 h and can last up to 8 h. Conjugated estrogens start action within 1 day, peak in 5 days, and last about 7 days. The dose is 0.6 mg/kg IV for 5 days, orally 2.5 mg to 25 mg daily or 50–100 mcg subcutane-ously twice weekly. Transfusion of cryoprecipitate (10 units every 12 h) can be given and acts within 1 h and may last up to 24 h [52, 53]. Erythropoietin-stimulating agents (ESAs) such as erythropoietin and darbepoetin can also be used in uremic patients [52]. Their maximum effect is seen when the hematocrit has reached a nor-mal level. The potential mechanism of ESAs is thought to be due to red cell mass pushing the platelets peripherally for better platelet-endothelial interaction and also by increasing the production of newer, more metabolically active platelets. Erythrocytes can also potentially act as nitric oxide scavenger.

Treatment

Patients with hematological malignancies who are not bleeding should be prophy-lactically transfused to a threshold of <10 × 109/L platelets (Table 12.3) [54]. The platelet transfusion threshold can be raised in patients with signs of hemorrhage, high white cell count, rapid decline in platelets, fever, or coagulation abnormalities


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(e.g., in acute promyelocytic leukemia). Patients undergoing invasive procedures or in case of scarcity of platelets (long distance from blood bank) should have platelets transfused to a higher level. Patients with allogeneic HSCT should be transfused prophylactically below the threshold of 10 × 109/L, while patients with autologous HSCT should be transfused only for signs of bleeding and not prophylactically. Patients with solid malignancies should also be transfused to a threshold of <10 × 109/L platelets. Patients who are not getting any active chemotherapy but have chronic severe thrombocytopenia may be observed and transfused only for signs of bleeding. Minor procedures such as biopsy (bone marrow) or central venous catheter removal may be performed with platelets ≥20 × 109/L; other major surgical procedures require counts between 40 × 109/L and 50 × 109/L.

Platelets can be pooled from multiple donors or from a single donor. Single-donor platelets are used only when histocompatible platelet transfusions are needed as they are expensive. To prevent RhD alloimmunization, platelets from RhD-negative donors can be utilized or via anti-D immunoprophylaxis. This is mostly used for female patients both children and adults of childbearing potential. Patients with acute myeloid leukemia (AML) should be transfused with leukoreduced plate-lets or RBCs. Patients with AML have a high incidence (>25%) of developing anti-platelet alloantibodies, and leukoreduced transfusions help reduce platelet transfusion refractoriness. Leukoreduced transfusions can probably be given in patients with other leukemias and those receiving chemotherapy, but data is lacking. The process of leukoreduction whereby leukocytes are removed from whole blood can be achieved by either filtration or alteration of their antigen-presenting capacity by radiation (UVB). It is suggested that platelets should be measured 10–60 min after transfusion in order to figure out transfusion refractoriness. If two consecutive unit (stored < 72 h) transfusions of ABO-compatible platelets fail to increase plate-lets by an absolute increment of 2000/unit of platelet concentrate or 10,000 after transfusion of apheresis platelets, then a workup should be undertaken to determine

Table 12.3 Platelet transfusion threshold in patients with cancer [54]

Condition Transfusion threshold (prophylactic)

Hematological malignancies <10 × 109/L plateletsHigher threshold: hemorrhage, high fever, hyperleukocytosis, rapid fall of platelet count, or coagulation abnormalities (e.g., acute promyelocytic leukemia), surgical procedures, and scarcity of platelet availability

Hematopoietic stem cell transplantation

Allogeneic: <10 × 109/L plateletsAutologous: no prophylactic transfusion

Severe chronic thrombocytopenia not receiving active treatment

Active bleeding and/or during active treatment

Solid tumors <10 × 109/L plateletsSurgical or invasive procedures

40 × 109/L to 50 × 109/L (no coagulopathy)≥20 × 109/L (bone marrow biopsies, central venous catheter removal)Other procedures: no data

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its cause. Importantly, platelet alloimmunization should be ruled out by performing antibody studies such as lymphocytotoxicity assays or platelet antibody testing. Other causes of poor increment after transfusion are DIC, hypersplenism, shock, and massive hemorrhage. Patients with alloimmune-refractory thrombocytopenia should be transfused with HLA-A- and HLA-B-compatible platelets [54]. Blood banks normally have a list of histocompatible donors.

Coagulation Abnormalities

Disseminated Intravascular Coagulation (DIC)

The incidence of DIC is approximately 7% in solid tumors, 15–20% in leukemias, and almost 90% in acute promyelocytic leukemia (AML-M3). This incidence increases in patients on active chemotherapy. Although DIC is a procoagulant state, a hyperfibrinolytic state can also occur as clotting factors are consumed as well as platelets and fibrin leading to hemorrhages. DIC can be chronic and associated with laboratory findings and subtle clinical signs, mostly with metastatic tumors or they can be acute when massive amounts of tissue factor (TF) are released leading to overt DIC. Tumors most causative of DIC are hematological malignancies espe-cially promyelocytic leukemia, other acute leukemias, and lymphomas, though cer-tain solid tumors also contribute to DIC in patients. Solid tumors more prone to causing DIC are prostate, mucin-secreting pancreatic adenocarcinoma, gallbladder, ovary, and thyroid. Excessive tumor burden and chemotherapy result in acute DIC [55]. The pathogenesis of DIC in cancer is not well understood, and the massive fibrinolysis is not clearly explained. There is excessive plasminogen activation which is not explained by physiological plasminogen activators such as urokinase-type plasminogen activator. A protein receptor called Annexin II is found on promy-elocytic leukemic cells, which activates plasminogen, causing hyperfibrinolysis. There is also a high level of circulating fibrinolytic inhibitor PAI-1 which makes lot of cancer states hypofibrinolytic and procoagulant. Microangiopathy is seen in can-cer and is characterized by aggressive platelet aggregation and addition to the endo-thelium resulting in platelet consumption and subsequently activation of coagulation pathway and fibrin deposition. The use of chemotherapy is implicated in the micro-angiopathy of cancer. Chemotherapy can induce damage to the endothelium which plays a central role in the processes of hemostasis, coagulation, and fibrinolysis. Factors such as tissue factor and thrombomodulin promote procoagulation, and fac-tors like urokinase-type plasminogen activator and tissue-type plasminogen activa-tor mainly inhibit fibrin formation. Any of the pathways in DIC are mediated through cytokines most importantly interleukin 6 (IL-6). It’s a potent pro-inflamma-tory cytokine and acts as a procoagulant cytokine. Other pro-inflammatory cyto-kines are IL-1β and IL-8. Cytokines such as tumor necrosis factor-a (TNF-a) act opposite of procoagulant cytokines and act on physiological anticoagulant path-ways. IL-10 which is an anti-inflammatory cytokine might even inhibit DIC [55].


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Diagnosis is usually clinical and corroborated by laboratory tests. DIC in cancer is usually an insidious process, and activation of the coagulation process is mostly subclinical. As platelets and coagulation factors are consumed, bleeding ensues and is usually the first sign of DIC. The liver usually forms coagulation factors, so only thrombocytopenia may be evident in the beginning. Fibrin degradation product measurements have not been well established in patients with DIC and cancer. Treatment of underlying medical disorder is the mainstay of DIC management, and as the malignant disease is treated, DIC tends to disappear. Supportive treatment may be instituted, and as DIC is characterized by activation of coagulation, it is reasonable to think to use anticoagulants such as heparin. There is no randomized trial to show any benefit of such therapy, although LMW heparin may improve labo-ratory numbers. Since cancer patients with DIC have high incidence of thrombotic events, prophylactic anticoagulation with low molecular weight heparin or unfrac-tionated heparin has become the standard of care. Since low platelets and decreased coagulation factors may lead to bleeding, transfusion of platelets or plasma should only be done in either actively bleeding patients or patients who require any surgical procedure as mentioned above in the platelet transfusion guidelines. Antifibrinolytic therapy such as aminocaproic acid may be considered in severe cases of bleeding especially in acute promyelocytic leukemia and in some cases of DIC associated with malignancies such as prostate cancer [56].

Acquired FVIII Inhibitors (Acquired Hemophilia A [AHA])

Acquired inhibitors of factor VIII are rare conditions found in non-hemophiliac pop-ulation with an estimated incidence of approximately 1.5 per million population annually [57]. Majority of cases are noted in the elderly, and about 50% of the cases are idiopathic, and no cause is found. It is associated with malignancy in 6.4% to 18–4% cases. These are most frequently found in lymphoproliferative disorders with mortality rates approaching 25%. Patients with AHA present with bleeding in more than 90% of the cases, and majority (70%) will present with spontaneous and serious bleeding with a decrease in hemoglobin by more than two grams below 8 g/dL. Factor VIII levels are predictive of bleeding risk and patients can have significant bleeding despite only mildly reduced factor VIII activity level. Patients with acquired AHA have bleeding patterns different than congenital AHA and develop infrequent joint bleeding. The most common bleeding pattern is subcutaneous (>80%), followed by muscular bleeding (40%) and gastrointestinal bleeding (20%) [58].

AHA should be suspected in patients who have recent onset of abnormal bleed-ing and isolated prolonged activated partial thromboplastin time (aPTT) and normal prothrombin time (PT) [53, 59]. In AHA the mixing study for 1–2 h and 37 °C does not correct aPTT in patients with AHA. Factor VIII inhibitor is confirmed and quan-tified by the Bethesda assay (BA), Nijmegen-Bethesda assay (NBA), or sometimes enzyme-linked ABO-sorbent assay (ELISA) with anti-factor VIII antibody. Both BA and NBA titers normally underestimated the inhibitor titer, and heat treatment

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of the sample prior to the assay (58 °C for 90 min) may improve inhibitor detection sensitivity as it eliminates the residual activated factor VIII. Lupus anticoagulant (LA) and heparins including heparinoid and direct anticoagulants may interfere with the test to detect circulating inhibitors. LA can usually be diagnosed through the use of dilute Russell Viper venom time (dRVVT), and confounding by heparin can be eliminated by measuring thrombin time which is prolonged in the presence of normal reptilase time. An anti-Xa assay is helpful in protecting the effects of FXa inhibiting anticoagulants such as fondaparinux, danaparoid, and direct factor Xa inhibitors.

Management involves suppression of the inhibitor and control of bleeding. Replacement of factor VIII is recommended in patients who have low antibody titer (<5 BU). Both human and porcine FVIII are now available, and recently recombi-nant porcine FVIII (Obizur) has been approved for its treatment in the United States, Canada, and Europe. Determining antibodies to both human and porcine factor VIII will determine the effectiveness of therapy. Desmopressin which helps release FVIII from vascular endothelium can be used but is of limited utility for AHA and may be used when titers of inhibitors are <2 BU/mL or FVIII levels are >5 BU/mL. The inhibitor activity can be bypassed by using agents such as recombinant factor VIIa (rFVIIa, NovoSeven®) and activated prothrombin complex concentrate (aPCC, FEIBA®—plasma-derived, containing factors II, IX, and X and VIIa). Attempts to eliminate the inhibitor should always be made. Modalities used to suppress antibod-ies in AHA include immunosuppressive therapy with corticosteroids, corticoste-roids and cyclophosphamide, and corticosteroids and rituximab. The most effective immunosuppressive therapy is cyclophosphamide with or without corticosteroids in achieving complete remission. If patients do not see a decline in the inhibitor or a rise in baseline factor VIII levels after 3–5 weeks of therapy, second-line therapy options include calcineurin inhibitors, mycophenolate mofetil, multiple immuno-suppressive agents, and immune tolerance protocols. Use of IVIG did not show any benefit. It is important that the underlying condition also be treated in addition to treatment of AHA [58].

Acquired Factor X Deficiency

Patients with light chain amyloidosis present with bleeding in 15–40% of cases, and hemorrhage can be even life-threatening. Due to vascular fragility and the inability to constrict, patients are more prone to bleeding. Factor X deficiency is the clinically most important coagulopathy found in patients with amyloidosis and occurs in 9% of cases. The likely mechanism is thought to be that factor X deposits on the light chain febrile in the liver and spleen. Factor X levels can be recovered after splenectomy in some patients. Treatment with plasma exchange and recombinant factor VII is rec-ommended. Replacement of factor X with plasma cell concentrate on fresh frozen plasma is not very successful due to rapid adsorption of factor X on light chain fibrils. Chemotherapy and stem cell transplantation can also help improve factor X.


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Thrombocytosis

There are a number of myeloproliferative neoplasms (MPN), and one of the subcat-egories is BCR-ABL1-negative MPN. In this category two of the disorders, polycy-themia vera (PV) and essential thrombocythemia (ET), are mostly associated with thrombocytosis [53, 60]. Other conditions such as chronic myelogenous leukemia and myeloid metaplasia with or without myelofibrosis are also a few of the chronic myeloproliferative disorders that are associated with thrombocytosis. ET involves sustained increase in platelet number >600 × 109 cells/L because of excessive pro-liferation of bone marrow megakaryocytes. Thrombocytosis is associated with both thromboses and bleeding tendencies due to platelet dysfunction. The etiology is believed to be multifactorial. Increased proteolysis of von Willebrand factor multi-mers by ADAMTS13 cleaving protease is seen as the platelet count rises. In ET, if the platelets are brought down less than 600 × 109 cells/L, thrombotic complications decrease. If the platelet count exceeds more than 1 million, bleeding can occur, and use of aspirin should be cautious. Reducing the platelet count helps correct this defect and control bleeding. Platelet function is abnormal as shown in platelet aggregation studies. Up to 37% of patients with ET will experience a hemorrhagic event. Patients who have platelet counts >1 million are at high risk for thrombosis or bleeding and urgent plateletpheresis along with cytoreductive therapy to treat the underlying condition should be instituted right away to rapidly decrease the platelet count. Long-term management with chemotherapy such as hydroxyurea, anagrelide, interferon therapy, and JAK2 (mutation found frequently in ET and PV) inhibitors can be used [63].

Hematologic Issues Associated with Antineoplastic Therapy

The majority of chemotherapeutic agents will induce bone marrow cytotoxicity and result in the development of leukopenia, anemia, and thrombocytopenia. Hematologic toxicity is usually subacute in presentation occurring a few days fol-lowing administration of chemotherapy but may be cumulative and persistent. Most myelosuppression will subside within a few days to weeks. In addition to causing bone marrow suppression, certain chemotherapeutic agents may cause drug-induced immune thrombocytopenia including cyclophosphamide, oxaliplatin, irinotecan, and fludarabine. In these cases, laboratory testing for drug-dependent antiplatelet antibodies can be helpful but is not required. The platelet count usually recovers following discontinuation of the chemotherapeutic agent. Patients with clinically important bleeding and/or platelet count <10,000/μL should receive platelet transfu-sions. For severe or life-threatening bleeding, intravenous immune globulin (IVIG) may also be given. Erythropoiesis-stimulating agents such as epoetin alfa and dar-bepoetin alfa may be used in patients with nonhematologic malignancies in whom the anemia is due to chemotherapy [61].

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In recent years, a number of immunotherapeutic agents including multiple anti-bodies against programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have been approved for the treatment of various solid malignan-cies such as melanoma, renal cell carcinoma and non-small cell lung cancer, and anti-cytotoxic T-lymphocyte-associated antigen 4 (CLA-4) antibody for patients with advanced melanoma. These agents have been associated with hematologic tox-icities including red cell aplasia, neutropenia, thrombocytopenia, acquired hemo-philia A, and cryoglobulinemia inhibitors [62–65]. Management includes the use of white blood cell growth factors, red cell and platelet transfusion support, and corti-costeroids with addition of other immunosuppressive agents if symptoms are ste-roid-refractory [66].

References

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21. van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treat-ment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2014;12(3):320–8.

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24. Matsuo K, Carter CM, Ahn EH, et al. Inferior vena cava filter placement and risk of hematog-enous distant metastasis in ovarian cancer. Am J Clin Oncol. 2013;36(4):362–7.

25. Streiff MB. Vena caval filters: a comprehensive review. Blood. 2000;95(12):3669–77. 26. Kearon C, Akl EA, Omelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline

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28. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146–53.

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30. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical catheter-directed throm-bolysis for deep-vein thrombosis. N Engl J Med. 2017;377(23):2240–52.

31. Navi BB, Reiner AS, Kamel H, Iadecola C, Okin PM, Elkind MSV, Panageas KS, DeAngelis LM. Risk of arterial thromboembolism in patients with cancer. J Am Coll Cardiol. 2017 Aug 22;70(8):926–38.

32. Grangé S, Coppo P. Thrombotic microangiopathies and antineoplastic agents. Nephrol Ther. 2017;13:S109–13.

33. Kappler S, Ronan-Bentle S, Graham A. Thrombotic Microangiopathies (TTP, HUS, HELLP). Hematol Oncol Clin North Am. 2017;31(6):1081–103.

34. Moake JL. Thrombotic microangiopathies. Bone Marrow Transplant. 2018;53(2):129–37. 35. Khosla J, Yeh AC, Spitzer TR, Dey BR. Hematopoietic stem cell transplant-associated throm-

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40. Opatrny L, Warner MN. Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia. Am J Hematol. 2004;76(3):240–4.

41. Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017;130(9):1104–13.

42. Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring sys-tem for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012;120(20):4160–7.

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52. Hedges SJ, Dehoney SB, Hooper JS, Amanzadeh J, Busti AJ. Evidence-based treatment rec-ommendations for uremic bleeding. Nat Clin Pract Nephrol. 2007;3(3):138–53.

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54. Schiffer CA, Bohlke K, Delaney M, et al. Platelet transfusion for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018;36(3):283–99.

55. Levi M. Management of cancer-associated disseminated intravascular coagulation. Thromb Res. 2016;140:S66–70.

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Chapter 13Hematologic Challenges in ICU Patients on ECMO

Cara Agerstrand, Andrew Eisenberger, and Daniel Brodie

Introduction

Extracorporeal membrane oxygenation (ECMO) has been used for nearly half a century to support patients with severe cardiac, pulmonary, or combined cardiopul-monary failure [1–3]. Throughout much of this time, however, ECMO was primar-ily limited to neonates and children. Though ECMO was used successfully in small numbers of highly selected adults at specialized centers, broader adoption of this technology was limited by high morbidity and mortality [4]. Hematologic compli-cations, such as bleeding, thrombosis, hemolysis, and disseminated intravascular coagulation were often severe and directly contributed to morbidity and mortality in ECMO-supported patients. In the last decade, however, ECMO has become simpler and safer. Advances in ECMO device technology and circuit biocompatibility, cou-pled with what many perceive as favorable results of recent studies, have led to a rapid expansion in ECMO use worldwide [5–7].

Despite the significant improvement in outcomes in the modern era of ECMO, hematologic complications remain common and are a leading cause of morbidity [5]. ECMO-supported patients have hematologic challenges beyond those experi-enced by many other critically ill patients in the intensive care unit (ICU), as not only are patients receiving ECMO subject to the hematologic dysregulation that can occur in critical illness, but they are notably impacted by the alteration in pro- and anticoagulant pathways precipitated by the ECMO circuit itself, as well as the anti-coagulation typically required to maintain it.

C. Agerstrand, MD (*) · D. Brodie, MD Division of Pulmonary, Allergy and Critical Care, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY, USAe-mail: [email protected]; [email protected]

A. Eisenberger, MDDivision of Hematology, Columbia University College of Physicians and Surgeons, New York, NY, USAe-mail: [email protected]





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Principles of ECMO

ECMO is a form of mechanical circulatory support that functions by supporting the heart, the lungs, or both. During ECMO, blood is pulled from a central vein, pumped across a gas-exchange device known as an oxygenator, and then returned to the circulation after having been oxygenated and decarboxylated. During venovenous ECMO, blood is returned to a central vein, thereby operating in series with the lungs and providing support for patients with respiratory failure. Patients with severe forms of the acute respiratory distress syndrome (ARDS), status asthmaticus, or select patients awaiting lung transplantation, such as those with cystic fibrosis, can be supported with venovenous ECMO [4, 7–10]. In venoarterial ECMO, blood is returned to an artery, so that the reinfused blood from the circuit bypasses both the heart and lungs and provides both respiratory and hemodynamic support. Venoarterial ECMO is used in patients with heart failure or combined cardiopulmo-nary failure, such as those with cardiogenic shock after myocardial infarction or cardiac surgery, massive pulmonary embolism, or as an adjunct to cardiopulmonary resuscitation [11–13].

Gas Exchange During ECMO

Gas exchange occurs within the oxygenator of the ECMO circuit. The oxygenator is divided into two chambers separated by a semipermeable membrane that is com-posed of small, hollow fibers coated with polymethylpentene, which permit the dif-fusion of gas but not liquid. Blood flows through one chamber of the oxygenator, and the sweep gas flows through the other (Fig. 13.1) [14]. The sweep gas is typi-cally composed of oxygen and ambient air in proportions controlled by a blender and supplied by an external tank. Due to the high concentration of oxygen in the sweep gas and low concentration of oxygen in venous blood entering the oxygen-ator, oxygen diffuses down a gradient from the gas chamber into the blood chamber. Conversely, carbon dioxide diffuses from the blood chamber across the oxygenator membrane into the gas chamber, where it is released from an exhaust valve.

Oxygen delivery during venovenous ECMO is primarily determined by the blood flow rate of the ECMO circuit. The higher the ECMO blood flow rate, the higher the percentage of cardiac output that is oxygenated maximally before return-ing to the body and mixing with blood flowing exclusively through the native circu-lation. The blood flow rate in either venovenous or venoarterial ECMO is determined by the rotational speed of ECMO pump, intravascular volume status of the patient, and resistance within the ECMO circuit, which may be increased with clot or fibrin deposition. Modern ECMO circuits use centrifugal pumps, which compared to older generation roller pumps exert less shear stress on the blood [15]. The maximal blood flow rate is primarily limited by the size of the venous drainage cannula and, to a much lesser extent, the reinfusion cannula. Larger-sized cannulas permit greater blood flow rates without exerting untoward pressure or shear stress on the blood, which can result in hemolysis.

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Unlike oxygen delivery, carbon dioxide clearance via the ECMO circuit is largely independent of ECMO circuit blood flow, except at lower blood flow rates. Since carbon dioxide is more soluble than oxygen and diffuses readily across the oxygen-ator membrane, adequate carbon dioxide clearance is primarily determined by the carbon dioxide gradient across the oxygenator membrane and can be achieved even at low blood flow rates [16]. This gradient is maintained through the continuous infusion of fresh sweep gas to the gas chamber of the membrane. At a higher sweep gas flow rate, diffused carbon dioxide is expelled from the gas chamber more rap-idly, a greater transmembrane carbon dioxide gradient is maintained, and more dif-fusion of carbon dioxide from the blood occurs.

Cannulation Strategies

Cannulation in venovenous ECMO can be from one or more sites. In a typical two-site venovenous cannulation, blood is often removed from a femoral vein and returned to an internal jugular vein (Fig. 13.2) [14]. In single-site cannulation, a dual-lumen cannula is commonly positioned in an internal jugular vein with its distal tip extending into the inferior vena cava, the advantages of which are greater patient mobility and increased circuit efficiency (Fig. 13.3) [14, 17].

In venoarterial ECMO, blood is commonly removed from the femoral vein and returned to the femoral artery, although, as with venovenous ECMO, multiple can-nulation strategies may be used. The reinfused blood, in this scenario, flows

Blender

Air

Oxygen

Oxygenator

Gas

Membrane

O2 CO2 O2 CO2

Blood

Pump

Fig. 13.1 Oxygenator membrane. Venous blood flows through one chamber of the oxygenator, and sweep gas flows through the other chamber. Gas exchange occurs by diffusion across the oxy-genator membrane; oxygen diffuses into the venous blood; and carbon dioxide diffuses out. Blood exiting the oxygenator has a high concentration of oxygen (partial pressure of oxygen 400–500 mmHg in a well-functioning circuit) and a low concentration of carbon dioxide

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retrograde up the aorta and competes with native cardiac output. Upper-body can-nulation strategies during which blood is removed from the internal jugular vein and returned to the subclavian or innominate artery or central cannulation, with drainage from the right atrium and reinfusion to the left atrium, for instance, are also possible in venoarterial ECMO [18, 19]. Patients receiving venoarterial ECMO are at higher risk of complications such as embolic stroke, neurovascular damage or limb isch-emia from hemorrhage, other systemic thromboembolism, or hypoperfusion of the limb distal to the arterial cannula [5, 20, 21].

Coagulation Cascade During ECMO

During ECMO support there is continuous contact between the non-biologic compo-nents of the ECMO circuit, including the cannulae, tubing, pump head and oxygen-ator membrane, and the blood, which induces an inflammatory response and activates pro- and anticoagulant pathways, as well as fibrinolysis. Activation of coagulation leads to the conversion of fibrinogen to fibrin, which then adheres to ECMO circuit components such as tubing and the oxygenator membrane. Turbulence from non-laminar blood flow generated during ECMO further propagates these processes. Conversely, the high shear which ECMO generates can render von Willebrand factor (vWF) multimers more susceptible to proteolysis by the vWF-cleaving protein, ADAMTS13 [22]; this can recapitulate the acquired type 2A von Willebrand disease

Blender

Control panel

Pump

Oxygenator

Fig. 13.2 Two-site venovenous ECMO configuration. Blood is pulled from a central vein into the ECMO circuit where it is oxygenated and decarboxylated. The blood is then returned to another central vein


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seen in severe aortic stenosis and in use of left ventricular assist devices. The large ECMO cannulae can also induce local vascular endothelium damage, which simul-taneously will further deplete vWF, in addition to promoting catheter-associated thrombosis. The widespread activation of coagulation throughout several parts of the ECMO circuit can induce a consumptive thrombocytopenia, as well. Therefore, the hematologic dysregulation that ensues from activation of the extrinsic and intrinsic coagulation pathways, fibrinolysis, and platelet consumption can increase the risk of both bleeding and thrombosis. The management of these problems is further compli-cated by the fact that both hemorrhagic and thrombotic complications may develop concurrently. Maintaining a balance between the continually activated pro- and anti-thrombotic pathways is one of the central challenges of providing ECMO support.

Anticoagulation During ECMO

Heparin

In order to mitigate the prothrombotic sequelae of ECMO, anticoagulation is required. Anticoagulation is typically achieved with the continuous infusion of intravenous unfractionated heparin, which is administered in a bolus dose of 50–100 units/kg at the time of cannulation and is continued throughout the duration of

Blender

Control panel

Pump

Oxygenator

Fig. 13.3 Single-site, dual-lumen venovenous ECMO configuration. Blood is pulled into the ECMO circuit via one lumen of the dual-lumen cannula and returned to another lumen within the same cannula, which can increase the efficiency of the ECMO circuit and allow for greater patient mobility


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ECMO support. While continuous, full-dose anticoagulation was required with older ECMO devices, low-dose heparin targeting subtherapeutic levels of antico-agulation may be adequate with modern, more biocompatible ECMO circuit com-ponents [23, 24].

Heparin acts by binding to and potentiating the effect of endogenous antithrom-bin. Antithrombin inhibits nearly all serine proteases of the intrinsic pathway, but its major effect is inhibition of factor Xa and thrombin, which inhibits the conversion of fibrinogen to fibrin. Inhibition of thrombin not only inhibits fibrin formation but also prevents thrombin-mediated platelet activation and activation of other coagula-tion factors [25]. Due to the conformation of these complexes, only the longer hepa-rin molecules (18 disaccharide units or 5 kDa) in unfractionated heparin bind to thrombin, while heparin of any length can bind to factor Xa [26]. Unlike tissue plasminogen activator, heparin does not break down existing clot, but allows natural fibrinolytic processes to occur. Heparin also inhibits anticoagulation from the extrinsic pathway by increasing the release of tissue factor pathway inhibitor from the vascular endothelium and its affinity to factor Xa [27].

Low molecular weight heparin (LMWH) does not possess the long polysaccha-ride side chains so it only binds to factor Xa [25, 28]. As it is subject to less degrada-tion in vivo, it may be administered by subcutaneous injection twice daily. LMWH has also been used during ECMO support, though with much less frequency [29]. Limited evidence exists as to effectiveness and bleeding risk of LMWH compared to unfractionated heparin in ECMO-supported patients.

Of note, while continuous anticoagulation remains standard in patients receiving ECMO, there is a small but growing experience of patients successfully managed for hours or days without any anticoagulation, such as in cases of severe hemor-rhage or coagulopathy [30, 31]. Even in patients with severe coagulopathy however or undergoing full anticoagulation, thrombosis of the ECMO circuit or thromboem-bolism may still occur.

Direct Thrombin Inhibitors

Heparin remains the mainstay of anticoagulation; however, there has been increased use in recent years of direct thrombin inhibitors (DTIs), such as bilvalirudin and argatroban, even though evidence for their use in ECMO is quite limited. DTIs work by inhibiting thrombin-mediated conversion of fibrinogen to fibrin. The action of DTIs is independent of the cofactor antithrombin and of other plasma proteins, which means they have more predictable pharmacokinetics than heparin [32, 33]. However, unlike heparin, no antidote to DTIs exists. Another potential disadvantage of DTI use is that their activity is imperfectly measured with the activated partial thromboplastin time (aPTT). The preferred method for monitoring DTIs, the ecarin clotting time, is not widely available.

DTIs are primarily used when heparin-induced thrombocytopenia (HIT) is sus-pected. Argatroban is the mainstay of treatment for suspected HIT, has a half-life of 45 min, and is primarily hepatically cleared, making it safe to use in patients with


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renal dysfunction. DTIs, and bilvalirudin in particular, are gaining favor as an alter-native to unfractionated heparin or in cases of suspected heparin resistance during ECMO [33–35]. It has a half-life of 25 min and is primarily cleared by intravascular proteolysis (although approximately 20% undergoes renal clearance), so it may be used in patients with impaired hepatic function. However, bilvalirudin is decreased in areas of blood stasis, which may cause unexpected thrombosis of the circuit in areas of stagnation or at lower blood flow rates [32].

Factor Xa Inhibitors

There is no data on using factor Xa inhibitors such as apixaban or rivaroxaban patients supported with ECMO. These agents inhibit factor Xa without requiring the cofactor antithrombin and have appeal as an orally administered anticoagulant. This could conceivably become relevant with the development of a durable artificial lung used for outpatient management of chronic respiratory failure. Such devices are cur-rently under development.

Antiplatelet Agents

Use of antiplatelet agents such as aspirin may also be incorporated into a multimodal-ity anticoagulation strategy. Some centers have incorporated aspirin into their ECMO protocols without increase in bleeding rates, but limited evidence exists [36–39].

Monitoring During ECMO

The best method for monitoring anticoagulation during ECMO is complex and a source of controversy. All assays of anticoagulation lack standardization and may vary significantly between labs. Frequency of monitoring of anticoagulation also varies widely by center. Until recently, measurements were taken multiple times daily though some centers now measure anticoagulation status as infrequently as once daily in stable patients [24, 40].

Activated Clotting Time

Activated clotting time (ACT) is a rapid, point-of-care test that measures the clotting of whole blood and global hemostatic function. Historically, ACT has been the most commonly used test during ECMO, but limitations of ACT exist as it is impacted by multiple patient parameters such as blood temperature, platelet count and function,


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coagulation factor and fibrinogen levels, hemodilution, and technical testing factors. Given these constraints, some centers, adult centers in particular, have moved away its use. In fact, in a retrospective review of 600 ECMO patients, only modest cor-relation between heparin effect and ACT was found (r = 0.48). Typical ACT targets in non-bleeding ECMO patients range from 160 to 220 s, depending on the analyzer, other hematologic parameters, and institutional practice [41, 42].

Activated Partial Thromboplastin Time

Activated partial thromboplastin time (aPTT), which is a plasma-based test that measures fibrin formation in the absence of cellular components, or activity of the intrinsic pathway, has become the predominant test used in adults undergoing ECMO, although it is not as reliable in neonates. Given the reduced thrombogenic-ity of modern ECMO circuits, in the absence of an indication for a therapeutic anticoagulation target, such as known hypercoagulable state or deep venous throm-bosis (DVT), heparin is titrated to an aPTT typically less than therapeutic, ranging from 40 to 70 s or 1.5 to 2.0 times normal, with great variation in practice between centers [15].

Anti-factor Xa Level

The anti-factor Xa level assay recently gained favor as a measure of heparin effect. Anti-factor Xa levels measure the heparin-antithrombin complex thus are specific to the anticoagulation effect of heparin and therefore considered more accurate than other testing modalities. Though the anti-factor Xa assay is not affected by other coagulopathies (such as the very high or very low factor VIII and fibrinogen levels that may be seen in patients receiving ECMO) or thrombocytopenia, it must be interpreted with caution in the setting of anemia or hyperbilirubinemia, hemolysis, or hyperlipidemia. Targets vary by lab; low anticoagulation may be achieved with an anti-Xa target of 0.1–0.3 units/mL, while a therapeutic target ranges from 0.3 to 0.7 units/mL for most patients [43].

Viscoelastic Testing

Viscoelastic testing (thromboelastography or rotational thromboelastometry) are newer tests for determining global coagulation status, in which time to clot forma-tion, clot stability and strength, fibrinolysis, and platelet function are analyzed. These tests are appealing in their multiparameter measurements and have the advan-tage of being a point-of-care test which can help identify the specific defect and


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direct therapy in bleeding patients. Though increasingly used, its validity and clini-cal impact are not well studied in ECMO patients.

Challenges, Complications, and Management During ECMO

Heparin Resistance

Antithrombin is a serine protease inhibitor that inactivates thrombin and activated factor Xa, therefore reducing rates of fibrin deposition. Since heparin potentiates the effect of antithrombin, a deficiency in antithrombin will negate the effects of hepa-rin. This may occur during ECMO due to circuit-related consumptive coagulopathy, as well as in patients with liver failure or disseminated intravascular coagulation. Low ACT, aPTT, and anti-factor Xa levels despite escalating heparin doses particu-larly a dose greater than 35 units/kg/h and as the duration of ECMO increases are characteristic of an antithrombin deficiency. Antithrombin can be replaced in the blood either by administration of fresh frozen plasma, which contains a small amount of antithrombin, or by antithrombin concentrate. However, literature is lim-ited, and the impact of antithrombin administration on heparin requirements, bleed-ing, or thrombotic events is mixed [43, 44]. Transition from heparin to DTIs such as bilvalirudin has also been used in cases of heparin resistance, although again, evi-dence for doing so is limited [33].

Hemorrhagic Complications

Bleeding is the most common complication of ECMO support, present in 27–60% of recent studies, although definitions of what constitutes bleeding vary widely [5, 6, 39, 45]. This occurs due to the use of anticoagulation, as well as from platelet and coagulation factor consumption in the ECMO circuit. Although common in the modern era of ECMO support, historically ECMO-related bleeding complications were nearly universal. Even in ECMO centers during the modern era, however, cause of death has been attributed to bleeding in up to 71% of cases [6, 46]. Overall bleeding risk likely varies substantially by the patient population as well as cannula-tion and anticoagulation approaches used.

The Extracorporeal Life Support Organization (ELSO) conducts research, pub-lishes management guidelines, and maintains registry of patients supported with ECMO at many centers worldwide. Though not all ECMO centers submit data to ELSO, the most common sites of bleeding are reported at cannulation and surgical sites, with frequencies of 6–23% depending on type of ECMO and patient age [5]. Bleeding from postsurgical sites, including chest tubes, may be particularly prob-lematic and difficult to control. Management of bleeding should include use of local hemostatic agents (such as pressure dressings, packing, or topical hemostatic agents),


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optimization of anticoagulation and other coagulation parameters, and surgical cor-rection (cauterization, suture placement), when appropriate. In hemodynamically stable patients receiving ECMO with small to moderate pneumothoraces, it may be reasonable to monitor for resolution and avoid chest tube insertion due to the risk of hemothorax following placement. Clinicians should have a high index of suspicion for abdominal compartment syndrome from intra-abdominal hemorrhage when ECMO is used during or following abdominal surgery or Cesarean section [47, 48]. Spontaneous or procedure-related retroperitoneal hemorrhages are also known com-plications of ECMO support and typically require supportive management.

The most feared bleeding complication in ECMO patients is intracerebral hem-orrhage (ICH), which carries a prevalence of at least 2–21% depending on patient age and the indication for ECMO [5]. A single-center review of more than 250 patients reported an ICH rate of 21% over a 10-year period, a significant percentage of which were incidentally detected on head imaging. Early detection of ICH is paramount to minimizing its associated morbidity. Risk factors for ICH in adults include pre-ECMO antithrombotic therapy and thrombocytopenia [49]. Frequent neurologic assessment for patients receiving ECMO should be a routine part of management. In addition to clear neurologic changes, complaints of headache, changes in behavior (such as new delirium or agitation), or any mild trauma should raise the level of suspicion for ICH and be accompanied by a low threshold for obtaining a head CT and neurologic consultation, as appropriate. If ICH does occurs, anticoagulation should be stopped in most cases, heparin reversal with prot-amine considered, and neurologic or neurosurgical consultation obtained, as needed.

Transfusion and Management of Hemorrhage

Transfusion Thresholds

Transfusion thresholds during ECMO support are not well established. Due to the fact that hemoglobin is a key determinant of oxygen content and that ECMO is often utilized when native oxygen delivery is inadequate, however, transfusion to a nor-mal hemoglobin level of 12–14 g/dL was traditionally recommended. This practice frequently required daily packed red blood cell (pRBC) transfusions. It was com-mon for patients to require 2–3 units of pRBCs daily, and requirements as high as 6 units daily have been reported [50–52]. In recent years, however, both transfusion requirements and the transfusion threshold have decreased leading to reduction in pRBC transfusions. The enhanced biocompatibility of modern ECMO circuits with heparin or phosphorylcholine-coated tubing, transition from a roller to centrifugal pump system, and simplification of the ECMO circuit have reduced the risk of clini-cally significant hemolysis. These factors have also decreased thrombotic propen-sity, meaning that lower-dose anticoagulation is often sufficient to prevent circuit or systemic thrombosis. All of these factors have attenuated the need for transfusions once essential during ECMO support.


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Fueled by an awareness of the deleterious effects of transfused blood and physi-ologic tolerance of a moderate degree of anemia, the hemoglobin threshold for transfusion has also decreased [4]. The Transfusion Requirements in Critical Care (TRICC) trial showed decreased mortality with a restrictive hemoglobin threshold of 7.0 g/dL compared with a liberal strategy of 10.0 g/dL in critically ill patients [53]. Additional high-quality studies since that time have similarly demonstrated that the number of transfusions and not the actual hemoglobin is associated with higher intensive care unit and inhospital mortality. Even small numbers of 1–2 units of transfusion increase morbidity from sepsis, pulmonary complications, and wound complications [54]. Based on this and other evidence, the 2016 guidelines of the American Association of Blood Banks recommend use of a restrictive transfusion strategy (hemoglobin 7.0–8.0 g/dL) for hemodynamically stable, hospitalized patients [55]. Though these trials did not include patients receiving ECMO, excel-lent clinical outcomes using a restrictive approach to transfusions in ECMO-supported patients have been reported, albeit in non-randomized, smaller studies [24, 56]. It has been shown that adoption of a blood conservation protocol including a restrictive approach to transfusions, low-dose anticoagulation protocol, and rein-fusion of circuit blood at termination of the ECMO run can markedly reduce trans-fusion requirements while achieving comparable clinical outcomes [24].

Management of bleeding during ECMO is challenging due to use of continuous anticoagulation and the multiple factors that may contribute to it. In stable patients, transfusion of pRBCs according to institutional guidelines is warranted. In bleeding patients, platelet transfusion should be considered to maintain platelet count above some reasonable threshold, such as greater than 50,000/μL. Desmopressin may also be administered if there is concern for impaired platelet function. Cryoprecipitate can be administered during bleeding if there is clinical concern for disseminated intravas-cular coagulation or for fibrinogen levels less than 100 mg/dL. When an international normalized ratio (INR) is greater than 2, fresh frozen plasma (FFP) should be consid-ered; the INR of FFP is 1.4–1.6, so the benefit of administration must be weighed against the risk of large volume required during FFP transfusion. Transfusion of cryo-precipitate is a more concentrated alternative to FFP, though cryoprecipitate lacks many of the clotting factors present in FFP, so the former should not simply be con-sidered a more concentrated form of the latter. Surgical site bleeding should be evalu-ated for surgical correction; placement of additional sutures around bleeding cannulae or tracheostomy sites can often reduce bleeding. In addition to bleeding, other sources of anemia during ECMO include excessive phlebotomy or hemodilution from circuit priming with increased volume of distribution. Given the significance of this in neo-nates and children, a blood prime is typically used at ECMO initiation.

Anticoagulation Management

When severe bleeding occurs, anticoagulation may be reduced or held altogether, particularly in patients with a venovenous ECMO configuration. Patients with severe bleeding have been managed successfully in this manner, including patients


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with intracranial hemorrhage [57, 58]. A patient with severe diffuse alveolar hemor-rhage was managed for 20 consecutive days without anticoagulation with no throm-botic or adverse sequelae [59]. The threshold for reducing or holding anticoagulation should be higher in patients receiving venoarterial ECMO, or in venovenous patients with an intracardiac shunt, given the risk of thrombus formation with embolization, particularly the risk of embolic stroke.

Antifibrinolytic Therapy

Antifibrinolytic therapy, such as tranexamic acid and ε-aminocaproic acid, has been used to inhibit naturally occurring fibrinolysis and may be used prophylactically or in bleeding patients. Evidence for administration of antifibrinolytic therapy during ECMO is limited, but some reports suggest there may be benefit in certain patient populations, such as trauma and those undergoing surgery during ECMO. Both agents can be administered for a defined duration of time or during specific clinical events, such as surgery during ECMO support. A retrospective review of 298 patients, mostly neonates, deemed high-risk for hemorrhagic complications (those with anticipated surgery, severe hypoxemia or acidosis, coagulation, prior bleeding, or prematurity) administered aminocaproic acid from 1991 to 2001 showed reduced surgical site bleeding compared to similar patients in the ELSO registry during that time (10% vs. 30%, p 0.001), although no difference in intracerebral hemorrhages or survival was found [60]. Of note, there was no difference in clinically significant thrombosis (cerebral infarction or major vessel thrombosis), but more circuit changes were required in the group that received aminocaproic acid. Small case series of adult patients with bleeding demonstrated improvement in hemostasis following administration of aminocaproic acid, without known increase in thrombosis [61].

Factor Concentrates

Recombinant activated factor 7a (rFVIIa) has been used off-label in refractory hem-orrhage during ECMO support; however, its use is controversial, and experience is limited to case reports and case series. While the literature suggests rFVIIa is effec-tive at reducing bleeding during ECMO, increased thrombosis—which has been fatal in some cases—has also been described [62–64]. The specific risk in patients receiving ECMO has not been established.

Similarly to rFVIIa, prothrombin complex concentrate (PCC) is composed of three or four factors (factors II, IX, and X with or without factor VII) and is a plasma-derived concentrate that may reduce severe bleeding. PCC is rapid-acting and highly concentrated but may be associated with higher rates of serious throm-botic events, such as embolic stroke, deep venous thrombosis, pulmonary embo-lism, and myocardial infarction, and must be administered with caution in all circumstances [65]. Experience with PCC during ECMO is extremely limited. In the one published case report of use during ECMO, fatal circuit and intracardiac thrombosis occurred [66].


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Thrombocytopenia

Thrombocytopenia during ECMO is a common occurrence, the reasons for which are incompletely understood. As described above, Von Willebrand factor-mediated binding of platelets to exposed collagen on the damaged vascular endothelium con-sumes circulating platelets. Platelets also bind to the fibrinogen bound to the ECMO circuit. Platelets not only decrease in quantity, but exhibit decreased binding affin-ity, as well. However, these processes may be reduced with the use of modern ECMO circuits. Thrombocytopenia during ECMO may be explained by other rea-sons, such as severity of illness, use of platelet-lowering medications, number of organ dysfunction, and pre-cannulation platelet count. When adjusting for these factors, the link between thrombocytopenia and duration of ECMO has not been consistently reproducible [67].

Recommendations for management of thrombocytopenia vary widely by center and reflect institutional opinion since specific evidence-based recommendations do not exist. The ELSO guideline on anticoagulation suggests transfusing platelets to a count greater than 100,000/μL in neonates and with consideration of lower targets in children and adults [68]. Although the transfusion threshold is not specified, in a survey of ELSO centers, platelet targets ranging from 20,000/μL to 100,000/μL are reported [69]. Prior to surgical procedures or if bleeding complications develop, it is reasonable to transfuse platelets to at least 50,000/μL.


HIT is a challenging complication of ECMO support given the combination of thrombocytopenia, hypercoagulability, and need for continuous anticoagulation, typically with heparin.

The concentration of circulating heparin-platelet factor 4 (PF4) complexes depends both on the propensity of heparin to bind to PF4 and the quantity of circulating PF4. During mechanical circulatory support, exposure of blood to the artificial circuit membrane increases platelet activation and may place patients at increased risk of heparin-PF4 antibodies as well as clinically significant HIT. This is well described in cardiopulmonary bypass where greater than 50% of patients may have heparin-PF4 antibodies; however, only about 20% of patients have actual HIT type II, as demonstrated by confirmatory testing measuring in vitro platelet activation performed with a serotonin release assay [70]. An even smaller percentage of approximately 2–3% develop clinical thrombosis [71]. The platelet activation that occurs with cardiopulmonary bypass also occurs with ECMO, though the frequency of HIT is unknown in this population. In relatively small single-center case series, HIT was diagnosed in 0–8% of patients supported with ECMO [67, 72, 73]. The impact of heparin-coated ECMO circuits on the inci-dence and propagation of HIT is unknown. Treatment of known or suspected antibody-mediated HIT during ECMO includes discontinuation of heparin, tran-sition to an alternative anticoagulation, most commonly argatroban, and


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evaluation for subclinical thrombosis, typically with venous and arterial duplex ultrasounds.

Von Willebrand Factor Deficiency

An acquired Von Willebrand factor (VWF) deficiency can occur during ECMO due to high shear stress exerted from the ECMO circuit and the increased proteolysis of large VWF multimers by ADAMTS13. This is similar to what may occur in other high shear states such as aortic stenosis and with ventricular assist devices. In small case series of ECMO-supported patients, VWF deficiency was present in greater than 90% of patients [74, 75]. This type of deficiency often manifests with mucocu-taneous bleeding or severe bleeding following surgical intervention.

Several tests must be used in tandem for accurate diagnosis of VWF deficiency. A VWF antigen may be checked to quantify the amount of VWF in the blood, while the hemostatic function of VWF is typically measured with the ristocetin cofactor assay (VWF:RCo) and less commonly with the VWF collagen-binding assay ratio (VWF:CB) [76]. Measurement of VWF multimers in patients receiving ECMO would be expected to demonstrate absence of the highest molecular weight multim-ers, as these are degraded in high shear scenarios.

Treatment of VWF deficiency often involves lowering the circuit blood flow rate to minimize shear stress as well as replacement of VWF with cryoprecipitate or fresh frozen plasma. Desmopressin has also been used to prompt release of VWF from the endothelial cells, although its effect in ECMO patients is not well charac-terized. It is important to recognize that without reducing shear by either increasing reduced flow rate or by replacing a circuit burdened with heavy fibrin deposition, increased VWF levels produced by blood component transfusion or desmopressin will be rapidly reduced.

Thrombosis

Thrombotic complications during ECMO are a relatively common occurrence, although their clinical significance varies considerably. According to the ELSO reg-istry, oxygenator thrombosis occurs with a frequency of approximately 13%, though cannula connectors or other sites of turbulence or stasis are also at risk [5]. Oxygenator thrombus decreases the gas exchange capability of the ECMO circuit and is the principle cause of oxygenator failure. Oxygenator thrombus is identified by a widening pressure gradient across the oxygenator or impairment in gas trans-fer. The normal gradient varies based on blood flow rate. Absolute or relative increases in the membrane gradient or marked increases in D-dimer are clues that non-visible clot is developing within the layers of the oxygenator membrane [15, 77]. Calculation of the oxygen transfer across the membrane, as determined by


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pre- and post- oxygenator blood gasses can quantify any associated impairment in gas exchange. Oxygenator thrombosis may also be identified by visual inspection of the visible portion of the membrane or cannulae (Fig. 13.4).

Pump head thrombosis occurs less frequently than does oxygenator thrombosis but can develop quickly and have notable consequences [5]. Severe hemolysis can occur with even small amounts of clot present in the of pump head. With large clots, the circuit itself may cease functioning altogether.

The frequency of thromboembolism during ECMO varies, but the published lit-erature suggests it is high, ranging from approximately 70 to 85% of postmortem examinations and may increase with duration of ECMO [78, 79]. The clinical con-sequence of thromboembolism is potentially greater overall in patients receiving venoarterial ECMO, as embolic strokes or other arterial emboli can occur. Review of ELSO registry data from 2012 to 2017 suggests that embolic CVAs occur in up to 4% of adult patients [5]. Management of embolic CVA is complicated. Patients receiving low-dose anticoagulation ideally need an increase to therapeutic targets, although this must be weighed again the risk of hemorrhagic conversion. Prompt recognition of CVAs is essential to optimizing patient outcome; some patients may

Fig. 13.4 Oxygenator membrane with deposited clot and fibrin


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be appropriate for mechanical thrombolysis with clot retrieval that can significantly and rapidly improve symptoms.

Clinical thrombosis most commonly occurs in the form of deep venous thrombo-sis (DVT); however, diagnostic patterns and frequency vary widely. Some centers routinely screen for DVTs with prevalence reported as high as 85% in one study [80].

In venoarterial patients with poor cardiac output, stasis of blood flow can result in intraventricular or intrapulmonary thrombosis, which can be fatal. It is essential to ensure continual flow through the native circulation in these patients, assisted by inotropes or other forms of mechanical support or left ventricular venting, if needed.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) may occur during ECMO due to the underlying disease process itself or the consumptive coagulopathy related to ECMO. Complicating the other existing hemostatic derangements, DIC during ECMO increases risk for both bleeding and thrombosis. Diagnosis can be difficult given that laboratory abnormalities characteristic of DIC can be altered in ECMO patients but should be suspected in the setting of thrombocytopenia, hypofibrino-genemia, and low levels of protein C and S in conjunction with elevated D-dimer, prothrombin time, and aPTT. Peripheral blood smears will show schistocytes. Management of DIC involves aggressive correction of coagulopathy and supportive care, including potentially replacing the ECMO circuit.

Hemolysis

Hemolysis is a potentially serious complication of ECMO support. The ELSO registry reports that hemolysis occurs in 5% of ECMO runs, the severity of which can range from clinically inconsequential to fatal [5]. Hemolysis is due to shear stress exerted on the blood cells from a variety of interactions with the ECMO circuit. Modern centrifu-gal pumps, while less injurious than older roller pumps, can exert a high negative pressure on drainage blood and result in red cell lysis. This risk is greater at higher blood flow rates, with more consistently negative pressures or with rapid swings in pressure. Higher pressure drops across the oxygenator, contact with the artificial cir-cuit materials, and the effect of deposited fibrin can also precipitate hemolysis.

Hemolysis is diagnosed by laboratory testing. ELSO defines hemolysis as a plasma-free hemoglobin greater than 50 mg/dL; normal values of plasma-free hemoglobin are less than 10 mg/dL. Surrogate markers for hemolysis include hemo-globin level, lactate dehydrogenase, aspartate aminotransferase, and indirect biliru-bin. Finding hemoglobinuria without demonstrable red blood cells in the urine is also common in patients with the intravascular hemolysis characteristic of ECMO. Abnormalities in these parameters may prompt additional investigation with plasma-free hemoglobin or peripheral blood smear.


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When hemolysis is recognized, prompt consideration of its etiology must occur. Mild hemolysis can quickly become severe if the precipitating factors persist. If the suspected cause is from high venous drainage pressures, blood flow rates should be decreased as much possible. If unable, insertion of a second drainage cannula will allow for continuation of a given amount of blood flow, with lower drainage pres-sures in each cannula. Thorough inspection of the circuit for fibrin or clot should also occur. If identified the oxygenator or circuit itself may need to be changed.

Surgery During ECMO

Surgical procedures during ECMO pose a challenge due to the need for operative hemostasis and anticoagulation. Based on a review of 563 patients supported with ECMO, 48% underwent a non-cardiac surgical procedure during the ECMO run with a total of 380 surgical procedures [21]. The most common procedures performed including abdominal exploration or bowel resection (18% of total procedures), vascu-lar or extremity operation to control hemorrhage (12.6%), exploratory thoracotomy or thoracoscopy (8%), lymph node biopsy or excision (6%), and lung/pleural biopsy, tracheostomy, and lobectomy/wedge resection (each approximately 5%). Eleven neu-rosurgical procedures occurred in this series (3%). Bleeding complications were sig-nificantly higher in the surgical cohort (27.9% versus 17.3%, p = 0.01) although mortality did not differ between the two cohorts. The only factor independently asso-ciated with mortality was need for blood transfusion (OR 1.7, p = 0.03) [21]. This suggests that while operative intervention during ECMO increases bleeding risk, nec-essary surgical procedures should not be withheld in this population. However, all efforts at reducing operative-related bleeding and optimizing hemostasis should occur.

Neurosurgical procedures during ECMO are less common; however, patients have been successfully supported with ECMO for traumatic brain injury with intra-cerebral pressure monitors in place, during repair of a ruptured aneurysm and dur-ing craniectomy [21, 81, 82]. Resumption of anticoagulation in these patients requires caution and multidisciplinary discussion, with close monitoring of the patient as well as the circuit.

Summary

The improved safety, efficiency, and outcomes of ECMO-supported patients have led to its widespread adoption as a strategy for severe cardiac, pulmonary, and car-diopulmonary failure. Coupled with this increased use is an enhanced understand-ing of the complex, often competing, hematologic challenges associated with ECMO. Though modern ECMO circuit components and contemporary approaches to anticoagulation have reduced the risk of these complications, disorders of antico-agulation and hemostasis remain common, difficult to manage, and potentially life-threatening. Understanding the multiple factors associated with bleeding,


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thrombosis, and hemolysis during ECMO, as well as the dynamic interplay between them, is critical to the safe delivery of ECMO support to increasingly varied and complex patient populations.

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55. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012;157(1):49–58.

56. Voelker MT, Busch T, Bercker S, Fichtner F, Kaisers UX, Laudi S. Restrictive transfusion practice during extracorporeal membrane oxygenation therapy for severe acute respiratory dis-tress syndrome. Artif Organs. 2015;39(4):374–8.

57. Wen PH, Chan WH, Chen YC, Chen YL, Chan CP, Lin PY. Non-heparinized ECMO serves a rescue method in a multitrauma patient combining pulmonary contusion and nonoperative internal bleeding: a case report and literature review. World J Emergy Surg. 2015;10:15.

58. Biscotti M, Gannon WD, Abrams D, et al. Extracorporeal membrane oxygenation use in patients with traumatic brain injury. Perfusion. 2015;30(5):407–9.

59. Herbert DG, Buscher H, Nair P. Prolonged venovenous extracorporeal membrane oxygenation without anticoagulation: a case of Goodpasture syndrome-related pulmonary haemorrhage. Crit Care Resusc. 2014;16(1):69–72.

60. Downard CD, Betit P, Chang RW, Garza JJ, Arnold JH, Wilson JM. Impact of Amicar on hem-orrhagic complications of ECMO: a ten-year review. J Pediat Surg. 2003;38(8):1212–6.

61. Buckley LF, Reardon DP, Camp PC, et al. Aminocaproic acid for the management of bleeding in patients on extracorporeal membrane oxygenation: four adult case reports and a review of the literature. Heart Lung. 2016;45(3):232–6.


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63. Repesse X, Au SM, Brechot N, et al. Recombinant factor VIIa for uncontrollable bleeding in patients with extracorporeal membrane oxygenation: report on 15 cases and literature review. Crit Care. 2013;17(2):R55.

64. Niebler RA, Punzalan RC, Marchan M, Lankiewicz MW. Activated recombinant factor VII for refractory bleeding during extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2010;11(1):98–102.

65. Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood. 2010;8(3):149–54. 66. Bui JD, Despotis GD, Trulock EP, Patterson GA, Goodnough LT. Fatal thrombosis after

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67. Abrams D, Baldwin MR, Champion M, et al. Thrombocytopenia and extracorporeal mem-brane oxygenation in adults with acute respiratory failure: a cohort study. Intensive Care Med. 2016;42(5):844–52.

68. Extracorporeal Life Support Organization. Anticoagulation Guideline. 2014:1–17 (www.elso.org/resources/guidelinesaspx).

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71. Sakr Y. Heparin-induced thrombocytopenia in the ICU: an overview. Crit Care. 2011; 15(2):211.

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73. Glick D, Dzierba AL, Abrams D, et al. Clinically suspected heparin-induced thrombocytope-nia during extracorporeal membrane oxygenation. J Crit Care. 2015;30(6):1190–4.

74. Heilmann C, Geisen U, Beyersdorf F, et al. Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med. 2012;38(1):62–8.

75. Kalbhenn J, Schmidt R, Nakamura L, Schelling J, Rosenfelder S, Zieger B. Early diagnosis of acquired von Willebrand syndrome (AVWS) is elementary for clinical practice in patients treated with ECMO therapy. J Atheroscler Thromb. 2015;22(3):265–71.

76. Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood. 2015;125(13):2029–37.

77. Lubnow M, Philipp A, Dornia C, et al. D-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxygenation. J Crit Care. 2014;29(3):473.e471–5.

78. Reed RC, Rutledge JC. Laboratory and clinical predictors of thrombosis and hemorrhage in 29 pediatric extracorporeal membrane oxygenation nonsurvivors. Pediatr Dev Pathol. 2010;13(5):385–92.

79. Rastan AJ, Lachmann N, Walther T, et al. Autopsy findings in patients on postcardiotomy extracorporeal membrane oxygenation (ECMO). Int J Artif Organs. 2006;29(12):1121–31.

80. Menaker J, Tabatabai A, Rector R, et al. Incidence of cannula associated deep vein thrombosis after veno-venous ECMO. ASAIO J. 2017;63(5):588–91.

81. Hwang GJ, Sheen SH, Kim HS, et al. Extracorporeal membrane oxygenation for acute life-threatening neurogenic pulmonary edema following rupture of an intracranial aneurysm. J Korean Med Sci. 2013;28(6):962–4.

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http://www.elso.org/resources/guidelinesaspx

http://www.elso.org/resources/guidelinesaspx


Chapter 14Hematologic Challenges in Intensive Care Unit Patients with Solid Organ Transplants

Gerardo Tamayo-Enríquez and Daniel Borja-Cacho

Introduction

The last 50 years have seen tremendous advances in the fields of transplantation and critical care, moving from experimental sciences to standard clinical practices. According to data from the Organ Procurement and Transplantation Network, there were 28,746 solid organ transplants (SOT) performed from January to October 2017 in the United States [1]. Although a significant proportion of these patients will require intensive care unit (ICU) stays, they still represent a small proportion of the overall critical care population. Exposure to these patients is therefore limited for most intensivists, and it is important to get familiarized with the complex medi-cal and surgical interactions in the SOT patient. As we move toward a widespread “closed” ICU model, it has been proposed that care for these patients should be provided in a collaborative fashion between the transplant team and the intensivist team. The ideal model would call for physicians with expertise in the following: (1) transplant and routine ICU skills and algorithms, (2) end-organ failure, (3) complex transplant surgical procedures, and (4) immunosuppressive medications and their interactions/complications [2]. The critically ill transplant patient presents unique hematologic challenges related to major surgical trauma, immunosuppressive medi-cations, antibiotics, post- transplant infections, and the physiology of end-organ fail-ure itself. Hematologic challenges in the SOT recipient may include pancytopenias, profound alterations in the coagulation cascade, and increased incidence of certain hematologic malignancies.

G. Tamayo-Enríquez (*) · D. Borja-Cacho Department of Surgery, Division of Transplant Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USAe-mail: [email protected]



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Hematologic Challenges in the Liver Transplant Recipient in the ICU

Orthotopic liver transplantation (OLT) represents a major physiologic derangement to the recipient, not only from the traumatic insult of the transplant surgery itself but also in the form of multiple transfusions, fluid and electrolyte shifts, and the intro-duction of immunosuppression. After the implementation of the model for end- stage liver disease (MELD) for the allocation of organs in March of 2002, the allocation scheme moved toward an objective severity-based model. This resulted in a trend toward longer waiting times, with sicker patients having higher priority on the trans-plant waiting list. Shortly after the implementation of the MELD scoring system, it was estimated that 15% of OLT were to recipients already in the ICU [3]. A second major change occurred in June 2013, after the introduction of the Share 35 policy, in which patients with a MELD score ≥35 achieve priority on the regional wait list over those with MELD <35 on the local wait list. This led to an increase in the pro-portion of patients in the ICU requiring respiratory, renal, or cardiovascular support at time of transplantation [4]. The overall effect is sicker, more complex patients in the ICU with the potential to develop the following hematologic complications.

Anemia

One of the most common reasons for anemia in the postoperative period is bleeding. In a large study series, up to 9% of patients developed anemia secondary to coagu-lopathy or iatrogenic injury, requiring either interventional radiology or surgical exploration [5]. Other etiologies for anemia in the immediate postoperative period include iron deficiency, renal insufficiency, hemolysis, sepsis, and medications [6].

Diagnosis of Anemia

The clinical diagnosis of acute hemorrhagic anemia in the OLT recipient is often difficult due to the unique cardiovascular physiology of the cirrhotic patient, which is characterized by a decrease in the systemic vascular resistance and arterial pres-sure. The subsequent increase in cardiac output results in a hyperdynamic state. These changes are difficult to differentiate from hypovolemia, and they tend to per-sist after transplantation, improving in the first 24 h but completely resolving in 6–12 months post-transplant [7]. There is significant debate regarding the transfu-sion threshold in transplant patients and in critically ill patients in general, with a trend toward lower values. A hemoglobin (Hb) of 6.0–7.0 g/dL is a widely accepted goal. The current guidelines recommend 6.0 g/dL for general ICU patients and 7.0 g/dL for patients on mechanical ventilation [5, 8]. A threshold of 6.0–7.0 g/dL is used at the University of Arkansas for Medical Sciences depending on comorbidi-ties, as there is significant evidence of worsened outcomes using a liberal transfu-sion approach. Poor outcomes are a result of immunosuppression, transfusion-related

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infections, and transfusion-related acute lung injury. In the OLT recipient, a liberal transfusion approach is associated with an overall increased mortality [6, 7]. The development of transfusion-related immunomodulation (TRIM) is of particular sig-nificance to the SOT recipient. This can lead to significant immunosuppression with increased susceptibility to bacterial infections, Cytomegalovirus (CMV), and recur-rence of malignancy. These effects are usually present when the allogeneic blood transfusion donor shares HLA-DR antigens with the recipient [9]. It seems prudent to use lower Hb values in SOT recipients to avoid these deleterious effects in a population that is already immunologically compromised. The incidence of iron deficiency in the OLT population pre-transplant can be as high as 59.2% and is associated with a high (>4U red blood cells (RBCs)) transfusion rate and worse outcomes. Iron studies should be part of the routine preoperative evaluation of these patients [10]. Alcohol remains a frequent cause of liver disease and OLT in the United States; these patients can have baseline macrocytic anemia from nutritional deficiencies or bone marrow suppression from direct ethanol toxicity.

Management of Anemia

Up to 50% of patients in the ICU require a transfusion of RBCs, and OLT recipients are not an exception. The first step in anemia management should be prevention, as iatrogenic anemia in the ICU has demonstrated significant impact on outcomes. The following four strategies should be used: (1) reduction in phlebotomy in laboratory testing, (2) use of pediatric or low-volume blood sampling tubes, (3) use of in-line blood conservation devices in arterial and central lines, and (4) cell salvage for major surgical procedures [11]. Once a decision has been made to transfuse RBCs, the minimum amount of blood needed to achieve the goal Hb should be used. Massive transfusion is associated with increased risk of death, early graft dysfunc-tion, and hyponatremia in the first 30 days post-transplant [12]. The liver is the main organ for iron storage and plays a central role in iron metabolism as the main pro-ducer of the iron hormone hepcidin. A reduction in hepcidin production produces an increase in iron stores in the liver, leading to an estimated 30% of hepatic iron overload in cirrhotic patients. Therefore, iron supplementation should be used with caution in OLT recipients as iron overload both pre- and post-transplant is associ-ated with reduced survival [13]. Common practice is to delay iron supplementation 4–6 weeks after transplant. Chronic anemia can also be present in the critically ill SOT patient and could be secondary to aplastic anemia, graft-versus-host disease (GVHD), and post-transplant lymphoproliferative disorder (PTLD).

Coagulopathy

The liver plays a critical role in the clotting physiology by maintaining a balance between procoagulant and anticoagulant mediators by means of synthesis of most coagulation factors (I, II, V, VII, IX, X, XI, XII, XIIIa) and the proteins responsible

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for fibrinolysis and thrombopoiesis (protein C, protein S, antithrombin, thrombo-poietin) [14]. The OLT recipient in the ICU will start reversing these abnormalities as soon as the graft is perfused. The rate of functional recovery is multifactorial and dependent on cold ischemic time, ischemia reperfusion injury, donor after cardiac death status, percentage of liver macrosteatosis, and overall condition of the recipi-ent. Thus, the OLT recipient initially tends toward the anticoagulant side of this delicate balance secondary to the decrease in coagulation factors, thrombocytope-nia, and platelet dysfunction. Some patients will have a deranged balance favoring the procoagulant side, due to a decrease in protein S, protein C, and upregulation of endothelial-derived von Willebrand factor (vWF). This upregulation of factor VIII, coupled with decreased plasma clearance of factor VIII, results in a procoagulant effect. Therefore, pre- and post-OLT patients are not auto-anticoagulated [15].

Diagnosis of Coagulopathy

Some of the biggest advances in OLT have been in the monitoring and management of coagulopathy both intraoperatively and in the ICU. The conventional testing for coagulopathy in the OLT recipient has been questioned due to its inaccuracy in this patient population. As mentioned, the coagulation profile in the OLT patient is rebalanced, with a decreased physiologic reserve that can easily tip toward bleeding or thrombosis. Conventional testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR), can provide an estimate of the deficiencies of procoagulant factors. However, these tests fail to reflect the new balance in the OLT recipient and do not account for the com-plex interactions with platelets, vascular endothelium, and fibrinolysis. Platelet counts are purely quantitative measures that have no reflection of function, even when using functional conventional testing like bleeding time. The results may be inaccurate, because they are affected by vasoreactivity and arterial dysfunction, both present in OLT recipients. To overcome these deficiencies, point-of-care (POC) whole blood testing including thromboelastography (TEG®) and rotational throm-boelastometry (ROTEM®) has been used, resulting in decreased perioperative blood loss and transfusion rates [16]. TEG and ROTEM are good indicators of fibrinogen function and dysfunction by means of analysis of the mechanical proper-ties of clot; however, they do not correlate well with PT or aPTT. Platelet function or quantity is not directly assessed by ROTEM, and also antiplatelet drug effects are not measured. Common practice is to use both conventional and POC testing to guide blood component replacement [17].


Once the diagnosis of coagulopathy has been established, the resuscitative efforts and correction of coagulation abnormalities should be goal directed as determined by the clinical picture, convention, and POC testing. In the absence of clinical


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bleeding, there is no need to normalize INR or ROTEM; as the graft’s synthetic function improves, it will provide enough factors for adequate hemostasis. Correction of INR, clearance of lactate via Cori’s cycle, and improvement in neuro-logic status with decreased encephalopathy are all common early indicators of good graft function. If there is slow graft function, as seen by an increasing INR and prolonged clotting time (CT) on ROTEM EXTEM, plasma (either fresh frozen or thawed) should be administered. After optimization for temperature (>36.0 °C), pH (>7.3), ionized calcium (>4.5 g/dL), and Hb (>8 g/dL), the administration of 4U of FFP for INR >1.8 or CT EXTEM >90s is associated with a decrease in overall FFP and RBC administration as well as decreased costs [18]. Thrombin generation is preserved in the cirrhotic patient, resulting in fibrinogen depletion as it is converted to fibrin over the glycoprotein IIb–IIIa platelet-bound receptor. Correction of the fibrinogen level to a minimum of 150–200mg/L and normalization of the maximum clot firmness (MCF) FIBTEM to >10 mm are recommended. FFP is not appropriate for the treatment of dysfibrinogenemia; in this scenario, cryoprecipitate should be used as each unit contains a minimum of 150 mg of fibrinogen, as well as factor XIII, factor VIII, and vWF, in an overall smaller volume (15 mL/unit). Transfusion with two pools of cryoprecipitate (10 units) will increase the fibrinogen by 70 mg/dL [18, 19]. In the last 15 years, there has been a growing interest for the use of cryoprecipitate and prothrombin complex concentrate (PCC) with ROTEM guid-ance versus transfusion with FFP. This has been an effective approach in cardiovas-cular surgery and severe trauma. Current non-activated, four-factor PCC formulation is a concentrate of the four vitamin K-dependent factors (II, VII, IX, X), protein C, and protein S. A single dose of PCC at 25 IU/kg should be administered for a MCF EXTEM of 35 mm; this replacement appears to decrease the amount of blood com-ponent transfusions without increasing thrombotic events [20, 21].

Thrombosis

The OLT recipient has a re-balanced hemostasis and is not auto-anticoagulated. Some of the most dreaded hematologic challenges in this critically ill population are related to thrombotic events, potentially resulting in hepatic artery thrombosis (HAT), portal vein thrombosis (PVT), hepatic vein thrombosis (HVT), inferior vena cava (IVC) thrombosis, and venous thromboembolism (VTE) with concomitant morbidity and mortality.

Diagnosis of Thrombosis

The presentation of hepatic vascular thrombosis in the ICU OLT recipient is usually very florid with a sudden increase in transaminases, INR, and lactate in a hemody-namically unstable comatose patient. However, some components of this presenta-tion may be absent, particularly in late thrombosis. Of note, these patients do not


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respond to the usual crystalloid and blood component resuscitation. The aforemen-tioned presentation usually prompts immediate Doppler ultrasound examination of the graft (Fig. 14.1), as these complications are surgical emergencies. In equivocal cases, angiographic arterial imaging with venous phases or magnetic resonance imaging (MRI) can be used as confirmatory testing.

VTE remains the most common cause of preventable death in the hospital setting in the United States, with some reports indicating an incidence as high as >900,000 cases per year with an associated mortality of around 300,000. The incidence in the OLT recipient varies between 5 and 8.6%, with administration of factor VII, cryo-precipitate, and FFP and decreased mobility being important risk factors for mor-bidity and mortality [22, 23]. The diagnosis of VTE is made using venous ultrasound and venous computed tomography, following general guidelines.

Management of Thrombosis

HAT has an incidence of 2–9% of adult OLT transplants and is a major cause of morbidity and mortality from graft loss. Options for management include surgical exploration with reconstruction and radiologically guided thrombolysis with stent-ing (Fig. 14.2). If performed early, these maneuvers can prevent further complica-tions. Even if successful, the reliance of the biliary tree for arterial blood as its sole supply can result in the development of ischemic cholangiopathy, biliary leaks, bile duct strictures, and cholangitis. Thus, retransplantation remains the gold standard for treatment if the patient’s general condition is acceptable and if there is an organ available [24]. Antiplatelet therapy with aspirin appears to decrease the incidence of HAT with early graft loss without increasing bleeding complications; a cross- sectional analysis demonstrated a reduction from 3.6% to 0% using this approach [25]. With an incidence of 2–7%, PVT is also a potentially devastating complication with similar management strategies to HAT, including surgical exploration, throm-bectomy, and guided thrombolytic therapy. The aim is to restore venous flow to at least 1.5 L/min followed by anticoagulation with heparin or vitamin K antagonists if suitable. The chemoprophylaxis of VTE in the OLT recipient is a matter of debate;

Fig. 14.1 Doppler ultrasound examination of the abdomen, concerning for existence of hepatic artery thrombosis, with no demonstrable flow in the hepatic artery (arrow)


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sequential compression devices and early mobility should be standard, and the most recent guidelines for management should be used when clinically appropriate [26].

Miscellaneous

A myriad of additional hematologic abnormalities can affect the OLT recipient in the ICU, among these hyperfibrinolysis, thrombocytopenia, and neutropenia.

a

b

Fig. 14.2 Panel A Selective angiography of the common hepatic artery (CHA) shows abrupt cutoff of the proper hepatic artery (arrow), just beyond the gastroduodenal artery (GDA) Panel B Completion angiography after thrombectomy and stenting of proper hepatic artery (arrow), showing reconstitution of flow to the graft


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Hyperfibrinolysis

Despite surgical and anesthetic advances in OLT, hyperfibrinolysis remains a sig-nificant nonsurgical cause of bleeding. Hyperfibrinolysis typically occurs in the anhepatic and post-reperfusion stages, as there is an increase in the level of circulat-ing tissue-type plasminogen activator. Additionally, cirrhotic patients also have reduced inhibition of fibrinolysis due to deficiencies in plasminogen, alpha2- antiplasmin, factor XIII, and histidine-rich glycoprotein [27]. The diagnosis is clini-cal, with a sudden increase in diffuse bleeding in the operative field and a low fibrinogen level. It has a characteristic collapsing tracing on ROTEM in the EXTEM test, which shows correction in the concurrent APTEM test. The incidence of fibri-nolysis up to 5 min after reperfusion can be as high as 85% when based only on EXTEM parameters; most patients will correct without intervention at 30 min [28]. The protease inhibitors tranexamic acid (TXA) and ɛ-aminocaproic acid have been used with success to reverse hyperfibrinolysis, consequently decreasing transfusion requirements without a significant increase in thromboembolic events or periopera-tive mortality [29]. However, the use of ɛ-aminocaproic acid has also been shown to be effective in preventing early graft loss, resulting in improved 90-day and 1-year patient survival rates in OLT recipients with hyperfibrinolysis [27].

Thrombocytopenia

Thrombocytopenia, defined as platelet counts <150 × 109/L, is present in up to 50% of patients in the ICU at some point during their stay. Platelet counts are regulated by a delicate balance between bone marrow production, pooling in the liver and spleen, and elimination in the reticuloendothelial system. Thrombocytopenia repre-sents a marker of abnormal physiology in the critically ill patient [30]. In OLT, it represents a unique challenge, as the patient with end-stage liver disease (ESLD) usually has low platelets secondary to increased destruction from hypersplenism as a consequence of portal hypertension. These patients also have decreased produc-tion of thrombopoietin by the hepatocytes, resulting in low thrombopoiesis. The thrombocytopenia is further aggravated after reperfusion of the graft by means of consumption coagulopathy. Immune-mediated heparin-induced thrombocytopenia (HIT) is another potential complication in OLT with a reported incidence of about 2%; therefore, the use of low molecular weight heparin for prophylaxis is a reason-able option once platelet count and renal function have improved [31]. Heparin is frequently used in patients with ESLD, especially in those requiring hemodialysis to prevent thrombosis in the dialysis circuit. Additionally, patients may be exposed to systemic heparin during the transplant procedure due to the use of heparin flushes. The diagnosis of HIT relies on the demonstration of anti-heparin/platelet factor 4 antibodies and the clinical presentation; however, the classic HIT presen-tation might not represent an autoimmune phenomenon in this patient popula-tion. The use of standard HIT criteria might overdiagnose the condition in OLT [32]. Treatment entails discontinuation of heparin-containing therapies and


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anticoagulation with a direct thrombin inhibitor, such as argatroban. Platelet trans-fusions should be avoided in patients diagnosed with HIT, as HIT is also a throm-bogenic state, and transfusion may worsen this, causing thrombosis. Other causes of thrombocytopenia in OLT include hemodilution, sepsis, and direct toxic effects of medications. The indications for platelet transfusions include thrombocytopenia with symptomatic bleeding or planned invasive procedures [30]. There is a lack of strong data on thresholds for platelet transfusions; expert opinion recommends transfusing for (1) <10 × 109/L in severe sepsis without bleeding, (2) <20 × 109/L for high risk of bleeding, and (3) <50 × 109/L for active bleeding, surgery, or proce-dures [33].

Neutropenia

On a recent review of 354 OLT, 136 (38%) had at least 1 episode of neutropenia in the first year post-transplant, with valganciclovir therapy as the main risk factor [34]. In another retrospective study of 304 OLT, 73 (24%) patients developed neu-tropenia; however, only five (7%) had severe neutropenia, defined as an absolute neutrophil count of <500/mm3 [35]. It remains common practice to stop valganci-clovir and trimethoprim-sulfamethoxazole (TMP-SMX), if the patient is treated with either, as the first intervention, followed by 300 mcg of subcutaneous filgrastim 1 to 3 times/week until the neutropenia resolves.

Hematologic Challenges in the Kidney Transplant Recipient in the ICU

With 13,060 kidney transplant (KTx) procedures performed in the United States in 2016, it is the most common solid organ transplant performed not only in the United States but also worldwide [36]. Five to ten percent of KTx recipients will require ICU admission at some point, with pulmonary edema, bacterial pneumonia, graft pyelonephritis, and bloodstream infections being the most common diagnoses [37]. The need for aggressive sepsis management and mechanical ventilatory support is high in these patients.

Anemia

Both the 1960 World Health Organization and the 2001 American Society of Transplantation define anemia as Hb <13.5 g/dL for males and <12 g/dL for females [38]. Post-KTx anemia has a prevalence of 20–41% and up to 60% in the first 30 days post-transplant, with a combination of surgical trauma, hemodilution, fre-quent sampling, iron deficiency, acute allograft rejection, medications, and


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infections as the main etiologies [39]. Anemia is also a prognostic indicator, with a low Hb at 2 years associated with increased mortality and graft failure [40].

Diagnosis of Anemia

The diagnosis of anemia follows general guidelines. Rapid drops in Hb in a hemo-dynamically unstable patient in the postoperative period unresponsive to resuscita-tive efforts point toward surgical bleeding. The majority of KTx recipients require an ICU admission for anemia present in the first 6 months post-txp; a full work-up for sepsis, per general guidelines, as well as hematologic disorders, must be per-formed [41]. The work-up should include iron studies, evaluation for hemolysis, and work-up for possible infections, such as parvovirus B19, and malignancies, including post-transplant lymphoproliferative disorder (PTLD). Clinicians should maintain a high suspicion of toxicity in patients on mycophenolate mofetil (MMF) as part of their induction immunosuppressive regimen, either by itself or in associa-tion with tacrolimus; a high suspicion of toxicity should be maintained, as MMF is associated with anemia and a transfusion rate of 72% [39]. As the KTx recipient frequently has comorbidities requiring oral anticoagulation, a careful history should look for antiplatelet therapy and anticoagulation agents as potential contributors to anemia and bleeding. Aspirin therapy is widespread in KTx as it reduces graft fail-ure, thrombosis, cardiac events, and mortality; however, its contribution to bleeding and anemia is not well known [42]. The decrease in eGFR and use of multiple medi-cations with interactions in the cytochrome p450 make anticoagulation manage-ment complex in these patients. The contribution of oral anticoagulation to bleeding and anemia in this setting has not been well studied [43].

Management of Anemia

As mentioned, rapid decreases in Hb in a hemodynamically unstable KTx recipient in the immediate postoperative period should prompt resuscitation with crystalloids and blood components as indicated, followed by emergent surgical exploration if there is no response. Up to 80% of patients develop anemia in the first month after transplant; this decreases to 40% at 3 months and 20% at 1 year [44]. Transfusion therapy is common in the KTx recipient with 64% of patients receiving RBCs in their first year; this practice puts them at risk of sensitization, with 7.2% of the patients developing donor-specific antibodies that would make finding an adequate match for potential future retransplantation more challenging [45]. Another com-mon approach to the management of anemia in the critically ill KTx recipient is with the use of recombinant erythropoietin; however, this approach is controversial as no improvement in anemia or delayed graft function in the first 3 months after transplant has been reported [46]. However, the use of erythropoiesis-stimulating agents (epoetin and darbepoetin) appears to be safe and improves graft survival and quality of life when a goal Hb of 13.0–15.0 g/dL is used [47]. Transfusion therapy should follow the already mentioned general guidelines.


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Infectious Agents

Cytomegalovirus

CMV, the human herpesvirus 5, is among the most common opportunistic infec-tious agents in SOT recipients and is associated with significant morbidity and mor-tality. Up to 75% of recipients will be infected, either by transmission from a seropositive donor or by reactivation of a latent infection. CMV has strong immu-nomodulatory effects and inhibits T cell responses by altering the production of cytokines. CMV is diagnosed using PCR to detect CMV DNA or by immunofluo-rescence to detect CMV antigenemia. Clinically, the so-called CMV syndrome presents as fever, neutropenia, and thrombocytopenia [48]. The hematologic effects may be aggravated by CMV prophylaxis which is also associated with myelosup-pressive effects. The treatment is with intravenous ganciclovir or oral valganciclo-vir, with weekly laboratory follow-up with quantitative nucleic acid testing or antigenemia determination to establish response to treatment or development of resistance. Reduction of immunosuppression (RIS) or treatment with foscarnet, cidofovir, and immunoglobulins should be individualized and considered for severe or resistant infection [49].

Parvovirus B19

Parvovirus B19 infection in SOT recipients presents with a nonspecific clinical pic-ture; however, 99% of patients will present with erythropoietin-resistant anemia with inappropriate reticulocyte response. The diagnosis is confirmed with serology or direct viral detection in the blood, bone marrow, or organ biopsy [50]. Pure red cell aplasia has been reported in severe cases of parvovirus infection in SOT recipi-ents. The usual and severe forms of the disease frequently respond to RIS or intra-venous immunoglobulin with a recurrence rate of 27.6% [51, 52].

Sepsis in SOT

Sepsis remains one of the leading causes of death worldwide in the general popula-tion. Multiple studies describe early and aggressive intervention reducing morbid-ity and mortality; however, there is little data on the management of sepsis in SOT, and consequently the general guidelines from the Surviving Sepsis Campaign are utilized [41]. Currently used definitions for sepsis using Sepsis-3 criteria are not easily applied to the SOT population as these patients have a blunted response to infections. Their decreased acute inflammatory response and a decreased chronic cellular infiltration response lead to a decreased febrile response, fewer clinical symptoms of sepsis, and less prominent leukocytosis [53]. Older criteria for the diagnosis of sepsis included the systemic inflammatory response syndrome (SIRS) criteria, with the following hematologic parameters: leukocytosis >12,000/mm3, leukopenia <4000/mm3, or bandemia >10% of immature bands. Newer criteria use


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the sequential organ failure assessment (SOFA) score, which utilizes thrombocyto-penia (<150,000/mm3) graded from 0 to 4 as the hematologic parameter [54]. A high index of suspicion must be maintained in these patients to make an early diagnosis, always remembering they may not have an overt clinical picture of sep-sis. Treatment involves the standard guidelines described for non-transplant patients [41].

Medications

Immunosuppression

Unique to the transplant patient is the use of immunosuppression to prevent the innate and the adaptive immune systems from mounting an alloimmune response and thus producing dysfunction, rejection, and eventual nonfunction of the graft. The three-signal model (Fig. 14.3) provides a useful reference to understanding the mechanism of action of these medications. Briefly, signal 1 constitutes the presenta-tion of antigen on the surface of dendritic cells to trigger T cells via the CD3 com-plex. Signal 2 is the co-stimulation of CD28 T cells. Both signals activate the calcineurin pathway among others. They also provide expression of interleukin-2, which along with other cytokines activates the mammalian target of rapamycin (mTOR) or signal 3 to provide T cell proliferation [55]. Immunosuppressants effect their hematologic actions by alteration of these pathways.

Antigen-presenting cell

Antigen

Anti-CD3mAb

Cyclosporine,Tacrolimus

T cell

Nucleus mRNA

Cellmembrane

S-1-P receptor(altered lymphocyte

recirculation)

CD52(depletion)

FTY720

Anti-CD52mAb

FK778

MPA

JAK3inhibitor

Sirolimus,Everolimus

Anti-CD154mAb

Anti-CD25mAb

Azathioprine

M

G1 S

G2

Cellcycle

CDK/cyclins

mTOR

PI-3KPI-3K

PI-3KIKK

MAP kinasesCalcineurin

TCR/CD3Synapse

CD154

CD25

CD28

Nucleotidesynthesis

JAK3JAK3

Interleukin-2Interleukin-15

Cell membrane

NFAT AP-1 NF-kB

MHC/peptides

CTLA-4–lg Costimulation

CD80, 86

CD40

Signal 2

Signal 3

Signal 1

Fig. 14.3 Individual Immunosuppressive Drugs and Sites of Action in the Three Signal Model


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Calcineurin Inhibitors

The elucidation of the calcineurin pathway and eventual discovery and clinical use of calcineurin inhibitors (CNIs) in the 1980s, first with cyclosporine (CSA) then tacrolimus, were a breakthrough in SOT, dramatically increasing both the graft and patient survival rates. Although these medications did not show the marked myelo-toxicity of the immunosuppressants of that era, they are not devoid of hematologic side effects [56]. Both CNIs have a similar adverse effect profile including signifi-cant nephrotoxicity and potential for producing thrombotic microangiopathy (TMA). TMA remains an infrequent complication in SOT with an incidence of less than 5%. TMA has three main components: (1) thrombi in the microvasculature, (2) thrombocytopenia, and (3) nonimmune hemolytic anemia. It appears to be related to ischemia reperfusion injury, immunosuppressive medications, acute interfering dis-ease, and deficiency of vWF cleaving protease (ADAMTS13). CNIs produce TMA in a dose- and time-dependent fashion with endothelial dysfunction, increased platelet aggregation, and inhibition of prostacyclin likely playing roles [57]. Management is by early recognition and early CNI withdrawal; treatment with plasma exchange remains controversial [58]. In renal transplant recipients, TMA incidence may be as high as 14%; presentation mimics hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura, with more renal dysfunction in the former and neurologic involvement in the latter. A synergistic effect has also been identified between CNIs and mTORs in these patients, with those receiving CSA and everoli-mus being at increased risk [59]. The severity of this complication may range from subclinical hemolysis, detected only by elevated haptoglobin levels, to massive hemolysis and renal failure with an associated mortality of 13%. Treatment is sup-portive; stopping CNI therapy, as opposed to switching from one CNI to another, does not appear to prevent recurrence [60].

Antimetabolites

Medications in this class include azathioprine (AZA) and MMF. They form an inte-gral part of the induction and maintenance immunosuppression of most SOT proto-cols. AZA is a purine analog that is converted to 6-mercaptopurine in the liver, while MMF inhibits the enzyme inosine monophosphate dehydrogenase required in purine synthesis, thus effectively inhibiting T and B cell replication. This inhibition is not selective, and bone marrow suppression with leukopenia, thrombocytopenia, and anemia is frequent. MMF has largely replaced AZA in most protocols. While MMF appears to be associated with more leukopenia and diarrhea, AZA produces more profound thrombocytopenia and anemia, as well as more severe nonhematologic side effects. [61]. Bone marrow suppression is managed either by decreasing the dose or by stopping the antimetabolites, as well as adding additional immunosuppressive agents or increasing their doses to provide adequate immunosuppression.


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Mammalian Target of Rapamycin Inhibitors

The mTOR inhibitors comprise a group of immunosuppressants that have become first-line agents in SOT and include sirolimus (rapamycin) and everolimus. mTOR is a protein kinase whose functions include lymphocyte proliferation and tumor cell growth, among others. They are frequently used as maintenance immunosuppres-sion in patients with chronic kidney disease due to their lack of nephrotoxicity. As 20% of OLT recipients will develop chronic kidney disease within 5 years of trans-plantation, mTORs are frequently used for LTx recipients as well. mTORs have the added advantage of decreasing the recurrence and de novo appearance of hepatocel-lular carcinoma and other malignancies [62]. Both agents are associated with time- and dose-dependent development of anemia, especially in kidney transplant recipients. This appears to be related to direct inhibition of the bone marrow and alterations in iron hemostasis. Leukopenia and thrombocytopenia are also frequent with both medications and are usually self-limited toxicities. Only 7% of patients require dose reduction and only 4% temporary discontinuation of the drugs, with recovery usually evident in the first 24 h but sometimes taking up to 50 days [63].

Depleting Antibody Therapies

Rabbit-derived antithymocyte globulin (rATG) is a polyclonal antiglobulin prepara-tion that has been an important part of the pharmaceutical armamentarium for induction of immunosuppression and management of cellular mediated rejection in SOT since the 1970s. Its effectiveness is related to its ability to deplete the body of T cells via complement-dependent cytotoxicity; thus close monitoring of leukocyte counts is necessary to avoid overt leukopenia and neutropenia. Platelet counts and conventional coagulation testing should also be routinely performed as rATG induces thrombocytopenia and hypercoagulability via platelet aggregation, alpha granule release, phosphatidylserine exposure, and release of platelet microvesicles [64]. Thrombotic or bleeding complications are infrequent and usually respond to decreasing the dose or increasing the dosing interval of rATG. Current immunosup-pression protocols for induction include dose corrections for leukopenia, thrombo-cytopenia, and chemoprophylaxis for cytokine-release syndrome (Table 14.1).

Corticosteroids

Historically, steroids have been a central part of SOT regimens for induction and maintenance immunosuppression and treatment of rejection. They exert their effects by inhibition of phospholipases and transcription of cytokines, which results in enhanced release of polymorphonuclear lymphocytes from the bone marrow, demarginalization from the intravascular pool, and decreased infiltration of periph-eral tissues [65]. This results in a blunted systemic inflammatory response as well as leukocytosis. This response is managed by ruling out any other more serious causes of the patient’s symptoms and leukocytosis, as this response is self-limited.


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Antimicrobials

Antivirals

CMV remains one of the most common opportunistic infections in SOT, causing significant morbidity and mortality. Medications for primary antiviral prophylaxis and treatment of CMV infection include ganciclovir, valganciclovir, acyclovir, and

Table 14.1 Standard high-risk immunosuppression protocol depicting dose adjustments for leukopenia, thrombocytopenia, and prophylaxis for cytokine-release syndrome

High risk kidney transplant

Criteria PRA >80% African American < 60 years oldCold Ischemia Time >36 h

DSA >1000MFI

DCD DonorInduction Immunosuppression

Thymoglobulina

Day 0: 1.5 mg/kg based on IBW in ORDay 1: 1.5 mg/kg based on IBWb

Day 2: 1.5 mg/kg based on IBWb

Day 3: 1.5 mg/kg based on IBWb

Maintenance Immunosuppression

SteroidsDay 0: Methylprednisolone 500 mgDay 1: Methylprednisolone 250 mgDay 2: Methylprednisolone 125 mgDay 3: Prednisone 60 mgDay 4: Prednisone 40 mgDay 5: Prednisone 20 mgDay 6: Prednisone 10 mgDay 7+: Prednisone 5 mg until tacrolimus trough level

is 8–12 ng/ml, then discontinuec

Mycophenolate mofetild

Day 0: 1000 mg in ORDay 1+: 1000 mg ql2hTacrolimus: Trough level:Initial dose:0.03–0.05 mg/kg BIDe

Day 1–90: 8–12 ng/mlDay 90–360: 6–8 ng/mlf

Day >360: 4–6 ng/mlf

aRound thymoglobulin doses to 25 mg intervals; Infuse over 5–7 h; Premedicate all doses with acetaminophen, diphenhydramine, and methylprednisolonebIf WBC 2000–3000 or platelets <75,000, decrease dose by 50%; If WBC <2000 or platelets <50,000, hold dose; Adjust dose for ALC per MD discretioncIf patient has lupus, continue prednisone 5 mg indefinitelydIf history of rejection and medication tolerated, suggest 1000 mg ql2h; If history of CMV, BK, EBV DNA +, recommend lower doseeIt is recommended to start the CN1 once the creatinine is less than 3 mg/dL or basal creatinine decreases >1 mg/dL in 24 hfAdjust trough levels based on patient’s history of acute cellular rejection, opportunistic infections, and CNI toxicity


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valacyclovir. Foscarnet, cidofovir, and CMV immunoglobulin are reserved for ganciclovir- resistant and selected cases. Ganciclovir and its prodrug valganciclovir are synthetic acyclic purine-nucleoside analogs of guanine and the most commonly used chemoprophylaxis agents. Both medications are associated with leukopenia, thrombocytopenia, and anemia in 5–50% of patients. Management is by decreasing the dose of ganciclovir or valganciclovir and converting the prophylaxis to CMV immunoglobulin in high-risk cases [66].

Antibiotics

Of all potential infections in SOT recipients, few require universal antibiotic pro-phylaxis. The notable exception is pneumocystis pneumonia, which requires low- dose daily TMP-SMX extending anywhere from 3 months to lifetime therapy after transplantation. It also provides protection against Toxoplasma gondii, Isospora belli, Cyclospora cayetanensis, and multiple nocardia and listeria species [67]. The mechanism of action of TMP-SMX is the inhibition of the enzymatic machinery responsible for the synthesis of tetrahydrofolic acid. This also affects the bone mar-row and can result in leukopenia in 2% of patients [68]. Management of leukopenia is discontinuation of TMP-SMX and conversion to monthly inhaled pentamidine prophylaxis.

Miscellaneous

Post-transplant Lymphoproliferative Disease

PTLD consists of a heterogeneous group of lymphoid proliferations, ranging from benign to overtly malignant B cell lymphomas that affect SOT recipients. Over 50% are associated with the Epstein-Barr Virus (EBV), which in the setting of immuno-suppression leads to a decreased T cell regulation of B cells and to uncontrolled proliferation, with the highest risk in seronegative recipients receiving seropositive organs [69]. Another significant risk factor is the degree of immunosuppression, as evidenced by an incidence of up to 10% in heart and lung recipients but only 1–5% in kidney and liver transplant recipients. rATG and CNIs have been identified as potential risk factors. The diagnosis requires a high level of suspicion as there is no definite clinical presentation; it is usually established by histopathological confir-mation in the setting of active EBV infection. The mainstay of management of PTLD involves RIS usually to 25–50% of baseline; this approach alone can achieve remission in some patients. Risk factors for failure to achieve remission after RIS include elevated lactate dehydrogenase, multi-organ failure/involvement, and BCL-6 mutation. The use of mTOR inhibitors in high-risk patients as an adjunct to RIS has shown some positive results. Administration of rituximab, a chimeric monoclonal antibody to the transmembrane protein CD20 expressed on the surface


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of immature B cells, is associated with a survival benefit. It is usually administered as part of an anthracycline-based chemotherapy regimen (e.g., R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) [70]. Antiviral therapy, surgical excision, and radiotherapy have also been used with varying rates of suc-cess. Polyclonal disease is more likely to be associated with EBV and to respond to RIS, while monoclonal disease has a decreased association with EBV, usually requires chemotherapy, and has a poorer prognosis. Prognosis is also dependent on age and extent of disease.

Graft-Versus-Host Disease

GVHD remains an uncommon disease in SOT; however, for those who develop it, the mortality is high. For example, of OLT recipients who develop GvHD, over 75% will die from it. The incidence is variable, from 5.6% after small bowel transplanta-tion to 1–2% after liver transplantation. The hallmark of GVHD is an immunologi-cal reaction of donor cells that are genetically different from their host. Three conditions are required for this to occur: (1) the graft must contain immunologically competent cells, (2) the host cannot mount an immunological reaction against the graft, and (3) the host has significant alloantigens such that it appears foreign to the graft [71]. The diagnosis is difficult as it may mimic multiple drug toxicities or infectious processes. The early manifestations may include a maculopapular rash, diarrhea, or fever, which should prompt a skin or small bowel biopsy. Characteristic histopathologic findings on biopsy as well as over 1% macro-chimerism on periph-eral blood are diagnostic of GvHD. Treatment includes broad infectious prophy-laxis and high-dose steroids, with mesenchymal stromal cells, basiliximab and infliximab, reserved as second-line therapies [72].

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279© Springer International Publishing AG, part of Springer Nature 2018A. Shander, H. L. Corwin (eds.), Hematologic Challenges in the Critically Ill, https://doi.org/10.1007/978-3-319-93572-0_15

Chapter 15Current Risks of Transfusion

Amy E. Schmidt, Majed A. Refaai, and Neil Blumberg

Introduction

One of the most common medical interventions in hospitalized patients is red blood cell (RBC) transfusion with approximately 11 million RBC units transfused yearly in the United States [1]. As with other medical interventions, blood transfusion is associated with risks. The risks have changed over time as product modifications evolved and novel blood-borne infections have been identified. Throughout the twentieth century, the main concerns were hemolytic reactions and viral infection. Both problems are now largely successfully addressed and represent the two major achievements of medical science during the first century of transfusion therapy.

When HIV first was identified in the 1980s, it took a few years to realize what it was and how it was transmitted. During that time, many patients had HIV transmit-ted via blood transfusion. New viruses are still and will continue to threaten the blood supply; in the past few years, we have been challenged with both the Ebola and Zika viruses, neither of which has been reported to be transmitted by transfusion as yet, unlike hepatitis B and C and other agents. There will always be new patho-gens appearing and/or mutating and posing a threat to the blood supply. Serologic techniques that have been perfected have largely made fatal hemolytic transfusions a rare occurrence, on the order of a few per year in most developed nations. Thus, the major risks of transfusion in the developed world today are not hemolytic trans-fusion reactions or infectious diseases transmitted from contagious donors.

Blood transfusions can cause relatively common and sometimes fatal transfu-sion reaction including transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), anaphylaxis, and alloimmunization to red

A. E. Schmidt, MD, PhD · M. A. Refaai, MD · N. Blumberg, MD (*) Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USAe-mail: [email protected]; [email protected]; [email protected]






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cell, platelet, or plasma antigens. Relatively milder but nonetheless distressing and sometimes quite unpleasant and dangerous reactions include febrile reactions and allergic reactions. Blood transfusions also cause additional changes in the immune system, only recently recognized as causal, and whose mechanisms are not fully elucidated. These include nosocomial infections, multi-organ failure (MOF), throm-bosis, transfusion-associated graft-versus-host disease (TA-GVHD), and perhaps transfusion-associated necrotizing enterocolitis (TANEC) [2–5]. This chapter will discuss these and other risks involved in blood component transfusion.

Blood components in the United States are regulated by the US Food and Drug Administration (FDA). Since 1976 it has been mandated that transfusion-related deaths be reported to the FDA. A voluntary hemovigilance network was only estab-lished in the United States in 2009 but existed and has been compulsory in many European countries and Canada for several decades now. The leading causes of reported mortality associated with blood transfusions have changed over the years. Presently, the two main causes are TRALI and ABO and non-ABO hemolytic trans-fusion reactions (HTR). Notably, a 10-year study in the United States showed that the rate of HTR due to ABO-incompatible transfusions was 1/38,000 and 1/76,000 in non- ABO- incompatible transfusions and that the rate of mortality from acute HTR was 1/1.8 million RBC transfusions [6]. This is in comparison with the current risk for transfusion-transmitted HIV 1:1,467,000, HCV 1:1,149,000, and HBV 1:843,000 to 1:1,208,000 [7, 8]. Events that are almost certainly caused or contributed to by transfusion, such as thrombosis, nosocomial infection, and multi-organ failure, are not reportable to the FDA, because they are commonly seen even in non-transfused patients, and the vast majority of transfusion medicine experts have yet to accept the link between these complications and transfusions, despite ample observational, epi-demiologic, animal model, and randomized trial data confirming causal relation-ships. Leukoreduction of transfusions, use of autologous transfusions, and restrictive transfusion thresholds have been shown in randomized trials and cohort studies to mitigate postoperative nosocomial infection, multi-organ failure, and thrombosis. Recently, pathogen inactivation (PI) technology has become available in the United States for platelets and plasma, but not red cells. These technologies have been widely used in Europe for over 10 years. The mechanism of PI technologies and their role in reducing blood transfusion risks will also be discussed in this chapter.

Critically ill patients commonly have or develop anemia, due to “exsanguination into the laboratory,” with nearly 95% of ICU patients having a below normal hemo-globin value by ICU at day 3 [9]. Furthermore, greater than 50% of ICU patients receive RBC transfusions, and ~85% of these patients have a length of stay (LOS) of >1 week [10, 11]. In 2004, the CRIT study illustrated that RBC transfusion was independently associated with increased ICU LOS, increased hospital LOS, and increased mortality [12]. Moreover, patients who received more transfusions were found to have more complications and were also more likely to have a complication [12]. This chapter will explore the risks and benefits for transfusion of critically ill patients and discuss recent studies that shed light on this topic.

The topics are in historical order of identification, rather than clinical impor-tance. Hemolytic transfusion reactions and viral infectious disease transmission,

A. E. Schmidt et al.

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once the major and most feared clinical risks, are now quite rarely seen. Newly identified and much more common risks, such as acute organ injury, volume over-load, inflammation, thrombosis, nosocomial infection due to immunomodulation, exacerbated bleeding to platelet and plasma transfusions, etc., are much more press-ing as public health issues and as bedside practice considerations, but have only recently come to the fore, are incompletely understood and will be addressed near the end of the chapter.

Hemolytic Transfusion Reactions due to Human Error

One of the most preventable risks related to transfusion is human error. Fortunately, serious complications from these common errors are not all that frequent. This can stem from mislabeling of the patient specimen for transfusion (“wrong blood in tube”) that results in an incorrect blood type for a patient, improper patient identifi-cation at the time of transfusion, and errors in the transfusion service or from a variety of other clerical errors. The 2016 annual serious hazards of transfusion (SHOT) report from the United Kingdom included 3288 reports of which 77.7% were from mistakes or human errors [13]. There were seven reported ABO incom-patible transfusions, one of which resulted in death [13]. In the United States, death due to ABO incompatibility is estimated to occur at a rate of 1 in 600,000 RBC transfusions [14]. The risk of ABO-incompatible blood transfusion in the United Kingdom is 1 in 263,157 RBC transfusions [15]. In the United States, ABO- incompatible blood transfusions account for 37% of all FDA-reported transfusion- associated fatalities [16]. While this is serious and seemingly correctable problem, contrary to much of the transfusion medicine literature, complications and fatalities due to unrecognized TRALI or TACO are probably orders of magnitude more common.

Nonetheless, wrong blood sampling, a situation where a different patient’s blood is collected, resulting in an incorrect patient blood type is more common than previ-ously anticipated. Dzik et al. surveyed 71 hospitals regarding blood sample collec-tion and found that the rate of mislabeling was 1 per every 165 samples [17]. Moreover, they found that wrong blood in tube occurred at a rate of 1 in every 1986 samples [17]. This rate is much higher than the risk of transfusion-transmitted viral diseases in the United States, but does not lead to transfusion complications in most instances, since severe ABO hemolytic reactions are considerably less common by several orders of magnitude. To prevent ABO-incompatible blood transfusions, multiple precautions are taken including using two separate patient identifiers as well as requiring two separate blood typings on a patient. This policy varies in inter-pretation. Some centers require two separate blood samples on a patient that has no previous ABO typing at that institution. Some centers require the ABO typing to be done twice by two different people on the same blood sample. Other centers require the presence of two nurses at time of blood collection and at time of infusing blood components. Despite these precautions, there are still failures resulting in wrong

15 Current Risks of Transfusion

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blood in tube and/or ABO-incompatible blood transfusions. Thus, human error remains a significant risk in blood component transfusion. Machine-readable patient wristbands and bedside computer technology that compares the data on the wrist-band with the transfused blood label should contribute to minimizing these remain-ing problems in patient identification and human error.

Transfusion-Transmitted Diseases

Overall, the risks of transfusion-transmitted infectious diseases are vastly lower than the incidence of noninfectious transfusion risks. For example, the incidence of urticarial reactions is ~1:100 RBCs transfused as compared to the rate of parasitic infection which is ~1:4,000,000 RBCs transfused [18]. Prior to the adoption of DNA-/RNA-based testing, the largest risk for transfusion-transmitted disease was viral, mostly hepatitis B and C. That risk has now shifted to bacterial infection pos-ing the greatest risk for transmission via transfusion [19–22]. Bacterial infection transmission is substantially more common with platelet transfusions due to their storage at room temperature. The most common bacterial contaminants of platelets are gram-positive skin flora, Staphylococcus epidermidis, and Staphylococcus aureus. Gram-negative bacteria transmission is more commonly associated with RBC transfusion [23]. Blood components are tested for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), West Nile virus (WNV), and Zika. However, blood components are not tested routinely for malaria, Babesia, prion diseases, or various other infectious agents, for instance. A total of 70 normal blood donors positive for Babesia were found to be associated with 67 cases of transfusion-transmitted babesiosis at the American Red Cross between 2010 and 2016 [24]. Blood is not tested for many of these agents due to lack of FDA-approved tests and/or the costs involved in extensive screening. For many infectious agents, donors are screened by history at the time of donation and excluded based upon recent or remote history of travel. Thus, there is always a remote risk of transfusion transmission of these and other new infectious agents. Additionally, the risk for transmission of various pathogens such as HIV, HBV, and HCV varies from country to country based upon the infection rate in the general population. To ameliorate these risks, pathogen reduction/pathogen inactivation systems can be used.

Pathogen Inactivation Technologies

Donor screening and infectious disease testing have been dramatically effective in reducing the transfusion transmittal of serious infectious diseases but not able to entirely eliminate them. Nevertheless, there will always be new viruses, parasites, and bacteria of which we are not aware and there are no available screening tests or


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testing is not required by FDA. It also is not feasible logistically or financially to test donors for every disease that can be transfusion transmitted. Moreover, as is the case today, there is likely to always be a window between infection and test positiv-ity. With all these caveats, pathogen reduction technologies have become an impor-tant area of development and investigation. Pathogen reduction technologies have already been applied to plasma fractionation where heat inactivation, solvent/deter-gent treatment, and ultrafiltration are employed. Notably, these approaches cannot be used for cell-based products such as RBCs and platelets. Currently pathogen inactivation technologies that are either available or under study for individual plasma units are psoralen with ultraviolet (UV) light, riboflavin with UV light, methylene blue with visible light, and solvent/detergent (Table 15.1). Current pathogen reduction technologies available and/or being studied for platelets are psoralen with UV light, riboflavin with UV light, and UV light alone. Importantly, pathogen reduction-treated platelets have an extended shelf life from 5 days to 7 days, at least in Europe. Current pathogen reduction technologies being devel-oped for RBCs are riboflavin with UV light and frangible nucleic acid cross-linkers.

In the United States, the INTERCEPT® Blood System (Cerus Corporation, Concord, CA) is the only pathogen reduction system that is currently FDA approved for platelets. INTERCEPT® uses amotosalen and UVA light. The amotosalen passes through cellular membranes and intercalates into DNA and RNA; UVA light exposure results in cross-linking of DNA and RNA [25]. The amotosalen is then recaptured which takes between 6 and 16 h, and only small residual amounts of amotosalen remain in the final product [26, 27]. This system reduces the infectivity of most pathogens tested by 4–6 logs [28–31]. Side effects such as urticaria, platelet activation, and decreased platelet corrected count increment (CCI) have also been observed with INTERCEPT® [32, 33]. However, a hemovigilance program in France, Spain, and Belgium studied 7437 INTERCEPT® platelet transfusions and found that the rate of undesired events was 0.9% and that there were no instances of viral or bacterial transmission [34].

Table 15.1 Pathogen inactivation technologies

PI technology Mechanism of actionTreats blood component Manufacturer Licensed

INTERCEPT® Amotosalen + UVA Platelets Cerus The United States and other countries

Mirasol® Riboflavin + UVB Platelets, plasma, whole blood

Terumo BCT Other countries

THERAFLEX® UVC light Platelets Macopharma Other countriesTHERAFLEX® Filtration + methylene

blue + visible lightPlasma Macopharma Other countries

Octaplas S/D Solvent/detergent Plasma Octapharma The United States and other countries

FRALE (S-303) Frangible anchor linker effector

RBCs and whole blood

Cerus No


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Another pathogen reduction technology for platelets and plasma, which is avail-able in Europe and may eventually become available in the United States, is Mirasol® (Terumo BCT, Lakewood, CO). This system uses riboflavin (aka vitamin B2), which acts as a photosensitizer, to mediate selective damage to nucleic acids upon exposure to UVA/UVB light [35]. Mirasol® has been shown to be effective in reducing the infectious load of both enveloped and non-enveloped viruses. Notably, Mirasol® was documented to reduce HAV by 1.8 log/mL; HAV is very resistant to heat inactivation and other chemicals [36]. Mirasol® has also been shown to effectively inactivate numerous strains of both gram-positive and gram-negative bacteria [36]. In the MIRACLE study, patients who received platelets treated with Mirasol® had lower CCI at 1 h as compared to patients who received standard platelets [37]. RBCs derived from whole blood treated with Mirasol® also tend to have increased potassium levels as compared to standard preparations of RBCs [38]. The potassium levels observed are similar to those in gamma-irradiated RBCs that have been stored. It is important to note that riboflavin in Mirasol® PI does not have to be removed from the transfusion as does the amotosalen in INTERCEPT® PI.

Another pathogen reduction technology that may soon be available in the United States is THERAFLEX® UV-C (Macopharma, Mouvaux, France) that uses UVC light which acts directly on DNA to cause pyrimidine dimers and impair DNA repli-cation for platelets [39, 40]. For plasma, the THERAFLEX® MB-Plasma system is used which is comprised of filtration, methylene blue, and 630 nm visible light [23, 41]. To date, THERAFLEX® is only being used for plasma components. Additionally, the combination of methylene blue and light is also being investigated as a pathogen reduction technology. Methylene blue is a positively charged dye that intercalates into DNA and when exposed to visible light produces oxygen-mediated DNA damage [42]. Methylene blue is not effective in inactivating leukocytes because it cannot get into cells, and it also does not inactivate non-enveloped viruses or intracellular patho-gens [25]. Methylene blue has been shown to cause decreases in Factor VIII, Factor VII, and fibrinogen levels in plasma [43, 44]. In one study, methylene blue-treated plasma had coagulation factor levels that were 5–47% lower than standard plasma levels [45]. Lastly, the FRALE method (Cerus, Concord, CA) is a frangible anchor linker effector which inactivates DNA/RNA by forming a covalent bond between nucleic acids using an alkylating agent. The FRALE method of pathogen inactivation has been shown to inactivate viruses, bacteria, protozoa, and leukocytes [46]. This method is used only for RBCs and may cause unwanted protein alkylation [47].

Several of the pathogen reduction technologies described above are approved for and being used for platelets. Studies have suggested that these systems alter the proteome of platelets with each system having a different effect. Mirasol® affects platelet adhesion and shape change. The INTERCEPT® system affects proteins involved in intracellular platelet activation pathways, and THERAFLEX® affects platelet shape change and aggregation [48]. A recent Cochrane review found that there is likely no difference between pathogen-reduced platelets (PR platelets) and standard platelets in incidence of clinically significant bleeding, severe bleeding, all-cause mortality, and adverse events [49]. Notably, they did find that PR platelets were associated with an increased risk of platelet refractoriness (RR 2.94, 95%


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confidence interval 2.08–4.16) [49]. Additionally, patients receiving PR platelets were found to require more platelet transfusions, have a shorter interval between transfusions, and had a lower 24-h CCI [49]. Additional studies are needed to fur-ther evaluate the effects of PI.

Donor leukocytes are known to cause TA-GVHD in immunocompromised recip-ients or in HLA similar recipients. Currently, the only mechanism to prevent TA-GVHD is gamma or X-irradiation. Both the Mirasol® and THERAFLEX-UV PI systems have been shown to be as effective as gamma irradiation in inactivating leukocytes [37, 50, 51]. Psoralen and UV light as well as FRALE have also been shown to be effective in inactivating leukocytes which would also theoretically pre-vent TA-GVHD.

Another pathogen reduction technology, available only for plasma, is a newer version of Octaplas S/D (solvent/detergent) called Octaplas LG (Octapharma, Hoboken, NJ). Octaplas LG is similar to Octaplas S/D but is prion-depleted [52]. Octaplas S/D effectively inactivates enveloped viruses; however, it has limited effectiveness in inactivating non-enveloped viruses [52]. Octaplas LG has an addi-tional step which involves treatment with an affinity ligand for prions. Several stud-ies have found Octaplas LG bioequivalent to Octaplas S/D [52, 53]. A recent study by Camazine et al. compared transfusion of S/D plasma to standard plasma in criti-cally ill children. They found that S/D plasma was independently associated with reduced ICU mortality (OR 0.40, p = 0.05) [54]. Notably, only 62 patients were in the S/D group compared to 357 patients in the standard plasma group. S/D plasma has been demonstrated to contain reduced amounts of TNF-α, IL-8, and IL-10 which play a role in immunomodulation [55, 56]. Additionally, S/D plasma does not contain HLA antibodies, microparticles, cell fragments, or bioactive lipids [56–58]. Consequently, the rates of TRALI and allergic transfusion reactions in several coun-tries using S/D plasma are much lower [59, 60]. Further studies are needed to evalu-ate the possible differences in S/D plasma and plasma in immunomodulation.

Regardless of which pathogen reduction technology is employed, implementa-tion results in increased costs for blood components. While these components are likely much safer in terms of transfusion-transmitted diseases and some other more common complications such as TRALI, not all technologies are equal, and some are more comprehensive in pathogen reduction. The increased costs of these technolo-gies are likely to impede the adoption in many countries.

Acute Febrile, Cardiopulmonary, and Allergic Transfusion Reactions

Febrile transfusion reactions occur in ~1% of transfusions, making them one of the most common transfusion reactions as shown in Table 15.2 [61]. Pre-storage leuko-cyte reduction (LR) has resulted in a decrease in febrile transfusion reactions, par-ticularly for red cell transfusions. It is believed that pre-storage LR decreases inflammatory cytokine release that typically occurs during blood component stor-age. Allergic transfusion reactions characterized by rash, urticarial, etc. are also


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quite common. These reactions are typically attributable to plasma proteins, dietary or environmental antigens, or proteins bound to the RBC or platelet membrane [62]. Typically, allergic reactions are donor specific; however, patients that have multiple allergic reactions (usually atopic individuals) to different donors can be provided with washed platelet or RBC components. Patients may also have anaphylactic reactions to blood components. These individuals should be evaluated for IgA defi-ciency; however, only ~5% of patients that are IgA deficient develop anti-IgA and are at risk for such reactions [63]. IgE-mediated histamine release from mast cells is the cause of a large number of anaphylactic transfusion reactions. The rate of TACO is about 1% as well [64]. In most cases, TACO is preventable by strategies such as reducing the transfusion rate or volume and/or with possible concomitant use of diuretics [65]. Other strategies that have been reported to reduce the inci-dence of TACO (as well as the incidence of TRALI) are implementation of univer-sal leukoreduction and removal of supernatant from cellular transfusions by washing [66]. TRALI is defined as acute lung injury, or worsening lung injury, occurring within, arbitrarily, 6 h of blood transfusion. TRALI is caused in many instances by HLA antibodies present in the blood component that recognize the recipient and/or by antineutrophil antibodies. A non-antibody-mediated mechanism for TRALI has also been reported. Bioactive substances such as lysophosphatidylcholine, nonpolar lipids, and CD40 ligand accumulate during storage of RBCs or platelets and can induce lung injury in animal models and in patients [67]. Previously, TRALI was most frequently reported with plasma transfusions; however, this is no longer the case following a change to all male donor plasma [68–70]. In an effort to mitigate TRALI and febrile transfusion reaction risk, apheresis platelets are also available with reduced plasma composition that have platelet additive solution instead. Additional strategies that may prove useful in the future are the use of pooled plasma components and removal of supernatant from red cells and platelets.

Table 15.2 Transfusion reactions

Transfusion reactions Signs/symptoms Treatment Frequency

Febrile transfusion reaction

1 °C increase in temperature Antipyretics and supportive care 1:100a

Allergic reaction Urticaria, hives, pruritus Antihistamines 1:100a

Anaphylactic reaction

Hypotension, urticarial, angioedema, bronchospasm, stridor, abdominal pain

IV fluids, epinephrine, antihistamines, corticosteroids, beta-2 agonists, washed cellular products

1:20,000–1:50,000a

Hemolytic transfusion reaction

Fever, chills, pain, nausea, vomiting, shock, dark urine

IV fluids ±diuretics 1:76,000a

TRALI Dyspnea, hypoxemia, bilateral lung infiltrates

Oxygen and supportive care 1:1200–1:190,000a

TACO Dyspnea, edema Diuretics and give blood component slowly

1:100a

aFrequencies taken from the technical manual [161]


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Transfusion-Associated Necrotizing Enterocolitis (TANEC)

Several studies have shown an association between RBC transfusion and subse-quent development of necrotizing enterocolitis (NEC) in newborns [71–75]. However, several randomized controlled trials that examined liberal versus restric-tive transfusion strategies in neonates did not find an association with NEC [76, 77]. Hay et al. performed a meta-analysis of NEC development within 48 h of transfu-sion; the observational studies showed that the odds ratio for transfusion favoring development of NEC was 1.13 [78]. The odds ratio for transfusion favoring NEC development at any time following transfusion was 1.95 in the observational studies [78]. However, the odds ratio for transfusion favoring NEC development was 0.60 in the RCT [78]. Hay et al. concluded that the quality of evidence linking TANEC with transfusion is very low and thus insufficient evidence to support a definitive associa-tion [78]. A systematic review by Rai et al., on the other hand, showed that RBC transfusion was actually protective against subsequent NEC development [79]. Further RCT studies are needed to clarify this possible association.

Thrombosis

The role of blood component transfusion, particularly platelet transfusion, in subse-quent development of thrombosis is currently under investigation. Initially, Khorana et al. examined the medical records of 15,237 hospitalized cancer patients who received platelet transfusions between 1995 and 2003 at 60 different medical cen-ters [80]. Interestingly, they found that patients who received platelet transfusions had increased risks of venous and arterial thromboembolism as well as death [80]. de Boer et al. performed a retrospective study in which they examined platelet trans-fusion and outcome in 433 adult patients undergoing first-time orthotopic liver transplant. They found that platelet transfusion had a negative effect on patient sur-vival and that increasing platelet transfusion was associated with worse survival in a dose-dependent fashion [81].

In several other studies, platelet transfusion has also been linked to coronary stent thrombosis. Cornet et al. reported that three patients with gastrointestinal (GI) bleeding who received platelet transfusions early in the course following stenting subsequently developed stent occlusion 6–17 h following platelet transfusion [82]. Similarly, Shin et al. reported that patient with aplastic anemia received a platelet transfusion and subsequently developed a late stent thrombosis in a drug-eluting stent [83]. The risks associated with platelet transfusion in coronary artery bypass grafting (CABG) have also been disputed in the literature with several studies showing platelet transfusions to be associated with adverse outcomes. Mangano was the first to report that platelet transfusions were associated with a statistically significant increased risk of death regardless of aspirin administration [84]. Several subsequent studies also found that platelet transfusions in cardiac surgery were associated with increased mortality [85–87]. Notably, there were several studies which showed there was no increased risk of mortality in patients having CABG


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procedures with platelet transfusion [88–90]. Recently, Schmidt et al. conducted a prospective observational study which looked at 7-day thrombosis and 30-day mor-tality in patients receiving prophylactic platelet transfusions for invasive procedures [91]. Of the 376 transfusions identified, a total of 19 thrombotic events were identi-fied for a thrombosis rate of 5.0%, and a total of 60 deaths (16% of all patients) occurred within 30 days of pre-procedure prophylactic platelet transfusion. Whether these findings are due to a substantially higher incidence of comorbidities and con-founding or to cause and effect, and to what degree, is not known. Warner et al. studied prophylactic preoperative platelet transfusion in 13,978 patients, of which 860 had a platelet count <100 × 109/L. In propensity-adjusted analyses, they found that patients who received platelets had increased ICU admission rates (OR 1.95, p = 0.022) and increased hospital LOS (p < 0.001) [92]. Notably, preoperative plate-let transfusion did not reduce the need for RBC transfusion in patients with throm-bocytopenia [92]. Thus, it appears that platelet transfusions may increase both the risk of thrombosis as well as mortality.

Lastly, Zakko et al. performed a retrospective cohort study of patients managed with antiplatelet agents and presented with GI bleeding [93]. Using univariate anal-yses, they found that patients who received platelet transfusions had higher rates of cardiovascular events, longer hospital stays, and death as compared to controls who did not receive platelet transfusions [93]. Notably, using multivariate analyses, they found that patients receiving platelet transfusions had an increased odds ratio of 5.57 for death as compared to controls [93]. Interestingly, the adjusted odds ratio for recurrent bleeding was 1.47 for patients receiving platelet transfusion versus control [93]. Thus, this and other studies suggest that platelet transfusions may pose a much higher risk of complications and adverse outcomes than previously thought.

The relationship between liberal red cell transfusion and thrombosis is demon-strated by a randomized trial of different transfusion thresholds in patients with traumatic brain injury. Robertson et al. found that there was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%]) as compared to 7 g/dL (8/99 [8.1%]), OR, 0.32, p = 0.009 [94]. The incidence of veno-occlusive disease (and thrombosis) in bone marrow transplant patients receiving aggressive RBC transfusion (at a hemoglobin of 12 g/dL) was suffi-ciently high in a randomized trial such that the trial had to be stopped after six patients. All three patients in the liberal arm developed thrombotic/inflammatory complications, as compared with none of three in the control arm (7 g/dL transfu-sion threshold) [95].

Nosocomial Infection

Numerous observational and randomized studies have associated RBC transfusion with increased risk for nosocomial infection [4, 96–105]. This increased risk of infection with RBC transfusion has been linked to the amount of blood transfused


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(dose dependent) as well as to the storage lesion [4, 96, 98, 99, 101–104]. Several studies have shown disparate results for storage duration and infection development [4, 96, 101–103]. Platelet transfusions have also been associated with postoperative infection in cardiac surgery patients as well as increased risk of secondary bacterial infection in sepsis patients [85, 106]. Juffermans et al. studied blood transfusions and infections in 134 ICU patients with sepsis. They found that 67 of the patients received blood transfusions and that 19 patients developed secondary infections [106]. Both the amounts of RBC and platelets transfused were found to be associ-ated with the development of secondary infections with adjusted OR of 1.18 and OR of 1.36, respectively [106]. Plasma transfusion has also been associated with the development of nosocomial infection [87]. Recently, Engele et al. assessed the risk of bacterial infection development in ICU patients receiving transfusion of various blood components. A total of 476 of the 3502 screened patients developed nosoco-mial infections [107]. Notably, these patients had increased APACHE IV scores, longer ICU LOS, and increased number of transfusions. They found that both RBC transfusion and number of RBC transfusions were associated with an increased risk of nosocomial infection with OR of 1.98 (p < 0.001) and OR 1.04 (p < 0.001), respectively [107]. Additionally, they found that plasma and platelet transfusion were also associated with increased risk of nosocomial infection with hazard ratio (HR) of 1.36 (p = 0.004) and 1.46 (p < 0.001), respectively. Following a hazard analysis, the associations of RBC transfusion with nosocomial infection disap-peared [107]. Another recent study by Aubron et al. explored the association of platelet transfusion and nosocomial infection in ICU patients. They studied 18,965 patients of which 2250 (11.9%) received platelet transfusions. They found that platelet transfusion was independently associated with nosocomial infection with an adjusted OR of 2.56 (p < 0.001) [108]. In a separate study, this group examined the effect of the age of the platelets on outcome in the 2250 transfusion recipients. No associations were found between storage duration of platelets and risk of mor-tality or infection [109].

A recent review and meta-analysis by Carson et al. evaluated numerous studies looking at risks associated with RBC transfusion. They included 31 trials with more than 12,000 total patients. They found that the 30-day mortality was similar in restrictive and liberal transfusion groups (RR 0.97) [1]. Additionally, they found essentially no differences between the two transfusion groups in rates of pneumo-nia, MI, and congestive heart failure [1]. They evaluated five trials which included a total of 2840 ICU patients and found that there was no difference in mortality between the restrictive and liberal transfusion groups (RR 0.97) [1]. Carson et al. concluded that the observational studies overestimated the risks of blood compo-nent transfusion. In contrast, Rohde and colleagues found a significant association between liberal transfusion and nosocomial infection in patients undergoing ortho-pedic surgery [105]. Finally, three sets of meta-analyses of leukoreduction of trans-fusions in surgical patients demonstrated a 30–40% reduction in postoperative infection in patients randomized to receive only leukoreduced red cells [110–112]. Autologous transfusion techniques are also associated with reduced septic and febrile illnesses in surgical patients in randomized trials [113].


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Multi-organ Failure (MOF) and Mortality

Transfusion of blood components has been associated with the development of MOF and/or mortality. Several studies have found that pediatric patients that receive RBC transfusion have longer ventilator times [114], increased time requiring vaso-pressor support [114], longer pediatric ICU LOS [114, 115], longer hospital LOS [115], and increased mortality [114, 115]. However, both of these studies had the limitation of not comparing equally sick patients; hence, it is possible that sicker patients were transfused and had poorer outcomes. A prospective study was done in critically ill pediatric patients that controlled for age and illness severity that found that RBC transfusion was associated with increased risk of cardiac arrest, nosoco-mial infection, increased PICU LOS, longer mechanical ventilation time, and increased mortality [116]. A retrospective study by Rajasekaran et al. looked at pediatric ICU patients, transfusions, and disease severity scores such as Pediatric Risk of Mortality (PRISM) III, Pediatric Index of Mortality (PIM2), and day 1 Pediatric Logistic Organ Dysfunction (PELOD) scores. They found that RBC trans-fusion is independently a risk factor for mortality exclusive of the illness severity scores [117]. Another recent study by Wang et al. looked prospectively at a cohort of extremely low birth weight (ELBW) infants and followed them for up to 2 years. They found that the number of transfusions within 7 days after birth was associated with risk of death prior to 1 month old with an odds ratio of 1.54 (p = 0.03) [118]. Additionally, the number of transfusions before 30 days of life was associated with an increased risk of developing threshold retinopathy of prematurity with an odds ratio of 1.27 (p = 0.02) [118]. At 18–24 months of age, infants that had received more transfusions within the first 7 days of life did better cognitively as assessed using the Mental Development Index score [118].

Recently, data in the Randomized Evaluation of Normal Versus Augmented Level (RENAL) replacement therapy study [119] was reanalyzed looking at RBC transfusion in ICU patients with severe acute kidney injury. Given that this was a secondary analysis of data, the patients were propensity matched. They found that RBC transfusion was independently associated with decreased 90-day mortality but that this effect disappears when patients who died within 5 days of ICU admis-sion were excluded [120]. Thus, there were no differences between transfused and untransfused patients in any primary or secondary outcomes (mortality, ventilator- free days, LOS in ICU or hospital) [120]. Ding et al. analyzed data from the Veteran Affairs ICU spanning 5 years. They found that transfusion was associated with decreased hospital mortality in patients without heart disease with Hgb <7.7 g/dL; however, at Hgb levels above this, transfusion was associated with increased mortality [121]. In patients with comorbid heart disease and AMI, they found that transfusion was associated with decreased mortality in patients with Hgb <8.7 g/dL and <10 g/dL, respectively, and that transfusion at hemoglobin val-ues above this was associated with increased mortality [121]. This study illus-trates that there are Hgb values at which the transfusion risk-benefit is favorable and unfavorable.


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Additional definitive data demonstrating that transfusion causes MOF and mor-tality comes from large randomized trials of leukoreduction in cardiac surgery patients who are transfused. Leukoreduction of transfusions resulted in an approxi-mately 50% reduction in mortality, mostly due to reduced infection/MOF [122, 123].

In addition to examining whether transfusion of blood components is associated with adverse outcomes, some researchers have attempted to explore what specifically may be causing the poor outcomes. Many researchers have focused on the age of RBCs in assessing patient outcomes. Most clinicians are concerned with the “storage lesion” as RBCs age. This is discussed in greater detail in another chapter. Several RCTs have been done which investigated the storage duration of blood and patient outcomes. None of these RCTs have shown an increase in adverse events in patients that received older RBCs [101, 124–126]. Indeed, it appears that shorter storage red cells may be associated with higher incidence of nosocomial infection [127].

To further investigate the possible risks associated with transfusion of older RBCs, Goel et al. retrospectively looked at morbidity, mortality, and length of stay (LOS) in 28,247 patients that were transfused with 129,483 RBC units [128]. They compared patients that received RBCs less than or equal to 21 days versus patients who received RBC stored 28 days or more versus patients who received exclusively RBCs older than 35 days [128]. They found that LOS was increased for all patients who received RBCs stored ≥28 days and ≥ 35 days [128]. Interestingly, RBCs ≥35 days were also associated with increased morbidity following risk adjustment with an adjusted odds ratio of 1.19 (p = 0.002) [128]. RBCs ≥28 days were not associated with increased morbidity, and neither group was associated with increased mortality [128]. Goel et al. also analyzed subgroups of patients including critically ill patients where they found that RBCs ≥35 days were associated with increased morbidity and mortality, with adjusted odds ratios of 1.25 (p = 0.002) and 1.38 (p = 0.009), respectively [128]. Similarly, in older patients, they found that RBCs ≥35 days were associated with increased morbidity with adjusted odds ratios of 1.22 (p = 0.01) but not increased mortality. In both patient subgroups, RBCs ≥28 days were not associated with increased morbidity or mortality [128]. Thus, the oldest RBCs appear to be associated with adverse outcomes. This study differs from other studies as most randomized studies have not involved RBCs toward the end of their shelf life (typically 42 days for RBCs in AS).

Heddle et al. conducted the Informing Fresh versus Old Red cell Management (INFORM) trial in which hospitalized patients in the general population were ran-domized to receive either short- or long-storage RBCs and assessed for mortality [129]. They found no difference in mortality between patients receiving short- or long-term stored RBCs. Notably, the difference in average age of the RBCs was not terribly different with 13.0 days for short-term and 23.6 days for long-term storage [129]. Thus, this study, as all other randomized trials, could not evaluate if RBCs toward the end of their storage life (35–42 days) are associated with increased risk of morbidity or mortality. Cook et al. performed a secondary analysis of the INFORM trial data and assessed the risk of in-hospital mortality in patients receiv-ing blood of different ages (≤7 days, 8–35 days, and >35 days) [130]. They found that transfusion of RBCs stored >35 days was not associated with increased


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mortality as compared to exclusive transfusion of RBCs ≤7 days old. Similarly, transfusion of RBCs stored 8–35 days was not associated with increased mortality as compared to exclusive transfusion of RBCs ≤7 days old [130]. One caveat to use in interpretation of this study is that the study was not designed to measure what they reanalyzed for. Thus, patients were classified into one of the three blood age exposure categories based upon the age of the oldest RBC unit that they received. Hence, patients may not have received as much “old” blood as in the study by Goel et al. [128]. The issue of whether the longest stored red cells are as safe (or danger-ous) as shorter- or medium-stored red cells may well not be determinable in a defini-tive fashion.

Cooper et al. performed a double-blind multicenter randomized trial looking at the effect of RBC age on critically ill patient mortality. They found no difference in mortality at 90 or 180 days between patients transfused with RBCs that were stored long term as compared to short term [131]. As in the Heddle et al. study [129], the average age difference between the two storage groups was small with short term being 11.8 days old and long term being 22.4 days old [131]. Thus, this study could not definitively address whether blood toward the end of its lifespan is associated with increased risks following transfusion.

What is the take-home message from all of these studies? From the large meta- analysis of Carson et al., it appears that transfusion of limited amounts of blood components is equivalent to or perhaps even superior to transfusion of larger amounts of blood components. However, from all of the studies, it is clear that trans-fusion of blood components is associated with worse outcome as compared to no transfusion. Transfusion is perhaps the only important medical therapy where the risks outweigh benefits for many or most patients and established practices are both nonevidence based and routinely sub-optimal. Taken together, these studies support immunomodulatory effects of blood transfusions.

Traumatic Brain Injury (TBI) and Spontaneous Intracranial Bleeding

The benefits and risks of RBC transfusion in TBI patients are unclear. There is some concern that the use of a restrictive transfusion approach in TBI patients could lead to ischemia, secondary brain injury, and worse outcomes [132, 133]. Several studies have implicated that RBC transfusion in critically ill TBI patients is associated with harmful effects [132, 134, 135]. RBC transfusion has been shown to increase brain tissue oxygenation (PbtO2), and the use of lower transfusion thresholds has been associated with slightly decreased PbtO2. However, no difference in long-term neu-rological outcome was seen in TBI patients managed with a restrictive versus liberal transfusion threshold [136]. Several additional studies have also looked at restric-tive versus liberal transfusion in patients with TBI and have found that restrictive transfusion is comparable to liberal transfusion [94, 137, 138]. In one study, liberal transfusion was found to be associated with thromboembolic events [94].


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Additionally, Warner et al. reported that RBC transfusion was associated with worse 6-month neurological outcome [135]. The largest evaluation of RBC transfusion in TBI patients was a retrospective study done by Ngwenya et al. who studied 1565 TBI patients [139]. They found that restrictive and liberal transfusion protocols were associated with similar ICU LOS, ventilator days, lung injury incidence, thromboembolic events, and mortality rates. They did find that restrictive transfu-sion was associated with a decreased number of days of fever (p = 0.01) [139]. Finally, platelet transfusion in patients with intracranial bleeding receiving anti-platelet drugs had worse neurologic outcomes and a trend toward increased mortal-ity compared with patients randomized to no platelet transfusions [140]. Similar adverse associations between plasma transfusion and adverse outcomes, including mortality, have been reported in observational studies of transfusion in patients with traumatic brain injury and coagulopathy [141]. These adverse and unfortunate effects of plasma transfusion have been confirmed in randomized trials of warfarin reversal, which demonstrate that four factor prothrombin concentrates reduce mor-tality by half compared with plasma transfusion [142]. These randomized trial and observational data argue against routine use of platelet and plasma transfusions for coagulopathy in traumatic brain injury and to reverse the effects of antiplatelet drugs or vitamin K antagonists. Both appear to worsen bleeding, neurologic deficits, and survival, contrary to previous expert opinion.

Transfusion-Related Immunomodulation (TRIM)

Transfusion of blood components causes suppression of T cell and NK cell effector functions and dysregulates innate immunity toward pro-inflammatory profile in many animal models and clinical settings. These effects are referred to generally as transfusion immunomodulation. The strongest evidence for the clinical importance of these effects are randomized trials demonstrating that leukoreduction of transfu-sions mitigates the effect of red cell transfusion in promoting postoperative infec-tion. There are also randomized trial data that demonstrate that the use of leukoreduced, washed transfusions improves survival in acute myeloid leukemia and reduces inflammation in pediatric cardiac surgery [143]. There are many obser-vational studies that support these randomized trials. Jeschke et al. studied immuno-modulation by transfusion in pediatric burn patients and found that increased number of transfusions was independently associated with the development of sep-sis [144]. Notably, this was most apparent in patients who were more severely injured. Patients who received >20 RBCs and >5 plasma transfusions were found to have a 58% risk of sepsis as compared to patients who received <20 RBCs and <5 plasma transfusions who only had an 8% risk of sepsis development (p < 0.05) [144]. Mortality was also increased in the highly transfused patients (OR 6.79, p < 0.001) [144].

Transfusion immunomodulation is comprised of complex immunosuppressive and pro-inflammatory effects that are mediated by leukocytes, apoptotic cells,


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cytokines, soluble mediators, soluble HLA peptides, cell-derived microparticles, and free hemoglobin [145, 146]. Several mechanisms have been proposed, includ-ing suppression of cytotoxic cell and monocyte activity, release of immunosuppres-sive prostaglandins, inhibition of IL-2 production, and increases in Tregs and suppressor T-cell activity [97, 147–149]. Immunomodulation after blood transfu-sion leads to release of endogenous recipient cytokines including IL-6, IL-8, and other acute phase proteins which may play a role in impaired host defense, organ dysfunction, and mortality. Immunomodulation is also likely to be in part mediated by transfusion of storage-damaged RBCs causing hemolysis in the microvascula-ture and spleen which then causes local release of free hemoglobin, heme, and iron. The RBC unit also contains free heme iron which together with the local release of iron likely contributes to proinflammatory responses [150–153].

The role of transfusion immunomodulation in cancer is less certain. The mecha-nisms involved in immunomodulation described may well contribute to the negative outcomes observed in cancer patients. While leukoreduction does not appear to mitigate the proposed transfusion effect, autologous transfusion [154] and saline- washed transfusions [155, 156] have shown preliminary promise for improving cancer-free survival in patients with colorectal cancer and acute myeloid leukemia, respectively.

However, it is entirely likely that factors in addition to immunomodulation con-tribute to the role that blood transfusion plays in cancer progression [157]. Researchers are exploring the role of the blood donor’s microbiome on immuno-modulation [158]. Additionally, the metabolomics and proteomics of stored blood are also being studied to better understand transfusion immunomodulation [159].

From the data and studies outlined above, transfusion of blood components is associated with increased risk of serious adverse effects including nosocomial infection, thrombosis, inflammation, multi-organ failure, and mortality. It is likely that critically ill patients are more susceptible to these effects. The best approach for these critically ill patients is parsimonious use of blood transfusions in which the risks are carefully weighed against the benefits.

The ABO Blood Group System and Transfusion Outcomes

Many practitioners are not aware that transfusion services routinely provide ABO nonidentical blood components to patients for inventory and logistic reasons. An assumption was made long ago that unless massive hemolysis occurs, minor hemo-lysis due to transfusing anti-A and anti-B to group A, B, or AB patients is not a concern. Likewise, the soluble antigen present in group A, B, and AB plasma and platelet transfusions was deemed a benefit, not a risk for immune complex forma-tion. While beyond the scope of this chapter, there is a growing body of data sug-gesting that our current transfusion service practices of infusing incompatible antigen and antibody in the ABO system may be sub-optimal and harming patients. ABO nonidentical transfusions cause unresponsiveness (refractoriness) to platelet


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transfusions in randomized trials and are associated in cohort studies with increased bleeding, sepsis, acute lung injury, thrombosis, and mortality. These data are sum-marized in a recent review [160].

Conclusions

Much has been learned about the biology and clinical utility of blood transfusions in recent decades. The seminal advances in the first few decades of transfusion prac-tice were the ability to avoid hemolytic transfusion reactions by giving transfusions of red cells that were serologically compatible with the recipient and to mitigate the infectious risks of transfusions by testing for antibody and nucleic acid of agents such as hepatitis B and C, HIV, etc. The most important advances of the last few decades have been identifying that transfusion causes serious harm to patients through lung injury, volume overload, inflammation, immunomodulation, increased bleeding, and, perhaps, low-level hemolysis due to labile donor red cells and storage issues. Transfusion practices such as ABO nonidentical transfusions may confound some of the studies of red cell storage duration, since low-level hemolysis is caused by both ABO nonidentical transfusions and storage injury. Methods of mitigating transfusion risks by employing patient blood management programs, restrictive transfusion practices, universal leukoreduction, autologous transfusion techniques, ABO matching, and supernatant removal by washing have been proven in random-ized trials in multiple centers, except for washing and ABO matching. These approaches will be expanded no doubt in the future, with attendant reductions in severe morbidity caused by transfusions being the goal.

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88. Kremke M, Hansen MK, Christensen S, Tang M, Andreasen JJ, Jakobsen CJ. The association between platelet transfusion and adverse outcomes after coronary artery bypass surgery. Eur J Cardiothorac Surg. 2015;48(5):e102–9.


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91. Schmidt AE, Henrichs KF, Kirkley SA, Refaai MA, Blumberg N. Prophylactic Preprocedure platelet transfusion is associated with increased risk of thrombosis and mortality. Am J Clin Pathol. 2017;149:87.

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93. Zakko L, Rustagi T, Douglas M, Laine L. No benefit from platelet transfusion for gastrointes-tinal bleeding in patients taking antiplatelet agents. Clin Gastroenterol Hepatol. 2016;15:46.

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95. Robitaille N, Lacroix J, Alexandrov L, Clayton L, Cortier M, Schultz KR, et al. Excess of veno-occlusive disease in a randomized clinical trial on a higher trigger for red blood cell transfusion after bone marrow transplantation: a Canadian blood and marrow transplant group trial. Biol Blood Marrow Transplant. 2013;19(3):468–73.

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104. Weinberg JA, McGwin G Jr, Griffin RL, Huynh VQ, Cherry SA 3rd, Marques MB, et al. Age of transfused blood: an independent predictor of mortality despite universal leukoreduction. J Trauma. 2008;65(2):279–82. discussion 82–4

105. Rohde JM, Dimcheff DE, Blumberg N, Saint S, Langa KM, Kuhn L, et al. Health care- associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA. 2014;311(13):1317–26.

106. Juffermans NP, Prins DJ, Vlaar AP, Nieuwland R, Binnekade JM. Transfusion-related risk of secondary bacterial infections in sepsis patients: a retrospective cohort study. Shock. 2011;35(4):355–9.

107. Engele LJ, Straat M, van Rooijen IHM, de Vooght KMK, Cremer OL, Schultz MJ, et al. Transfusion of platelets, but not of red blood cells, is independently associated with nosoco-mial infections in the critically ill. Ann Intensive Care. 2016;6(1):67.

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110. Fergusson D, Khanna MP, Tinmouth A, Hebert PC. Transfusion of leukoreduced red blood cells may decrease postoperative infections: two meta-analyses of randomized controlled tri-als. Can J Anaesth. 2004;51(5):417–24.

111. Blumberg N, Zhao H, Wang H, Messing S, Heal JM, Lyman GH. The intention-to-treat principle in clinical trials and meta-analyses of leukoreduced blood transfusions in surgical patients. Transfusion. 2007;47(4):573–81.

112. Kwon S, Lew S, Chamberlain RS. Leukocyte filtration and postoperative infections. J Surg Res. 2016;205(2):499–509.

113. Vanderlinde ES, Heal JM, Blumberg N. Autologous transfusion. BMJ. 2002;324(7340): 772–5.

114. Kneyber MC, Hersi MI, Twisk JW, Markhorst DG, Plotz FB. Red blood cell transfusion in critically ill children is independently associated with increased mortality. Intensive Care Med. 2007;33(8):1414–22.

115. Stone TJ, Riesenman PJ, Charles AG. Red blood cell transfusion within the first 24 hours of admission is associated with increased mortality in the pediatric trauma population: a retro-spective cohort study. J Trauma Manag Outcomes. 2008;2(1):9.

116. Bateman ST, Lacroix J, Boven K, Forbes P, Barton R, Thomas NJ, et al. Anemia, blood loss, and blood transfusions in north American children in the intensive care unit. Am J Respir Crit Care Med. 2008;178(1):26–33.

117. Rajasekaran S, Kort E, Hackbarth R, Davis AT, Sanfilippo D, Fitzgerald R, et al. Red cell transfusions as an independent risk for mortality in critically ill children. J Intensive Care. 2016;4:2.

118. Wang YC, Chan OW, Chiang MC, Yang PH, Chu SM, Hsu JF, et al. Red blood cell transfu-sion and clinical outcomes in extremely low birth weight preterm infants. Pediatr Neonatol. 2017;58(3):216–22.

119. Investigators RRTS, Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009;361(17):1627–38.

120. Bellomo R, Martensson J, Kaukonen KM, Lo S, Gallagher M, Cass A, et al. Epidemiology of RBC transfusions in patients with severe acute kidney injury: analysis from the ran-domized evaluation of normal versus augmented level study. Crit Care Med. 2016;44(5): 892–900.

121. Ding YY, Kader B, Christiansen CL, Berlowitz DR. Hemoglobin level and hospital mortal-ity among ICU patients with cardiac disease who received transfusions. J Am Coll Cardiol. 2015;66(22):2510–8.

122. van de Watering LM, Hermans J, Houbiers JG, van den Broek PJ, Bouter H, Boer F, et al. Beneficial effects of leukocyte depletion of transfused blood on postoperative com-plications in patients undergoing cardiac surgery: a randomized clinical trial. Circulation. 1998;97(6):562–8.

123. Bilgin YM, van de Watering LM, Eijsman L, Versteegh MI, Brand R, van Oers MH, et al. Double-blind, randomized controlled trial on the effect of leukocyte-depleted erythrocyte transfusions in cardiac valve surgery. Circulation. 2004;109(22):2755–60.

124. Fergusson DA, Hebert P, Hogan DL, LeBel L, Rouvinez-Bouali N, Smyth JA, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA. 2012;308(14):1443–51.

125. Steiner ME, Ness PM, Assmann SF, Triulzi DJ, Sloan SR, Delaney M, et al. Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med. 2015;372(15):1419–29.

126. Dhabangi A, Ainomugisha B, Cserti-Gazdewich C, Ddungu H, Kyeyune D, Musisi E, et al. Effect of transfusion of red blood cells with longer vs shorter storage duration on elevated blood lactate levels in children with severe Anemia: the TOTAL randomized clinical trial. JAMA. 2015;314(23):2514–23.


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127. Alexander PE, Barty R, Fei Y, Vandvik PO, Pai M, Siemieniuk RA, et al. Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta- analysis. Blood. 2016;127(4):400–10.

128. Goel R, Johnson DJ, Scott AV, Tobian AA, Ness PM, Nagababu E, et al. Red blood cells stored 35 days or more are associated with adverse outcomes in high-risk patients. Transfusion. 2016;56(7):1690–8.

129. Heddle NM, Cook RJ, Arnold DM, Liu Y, Barty R, Crowther MA, et al. Effect of short-term vs. long-term blood storage on mortality after transfusion. N Engl J Med. 2016;375(20):1937–45.

130. Cook RJ, Heddle NM, Lee KA, Arnold DM, Crowther MA, Devereaux PJ, et al. Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised con-trolled trial. Lancet Haematol. 2017;4:e544.

131. Cooper DJ, McQuilten ZK, Nichol A, Ady B, Aubron C, Bailey M, et al. Age of red cells for transfusion and outcomes in critically ill adults. N Engl J Med. 2017;377:1858.

132. Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, et al. Role of anemia in traumatic brain injury. J Am Coll Surg. 2008;207(3):398–406.

133. Duane TM, Mayglothling J, Grandhi R, Warrier N, Aboutanos MB, Wolfe LG, et al. The effect of anemia and blood transfusions on mortality in closed head injury patients. J Surg Res. 2008;147(2):163–7.

134. Kiraly LN, Underwood S, Differding JA, Schreiber MA. Transfusion of aged packed red blood cells results in decreased tissue oxygenation in critically injured trauma patients. J Trauma. 2009;67(1):29–32.

135. Warner MA, O'Keeffe T, Bhavsar P, Shringer R, Moore C, Harper C, et al. Transfusions and long-term functional outcomes in traumatic brain injury. J Neurosurg. 2010;113(3):539–46.

136. Yamal JM, Rubin ML, Benoit JS, Tilley BC, Gopinath S, Hannay HJ, et al. Effect of hemo-globin transfusion threshold on cerebral hemodynamics and oxygenation. J Neurotrauma. 2015;32(16):1239–45.

137. George ME, Skarda DE, Watts CR, Pham HD, Beilman GJ. Aggressive red blood cell trans-fusion: no association with improved outcomes for victims of isolated traumatic brain injury. Neurocrit Care. 2008;8(3):337–43.

138. McIntyre LA, Fergusson DA, Hutchison JS, Pagliarello G, Marshall JC, Yetisir E, et al. Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care. 2006;5(1):4–9.

139. Ngwenya LB, Suen CG, Tarapore PE, Manley GT, Huang MC. Safety and cost efficiency of a restrictive transfusion protocol in patients with traumatic brain injury. J Neurosurg. 2017:1–8.

140. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605–13.

141. Zhang LM, Li R, Zhao XC, Zhang Q, Luo XL. Increased transfusion of fresh frozen plasma is associated with mortality or worse functional outcomes after severe traumatic brain injury: a retrospective study. World Neurosurg. 2017;104:381–9.

142. Chai-Adisaksopha C, Hillis C, Siegal DM, Movilla R, Heddle N, Iorio A, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost. 2016;116(5):879–90.

143. Schmidt AE, Refaai MA, Heal JM, Blumberg N. Transfusion-induced immunomodulation. In: Michael Murphy DJR, Yazer MH, editors. Practical transfusion medicine. 5th ed: Wiley; Oxford, UK: 2017.

144. Jeschke MG, Chinkes DL, Finnerty CC, Przkora R, Pereira CT, Herndon DN. Blood transfu-sions are associated with increased risk for development of sepsis in severely burned pediatric patients. Crit Care Med. 2007;35(2):579–83.

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147. Berezina TL, Zaets SB, Morgan C, Spillert CR, Kamiyama M, Spolarics Z, et al. Influence of storage on red blood cell rheological properties. J Surg Res. 2002;102(1):6–12.

148. Jensen LS, Andersen AJ, Christiansen PM, Hokland P, Juhl CO, Madsen G, et al. Postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery. Br J Surg. 1992;79(6):513–6.

149. van Twuyver E, Mooijaart RJ, ten Berge IJ, van der Horst AR, Wilmink JM, Kast WM, et al. Pretransplantation blood transfusion revisited. N Engl J Med. 1991;325(17):1210–3.

150. Ozment CP, Mamo LB, Campbell ML, Lokhnygina Y, Ghio AJ, Turi JL. Transfusion-related biologic effects and free hemoglobin, heme, and iron. Transfusion. 2013;53(4):732–40.

151. Hod EA, Zhang N, Sokol SA, Wojczyk BS, Francis RO, Ansaldi D, et al. Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation. Blood. 2010;115(21):4284–92.

152. Hod EA, Spitalnik SL. Stored red blood cell transfusions: Iron, inflammation, immunity, and infection. Transfus Clin Biol. 2012;19(3):84–9.

153. Benson AB, Burton JR Jr, Austin GL, Biggins SW, Zimmerman MA, Kam I, et al. Differential effects of plasma and red blood cell transfusions on acute lung injury and infection risk fol-lowing liver transplantation. Liver Transpl. 2011;17(2):149–58.

154. Heiss MM, Mempel W, Delanoff C, Jauch KW, Gabka C, Mempel M, et al. Blood transfusion- modulated tumor recurrence: first results of a randomized study of autologous versus alloge-neic blood transfusion in colorectal cancer surgery. J Clin Oncol. 1994;12(9):1859–67.

155. Greener D, Henrichs KF, Liesveld JL, Heal JM, Aquina CT, Phillips GL 2nd, et al. Improved outcomes in acute myeloid leukemia patients treated with washed transfusions. Am J Hematol. 2017;92(1):E8–9.

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157. Goubran H, Sheridan D, Radosevic J, Burnouf T, Seghatchian J. Transfusion-related immu-nomodulation and cancer. Transfus Apher Sci. 2017;56(3):336–40.

158. Goubran H, Seghatchian J, Radosevic J, Ragab G, Burnouf T. The microbiome and transfu-sion in cancer patients. Transfus Apher Sci. 2017;56(3):330–5.

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305© Springer International Publishing AG, part of Springer Nature 2018A. Shander, H. L. Corwin (eds.), Hematologic Challenges in the Critically Ill, https://doi.org/10.1007/978-3-319-93572-0_16

Chapter 16Clinical Outcomes and Red Blood Cell Storage

Shuoyan Ning and Nancy M. Heddle

Transfusions remain a cornerstone of medical therapy in the critically ill patient, with at least 30% of patients in the ICU receiving one or more red blood cell transfusions [1–3]. Our understanding of the biochemical, structural, and functional changes that occurs to red blood cells with storage – also known as the storage lesion – has fueled concerns around transfusion of stored blood. To date, 16 randomized controlled trials across various clinical settings in both the pediatric and adult literature have estab-lished that transfusion of red blood cells stored for shorter durations does not reduce the risk of recipient mortality. These studies have also shown that transfusion of long-term stored blood (stored for 36–42 days) is not harmful, and thus, current practice remains appropriate. Interestingly, randomized trials may have raised questions around the safety of “fresh” blood. Building on this body of work, an emerging area of research explores the potential clinical impacts of blood donor age and sex as well as the method of whole blood processing on recipient outcomes.

Basics of Blood Storage

Blood storage is the foundation of modern blood banking. Storage technology enabled the transport, availability, and accessibility of blood for all patients by sepa-rating donors and recipients in both space and time. Today, blood collection, pro-cessing, and storage methods are tightly regulated by regional and national standards and often vary between jurisdictions.

In Canada, red blood cells are universally leuko-reduced and manufactured from whole blood collections using either the whole blood filtration or the red blood cell filtration method [4]. In other countries, some of the red blood cell supply may also

S. Ning · N. M. Heddle (*) Department of Medicine, McMaster University, Hamilton, ON, Canadae-mail: [email protected]



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be produced as a single product from apheresis. Regardless of the collection and processing method, anticoagulant, nutrients, and preservatives are added to the final product to allow for red blood cell storage at controlled temperatures (e.g. 1–6 °C).

The earliest storage solutions used in the twentieth century consisted of citrate (anticoagulant) and glucose (nutrient) [5]. In 1943, the advent of ACD (acid citrate dextrose) allowed blood to be stored for 21 days following collection [6]. Subsequently, the use of plastic bags, phosphate, and adenine further prolonged red blood cell storage duration by limiting membrane vesiculation, promoting ATP syn-thesis, and improving red blood cell recovery and membrane integrity [5]. In the 1970s, additive solutions were introduced [7] and continue to be used today. SAGM (saline, adenine, glucose, mannitol) is the standard additive solution in Europe and Canada with a 42-day storage approval [8]. AS-1, AS-3, and AS-5, solutions similar to SAGM, are approved for use in the United States [8]. MAP and PAGGSM are two other commercially available additive solutions; PAGGSM is approved for a storage duration of 49 days in Germany [9]. The maximum permitted shelf life of red blood cells in some of the world’s blood suppliers are listed in Table 16.1.

Duration of permissible red blood cell storage depends on a number of factors which may include but are not limited to (1) additive solution used, (2) in vitro hematologic and biochemical indices, (3) red blood cell recovery studies, (4) prod-uct manipulations (washing, irradiation), and (5) national/regional blood supply. Concerns around risks of blood storage, such as red blood cell changes with age (“storage lesion”) and bacterial contamination, have led some blood suppliers to further restrict storage durations. For example, the United Kingdom, Ireland, Netherlands, and Norway have maximum red blood cell storage durations of 35 days [9]. In Japan, red blood cells are only stored maximally for 21 days [9].

The “Storage Lesion”

The biochemical, structural, and functional changes that occur with red blood cell storage are collectively known as the “storage lesion.” An appreciation of these qualitative changes is fundamental to understanding the concerns around the dura-tion of blood storage. Storage impairs Na+/K+ pump function, ATP production, and 2,3-DPG generation; in turn, these changes cause hyperkalemia, impair red blood cell survival, and reduce oxygen delivery, respectively [10–12]. Storage-related enzymatic dysfunction also occurs and may adversely affect the red blood cell’s native antioxidant system [13, 14]. With prolonged storage, red blood cell structural changes such as membrane loss, micro-vesiculation, and disruption of phospholipid distribution will ensue [15]. These changes impair red blood cell deformability [15] and decrease red blood cell survival by increasing their likelihood of macrophage- mediated phagocytosis [16] and splenic destruction [17]. In turn, increased red blood cell clearance leads to accumulation of non-transferrin-bound iron (NTBI) [18, 19]. In murine models, increased inflammation following transfusion of long- term storage red blood cells has been shown and is thought to be NTBI-mediated [20–22]. In human studies, NTBI levels correlate with in vitro bacterial prolifera-tion [23]. Loss of membrane integrity with storage also results in release of

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hemoglobin- containing microvesicles and free hemoglobin, leading to nitric oxide depletion and vasoconstriction [24–26]. Pro-inflammatory bioactive lipids may also be released with membrane breakdown [27] and storage-related platelet adhesion, and activation has been described [28, 29]. More recently, integrated metabolomics and proteomics studies, capable of analyzing hundreds to thousands of molecules at once, have deepened our understanding of the dynamic and complex nature of the qualitative changes occurring with storage [30–33]. Other factors such as the addi-tive solution of choice [9, 33], blood processing method [34], and donor character-istics [34–36] are just a few variables shown to impact the way blood ages when stored.

Irradiation and washing of red blood cell components may also impact product quality and contribute to the “storage lesion.” Blood components are often irradi-ated prior to transfusion in the context of severe recipient immune-compromise or HLA semblance between donor and recipient. Irradiation prevents transfusion asso-ciated with graft-versus-host disease (Ta-GVHD) – an exceedingly rare but habitu-ally fatal complication of transfusion that occurs when transfused donor lymphocytes

Table 16.1 Maximum red blood cell shelf life and mean age of blood at time of administration in various countries

Maximum red blood cell shelf life (days)a

Mean age of blood at administration in randomized clinical trialsb (mean ± SD, days)

United States 42 23.6 ± 8.9c

Canada 42 23.6 ± 8.9c

22 ± 8.4d

United Kingdom

35 22 ± 8.4d

Germany 42–49 N/AItaly 42 N/AFrance 42 22 ± 8.4d

Netherlands 35 22 ± 8.4d

Norway 35 N/AAustralia 42 23 ± 8.4e

23.6 ± 8.9c

22.4±7.5f

China 21–42 N/AJapan 21 N/A

aUS – FDA requirements (https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecom-plianceregulatoryinformation/guidances/blood/ucm364593.pdfUK – JAPC UK Advisory Committee (https://www.transfusionguidelines.org/red-book). Germany – regulatory guidelines (http://www.bundesaerztekammer.de/richtlinien/richtlinien/blut/) and confirmed through pers. comm. with Drs. Jason Acker and Andrew ShihAustralia - https://transfusion.com.au/blood_components/storage/storage_temperature_rangeNetherlands, Norway – pers. comm with Dr. Andrew ShihItaly, France, China, Japan - Flegel et al. [9]bOnly randomized trials with a standard issue arm were includedcHeddle et al. [63]dLacroix et al. [57]eAubron et al. [56]fCooper et al. [55]

16 Clinical Outcomes and Red Blood Cell Storage

https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/blood/ucm364593.pdf

https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/blood/ucm364593.pdf

https://www.transfusionguidelines.org/red-book

http://www.bundesaerztekammer.de/richtlinien/richtlinien/blut

http://www.bundesaerztekammer.de/richtlinien/richtlinien/blut

https://transfusion.com.au/blood_products/storage/storage_temperature_range

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attack the recipient. Irradiation inactivates residual donor lymphocytes that may still be present in the red blood cell component. However, irradiation causes red blood cell membrane damage [37, 38], reduces deformability [39], and induces hemolysis [40] – leading to changes that both resemble and exacerbate existing storage lesions. As such, many countries institute restrictions on the age of components that can be irradiated and duration of storage following irradiation. In Canada, red blood cells may be stored for a maximum of 14 days from irradiation or 28 days after collection if irradiated, whichever is sooner.

Washing of red blood cells is another product modification that affects cellular quality. Usually performed with normal saline, this procedure aims to reduce unde-sired proteins and/or electrolytes prior to transfusion. Washed cells can be prepared in either an open or closed system using either manual, semiautomated, or auto-mated methods [41]. In Canada, the manual and open system often used by hospi-tals to wash red blood cells limits product expiry to 24 h due to concerns of bacterial contamination and accelerated red blood cell aging, as the product is re-suspended in saline instead of additive solution [41]. Post-wash storage time can be extended with the use of semi- or fully automated processors which uses a closed system and re-suspends red blood cells in additive solution [41]. Washing has been shown to reduce various components of blood storage (such as potassium, plasma-free hemo-globin, immunomodulatory proteins and cytokines) as well as IgA [42–45]. As such, washing may be indicated in the context of severe and recurrent febrile or allergic transfusion reactions [46], recipient IgA deficiency [43], and potassium intolerance [47, 48]. However, indications remain limited due to concerns of con-tamination, variability of red blood cell quality with the method of washing [45], and limited red blood cell recovery and hemolysis following washing [40].

Clinical Studies of Short- Versus Long-Term Blood Storage

With the vast number of membrane, biochemical, and immunomodulatory changes that are known to occur as red blood cells are stored, it was not surprising that the “storage lesion” led to the hypothesis that transfusion of blood which had under-gone longer-term storage could be harmful. “Older” red blood cells were thought to not only be functionally inferior with regard to oxygen delivery and survival but may also impair vasodilatation and cause recipient inflammation, infection, and hypercoagulability. These concerns fueled a large body of observational studies beginning in the 1990s studying the association between storage age and mortality [12]. A recently published meta-analysis that included 31 observational studies found an increased risk of death when longer-term storage red blood cells were transfused (OR 1.13, 95% CI 1.03–1.24, p = 0.01) [49]. However, while observa-tional studies from North America frequently reported harm with prolonged blood storage (>21 days), studies from Europe tended to show no difference [12]. This inconsistency in the literature has been termed the “continental divide” by van de Watering [12]. Multiple hypotheses were proposed to explain this discrepancy: (1)


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confounding by indication because of differences in number of red blood cell trans-fusions between study groups, (2) lack of adjustment for other confounders and unrecognized sources of bias, (3) lack of clarity regarding the temporal relationship between transfusion with outcomes, (4) arbitrary definitions of “fresh” vs “old”, and (5) potential impact of blood processing methods, which were unaccounted for in prior studies [12].

There was a need for randomized controlled trials (RCTs) to address this issue, and over two decades, numerous studies were designed and implemented. To date 16 RCTs have been completed and published with sample sizes ranging from 17 to 31,497 patients (Fig. 16.1). The patient populations studied include neonatal ICU [50–52], pediatric acute care [53, 54], adult critical care [55–59], adult cardiovascu-lar surgery [60, 61], general hospitalized patients [62, 63], and trauma [64, 65]. Most of these studies were designed as efficacy studies (enrolled selective high-risk patients and red blood cells stored a short duration (less than 8–10 days) in the inter-vention arm); however, several studies used a more pragmatic (real-life) approach including a broader patient population and transfusing the freshest blood available to patients randomized to the intervention arm rather than using a specific storage

1996 StraussN = 40VLBW InfantsFresh : ≤7 dOld : ≤42d

2002 SchulmanN= 17TraumaFresh: ≤20dOld: Std Issue

2005 da CunhaN = 52VLBW InfantsFresh:≤3dOld: RBCs up to 28d

2005 HebertN= 57Card Surg & ICUFresh: <8 dOld: Std Issue

2009 Bennett-GuerreroN= 43Card SurgFresh: 7 ±4 dOld: 21 ±4 d

2012 AubronN= 51ICUFresh: freshestavailableOld: Std Issue

2012 HeddleN= 910Tx hospital ptsFresh: FreshestOld: Std Issue

2012 KorN= 99ICUFresh: <5dOld: Std Issue

2013 DhabangiN= 74Acute careFresh: 1-10dOld: 21-35 d

2015 DhabangiN= 290Acute careFresh: 1-10dOld: 25-35 d

2015 LacroixN= 2430ICUFresh: <8 dOld: Std Issue

2015 SchreiberN= 167TraumaFresh: ≤14dOld: >14 d

2015 SteinerN= 1098Card SurgFresh: ≤10dOld: 21 d

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sA

dults

2016 HeddleN= 20,858Tx hospital ptsFresh: FreshestOld: Std Issue

2017 CooperN= 4919ICUFresh:freshestavailableOld: Std Issue

1996

2017

2012 FergussonN= 377VLBW InfantsFresh:≤7 dOld: Std Issue

Fig. 16.1 Time line for reporting of the 16 randomized controlled trials included in the meta- analysis by McQuilten et al. (2018) and separated by neonates, pediatrics, and adults. For each study the n represents the number of patients included in the analysis. VLBW, very low birth weight; ICU, intensive care unit; card surg, cardiac surgery; std. issue, standard issue (issuing the red blood cell unit in inventory that has been stored for the longest period of time). (Dates refer to the online publication of the article)


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duration threshold. A meta-analysis of these 16 studies concluded that the risk ratio for the latest reported mortality was 1.04 (95% CI 0.98 to 1.09), which represents the potential for three fewer deaths when fresh blood is transfused to 12 more deaths with a fresh blood transfusion strategy [97]. A sensitivity analysis of seven studies that were scored at a low risk of bias gave similar results RR 1.03 (95% CI 0.98–1.09). Using the observed baseline mortality of 12% from these 16 studies, the meta- analysis excludes 10% increase or decrease in the relative risk of death. This meta- analysis and two previous meta-analyses (13 and 14 studies included) have consistently shown a risk ratio of 1.04 with confidence intervals getting narrower with each additional published study [66, 67, 97]. The conclusion is that transfusion of fresher red blood cells does not decrease the risk of mortality and that current inventory management practice of issuing the red blood cell components that have been stored for the longest is appropriate. Several secondary outcome measures included in the meta-analysis were found to be statistically significant: inhospital infections were increased when patients received fresher red blood cells (RR 1.08, 95% CI 1.0 to 1.17; p = 0.05), and there was an increased risk of transfusion reactions when fresher red blood cells were transfused (RR 1.35, 0.04 to 1.76; p = 0.02) [97]. Another recent meta-analysis only included studies enrolling adult patients admitted to the ICU and also found no benefit of fresh blood transfusions in this subgroup (RR 1.04, 95% CI 0.97–1 [98]). Hence, there is no evidence currently to suggest a positive impact on recipient morbidities and mortality when fresher blood is transfused.

There are still two large randomized controlled trials being conducted with com-pletions dates within the next year to two. Both are designed as efficacy studies. One study is being conducted by the Cleveland Clinic in patients undergoing cardiac surgery (NCT00458783) [68]. Patients are being randomized to receive fresh red blood cells (stored less than 14 days) or standard issue red blood cells (stored for more than 20 days). The primary outcome is postoperative mortality with a targeted sample size of 2800 patients. The published RECESS trial (1098 patients studied) also investigated the effect of fresh blood in patients having cardiac surgery but used a more restrictive definition of fresh red blood cells (less than or equal to 10 days of storage), and the outcome was a change in multiple organ dysfunction syndrome (MODS) [61]. Hence, the study being done in Cleveland will provide additional information on the effect of blood storage on mortality in the cardiovascular surgery population. The second trial is the ABC PICU study which is a multicenter interna-tional study determining the effect of blood storage in transfused pediatric patients in the intensive care unit (NCT01977547) [69]. The fresh blood intervention is defined as red blood cells stored for equal to or less than 7 days, and standard prac-tice is defined as the oldest blood in the hospital inventory at the time the transfusion is requested. New or progressive multiple organ dysfunction syndrome (NPMODS) is the primary outcome with an anticipated sample size of 1538 patients. This will be the third randomized controlled trial conducted exclusively in pediatric patients. The two previous studies in pediatrics patients included a pilot study followed by a full-scale RCT conducted in Uganda in critically ill children with lactic acidosis [53, 54]. The primary outcome for the full-scale RCT (n = 290) was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 h post transfusion. The


311

results showed that transfusion of red blood cells stored for a longer duration was not inferior to transfusion with fresher blood. The ABC PICU study will provide information on the pediatric population using NPMODS as the outcome instead of the laboratory measurement of lactate levels.

Does Transfusion of Red Blood Cells Stored for 36–42 Days Cause Harm?

In spite of the RCT data, controversy still exists whether exposure to only red blood cells stored for greater than 35 days could be harmful for patients as none of the RCTs specifically addressed this question [70]. Animal studies have shown that free NTBI increases during red blood cell storage and contributes to bacterial growth and inflammation [20, 71, 72]. In human volunteers, transfusion of autolo-gous red blood cells stored for 40–42 days resulted in increased extracellular hemolysis, serum transferrin, and NTBI levels [19, 23]. These findings have con-tributed to the ongoing concerns of transfusing red blood cells stored for a longer duration; however, two patient studies did not find harm following transfusion of red blood cells stored for the longest periods of time. Analysis of data from the Scandinavian Donations and Transfusion Database (SCANDAT) analyzed over 800,000 patients transfused between 2003 and 2012 and found no association between duration of storage and 30-day mortality [73]. The differences in absolute mortality between extremes of exposure were less than 1%. INFORM trial data were also explored, and the hazard ratio for inhospital mortality was 0.94 (95% CI 0.73, 1.20, p = 0.60), when patients exposed exclusively to fresh blood were com-pared to those receiving at least one unit of blood stored for 36–42 days, suggest-ing that inhospital mortality was not increased when very old blood was transfused [74]. Hence, the clinical data suggest that the transfusion of stored red blood cells (36–42 days) is not harmful [75].

Could Short-Term Blood Storage Be Harmful?

Studies on blood storage have unexpectedly raised the question of potential harm when transfusing red blood cells stored for short periods of time. Eleven of the 16 RCTs show a trend toward higher mortality when fresh blood is transfused [97]. Figure 16.2 illustrates the absolute frequency of mortality by treatment arm in the six largest RCTs that have been performed (INFORM [63], Transfuse [55], ABLE [57], RECESS [61], ARIPI [50] and TOTAL [54]). Mortality by treatment arm for the three pilot studies that preceded some of the full-scale RCTs are also presented in Fig. 16.2. The three largest studies accounted for 98.4% (30,990/31,482) of all patients included in the analyses of studies to date [55, 57, 63]. The INFORM study was the largest; a pragmatic trial randomizing 31,497 patients of which 20,858


312

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patients were included in the primary analysis. Mortality in the fresh group (mean storage duration 13.0 ± 7.6 days) was 9.1% compared to 8.7% in the longer-term storage group (23.6 ± 8.9 days): a 0.4% higher frequency in those receiving fresher red blood cells [63]. The recently published TRANSFUSE study (second largest) was a trial of fresher (mean 11.8± 5.3 days) vs longer-term (22.4 ± 7.5 days) red blood cell storage in 4994 critically ill patients. The 90-day mortality was 0.7% higher in the fresher group (24.8% versus 24.1%) [55]. In the ABLE study (n = 2430), critically ill patients were randomized to fresher (<8 days, mean 6.1 ± 4.9 days) versus standard issue (mean 22.0 ± 8.4 days) red blood cells. The 90-day mortality was 1–7% higher in the group receiving fresher red blood cells (37% versus 35.3%) [57]. The pilot studies perform by these three groups of inves-tigators also showed trends of higher mortality when patients were transfused with fresh blood [56, 59, 62].

A few observational studies also raise the issue of harm from fresh blood. A retrospective study from the Netherlands reported a hazard ratio of 0.56 (95% CI 0.32 to 0.97) for death within 1 year of transfusion in patients transfused with red blood cells stored for more than 24 days compared to those given red blood cells stored for less than 10 days [76]. An observational study linking whole blood pro-cessing information from transfused red blood cells (n = 91,065) to patient out-comes (23,634 patients) showed an association between inhospital mortality and fresh red blood cells that were prepared in Canada by a process termed whole blood filtration (whole blood donation cooled to 4 °C and stored for up to 72 h before leukoreduction and processing into red blood cell concentrate and plasma) [77]. Other observational studies have reported increased rates of deep venous thrombo-sis [78] and infection [66] in recipients transfused with fresher red blood cell com-ponents. Although authors of these exploratory studies controlled for known confounders in their analyses, the results should be considered hypothesis generat-ing as the risk of bias still exists.

Hypotheses involving three biologic modifiers – cell-free DNA (cfDNA), dam-age-associated molecular patterns (DAMPS), and extracellular vesicles (EVs) – have been proposed to explain these findings [79]. CfDNA, a form of circulating DNA released from granulocytes and other nucleated cells, is found in higher levels in fresh red blood cells [80]. CfDNA is able to engage and activate platelets and the coagulation cascade [81]. In sepsis and trauma, cfDNA has been shown to be prog-nostic [82, 83]. Therefore, higher cfDNA levels in components stored for a shorter duration could theoretically elicit harm. The role of DAMPs has also been ques-tioned as a contributing factor to the harm of fresh blood. DAMPs are mitochondrial and cellular DNA released from platelets and leukocytes with pro-inflammatory properties [84, 85]. Levels may vary substantially with blood processing methods, and fresh components with high DAMP levels could plausibly incur harm [86]. Lastly, EVs, microvesicles containing lipids, proteins, and microRNA may also play a role. EVs are derived from the cellular components of blood with paradoxical effects on the immune system, sometimes activating and other times deactivating [87–89]. Aside from storage duration during which EVs may accumulate [90], EV levels are also affected by blood processing methods [91]. Overall, there is biologic


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plausibility for harm of fresher blood. Further studies are required to explore this potential harm especially in neonates and some chronically transfused patients where fresh blood is commonly used.

New Frontiers: Donor Characteristics and Methods of Blood Processing

Beyond the age of blood, a new area of research is emerging which explores other variables known to affect red blood cell quality and the potential impact of these variables on transfusion recipients. Product variances are known to arise due to differences in donor age, donor sex, and the method of blood processing. Male donors produce components with higher hematocrits and hemoglobins [34, 36] and are less susceptible to membrane rigidity than female erythrocytes when exposed to adrenaline [92]. Male erythrocytes also exhibit higher grades of hemolysis than erythrocytes from female donors [36]. Donor age affects red blood cell quality as well; older donors produce red blood cells that demonstrate higher rates of hemolysis with storage [36]. Even the frequency of donation has been shown to impact product quality [93]. The method of blood processing is also known to affect product quality. In Canada, the red blood cell filtration method of blood production results in components with less red blood cell hemo-lysis and improved cellular integrity but larger plasma volumes than the whole blood filtration method [34]. Differences in levels of potassium, residual platelet and white cell counts, cytokines, EVs, DAMPs, and cfDNA also vary with pro-cessing methods [79].

The clinical impacts of these differences are just beginning to be explored. A single retrospective observational study of 30,503 transfused patients showed a dose-dependent effect on mortality with the transfusion of red blood cells from female donors and from donors younger than age 30 [94]. A second retro-spective observational study of 22,634 transfused adults showed increased inhospital mortality in the setting of sex mismatch between blood donor and recipient [95]. However, no associations between donor age and sex and recipi-ent mortality were found in another observational study of 968,264 transfused patients [96].

A recent Canadian cohort study of 91,065 red blood cell transfusions in 23,634 patients was the first to explore the impact of blood processing on transfusion recip-ient outcomes. The authors found that red blood cell filtered units were associated with a lower hazard ratio for recipient mortality compared to whole blood filtered components [77]. While still an area of research in its beginnings, understanding how donor characteristics and blood processing methods may ultimately alter the outcomes of patients is an extremely important area of work with far-reaching implications. Further studies are actively ongoing.


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81. Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, et al. Neutrophil extracel-lular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol. 2014;34(9):1977–84.

82. Margraf S, Logters T, Reipen J, Altrichter J, Scholz M, Windolf J. Neutrophil-derived circulat-ing free DNA (cf-DNA/NETs): a potential prognostic marker for posttraumatic development of inflammatory second hit and sepsis. Shock. 2008;30(4):352–8.

83. Dwivedi DJ, Toltl LJ, Swystun LL, Pogue J, Liaw KL, Weitz JI, et al. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care. 2012;16(4):R151.

84. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81(1):1–5.

85. Land WG. Transfusion-related acute lung injury: the work of DAMPs. Transfus Med Hemother. 2013;40(1):3–13.

86. Bakkour S, Acker JP, Chafets DM, Inglis HC, Norris PJ, Lee TH, et al. Manufacturing method affects mitochondrial DNA release and extracellular vesicle composition in stored red blood cells. Vox Sang. 2016;111(1):22–32.

87. Belizaire RM, Prakash PS, Richter JR, Robinson BR, Edwards MJ, Caldwell CC, et al. Microparticles from stored red blood cells activate neutrophils and cause lung injury after hemorrhage and resuscitation. J Am Coll Surg. 2012;214(4):648–55. discussion 56–7

88. Danesh A, Inglis HC, Jackman RP, Wu S, Deng X, Muench MO, et al. Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro. Blood. 2014;123(5):687–96.

89. Ren Y, Yang J, Xie R, Gao L, Yang Y, Fan H, et al. Exosomal-like vesicles with immune- modulatory features are present in human plasma and can induce CD4+ T-cell apoptosis in vitro. Transfusion. 2011;51(5):1002–11.

90. Lorincz AM, Timar CI, Marosvari KA, Veres DS, Otrokocsi L, Kittel A, et al. Effect of stor-age on physical and functional properties of extracellular vesicles derived from neutrophilic granulocytes. J Extracell Vesicles. 2014;3:25465.

91. Bicalho B, Pereira AS, Acker JP. Buffy coat (top/bottom)- and whole-blood filtration (top/top)-produced red cell concentrates differ in size of extracellular vesicles. Vox Sang. 2015;109(3):214–20.

92. Hilario S, Saldanha C, Martins e Silva J. An in vitro study of adrenaline effect on human eryth-rocyte properties in both gender. Clin Hemorheol Microcirc. 2003;28(2):89–98.

93. Jordan A, Acker J. Frequency of donation affects red blood cell product quality. Transfusion. 2016;56(S4):64A.

94. Chasse M, Tinmouth A, English SW, Acker JP, Wilson K, Knoll G, et al. Association of Blood Donor age and sex with Recipient Survival after red Blood Cell Transfusion. JAMA Intern Med. 2016;176(9):1307–14.

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98. Rygård SL, Jonsson AB, Madsen MB, Perner A, Holst LB, Johansson PI, et al. Effects of shorter versus longer storage time of transfused red blood cells in adult ICU patients: a system-atic review with meta-analysis and Trial sequential analysis. Intensive Care Med. 2018;44:204. https://doi.org/10.1007/s00134-018-5069-0. [Epub ahead of print].


https://doi.org/10.1007/s00134-018-5069-0


Chapter 17Anticoagulants in the ICU

Pablo Perez d’Empaire, Pulkit Bhuptani, Selina Ho, and C. David Mazer

Introduction

There are several indications for the use of anticoagulants in the ICU. Currently there are several different options for anticoagulation therapy, and these options have been increasing significantly over the last few years. A clear understanding of the pharma-cology of these anticoagulants is key for every clinician working in a critical care environment. The objective of this chapter is to provide the clinician with a working knowledge of currently available anticoagulants and their management in the ICU.

Unfractionated Heparin

Unfractionated heparin (UFH) is the most commonly used anticoagulant, especially in an ICU setting. Heparin is isolated from porcine intestine where it is stored in the mast cell granules. It consists of a mixture of polysaccharide chains of different

P. Perez d’Empaire, MD, FRCPC, FCCM Department of Anesthesia, St. Michael’s Hospital and Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

P. Bhuptani, BHSc, PharmD Pharmacy Department, St. Michael’s Hospital, Toronto, ON, Canada

S. Ho, MBChB, FRCA Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

C. D. Mazer, MD, FRCPC (*) Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

Li Ka Shing Knowledge Institute and Keenan Research Center of St. Michael’s Hospital, Toronto, ON, Canadae-mail: [email protected]



322

lengths, with molecular weights ranging from 3000 to 30,000 Dalton (da). The mechanism of action of heparin is via binding to antithrombin, increasing the rate of thrombin-AT complex formation (Fig. 17.1). Heparin also results in a decreased pro-duction of activated factor X (Xa) and thrombin (IIa), the principal factors respon-sible for clot formation. In addition, heparin can inhibit factors IX, XI, and XII [1].

Unfractionated heparin (UFH) is primarily administered as a continuous intravenous (IV) infusion, as its bioavailability is much more predictable (Table 17.1). The other route of administration is subcutaneous injection. The half-life of UFH is approximately 60 min at standard therapeutic doses; however, this can be prolonged with higher doses and longer durations of therapy. Dosing of UFH is weight-based (nomogram). Monitoring of heparin involves evaluating activated partial thromboplastin times (aPTT).

Significant adverse effects of heparin include bleeding and heparin-induced thrombocytopenia (HIT). Heparin-induced thrombocytopenia is a rare (≤5%) but potentially devastating complication which typically presents with thrombocytope-nia (50% decrease in platelets from baseline) after heparin re-exposure and can lead to systemic thrombosis approximately 5–10 days after initiation of UFH [2, 3].

Anticoagulation with heparin has significant advantages in an ICU setting as it can be rapidly reversed with protamine and has a short half-life of approximately 1 h (Table 17.2). Also, it is one of the few anticoagulants that can be readily admin-istered in patients with impaired renal function without any prolongation of the half-life. The recommendation for heparin reversal is 1 mg of protamine for every 100 units of unfractionated heparin [4].

Low-Molecular-Weight Heparins

Low-molecular-weight heparins (LMWHs) are purified from UFH, having an average molecular weight of approximately 5000 da. LMWHs have a similar pharmacological effect to UFH by increasing the thrombin-AT complex (Fig. 17.1).

Propagation

Initiation

Fibrin formation

Fibrinolysis

Fibrinogen

Plasminogen Plasmin

Fibrin

Ila

Il

X IX

IXaVIIIa

Va AT

Xa

Antiplatelet Agents

FondaparinuxLMWHDanaproidUFH

RivaroxabanApixabanEdoxabanBetrixaban

DabigatranArgatrobanBivalirudin

UFHDesirudin

TF/VIIa

Fig. 17.1 Coagulation pathway and the site of action of anticoagulants

P. Perez d’Empaire et al.

323

Table 17.1 Anticoagulant agent overview

Drug

Dose range (depends on indication) Renal excretion Onset time Half-lifea

Factor Xa inhibitors – oralApixaban 2.5–10 mg BID 25% 3–4 h 8–15 hBetrixaban 80–160 mg × 1

then 40–80 mg daily

11% 3–4 h 19–27 h

Edoxaban 30 or 60 mg daily

50% 1–2 h 10–14 h (for CrCL >50 ml/min)

Rivaroxaban 10–20 mg daily 33% (active drug) 1–3 h 7–17 hFactor Xa inhibitors – parenteralFondaparinux 2.5–10 mg SC

daily77% as unchanged drug

Peak activity at 2–3 h

17–21 h (prolonged with renal impairment and in the elderly)

Vitamin K antagonistWarfarin Variable Minimal renal

clearance of active drug

4 h (3–7 days to get INR within therapeutic range)

20–60 h

Direct thrombin inhibitor – oralDabigatran 110–220 mg

BID80% 1–3 h 7–35 h

Direct thrombin inhibitor – parenteralArgatroban 0.2–2 mcg/kg/

min IV then titrated to aPTT

Minimal Rapid 40–50 min. 180 min with liver dysfunction

Bivalirudin 0.75–1 mg/kg IV bolus; 0.15–2.5 mg/kg/hr

20% Immediate 25 min

Parenteral factor Xa and IIa inhibitorsDanaparoid 750–1250 units

SC Q8-12HorLoad: 1250–3750 units IV then 150–400 units/h

Extensive IV: immediateSC: peak activity at 4–5 h

25 h (up to 35 h with impaired renal function)

Dalteparin 2500–7500 units SC Q24Hor100–200 units/kg SC Q12H

Primarily renal elimination

IV: immediateSC: 1–2 h

3–5 h (SC route) aprolonged in renal impairment

(continued)

17 Anticoagulants in the ICU

324

In addition, the smaller fragments of LMWHs promote the inactivation of factor Xa [5].

LMWHs have a longer half-life than UFH. This allows for once or twice daily dosing that offers some advantages in medical patients but can be challenging for critically ill patients with a high risk of bleeding. Monitoring of anticoagulant activ-ity is usually not required; however, anti-Xa levels can be measured if monitoring is needed.

Enoxaparin is the only LMWH with specific recommendations for dose adjust-ments in patients with a creatinine clearance less than 30 mL/min (Table 17.1) [5]. Protamine has been used for the reversal of enoxaparin in a 1:1 ratio dosing; how-ever, it only produces partial reversal and is not approved for this use (Table 17.2). If protamine is contraindicated, the use of recombinant factor VIIa (rFVIIa) has also been suggested for severe cases of uncontrolled bleeding such as intracranial hem-orrhage, although there is potential risk of thrombotic complications [4].

Fondaparinux

Fondaparinux is a synthetic pentasaccharide that anticoagulation with specific anti- Xa activity through selective binding to antithrombin III (Fig. 17.1). The molecular structure of fondaparinux lacks a sugar domain; this is relevant because its presence can interact with platelet factor 4 that can lead to the development of HIT [6].

The route of administration for fondaparinux is subcutaneous, with 100% bio-availability (Table 17.1). Dosing is weight based and can be adjusted based on steady state. The elimination half-life is 17–21 h with renal clearance. Therefore,

Table 17.1 (continued)

Drug

Dose range (depends on indication) Renal excretion Onset time Half-lifea

Enoxaparin 30–40 mg SC Q12–24Hor1–1.5 mg/kg SC Q12–24H


SC: 3–5 h 4.5–7 h aprolonged in renal impairment

Tinzaparin 175 units/kg SC daily


SC: peak in 4–6 h

82 min aprolonged in renal impairment

Unfractionated heparin

5000 units SC Q8–12HorIV bolus plus infusion to target aPTT or anti-Xa activity

Minimal renal elimination at therapeutic doses. Renal elimination may play a role at very high doses

IV: immediateSC: 20–30 min

1–2 h

aHalf-lives provided as ranges given variability depending on renal function


325Ta

ble

17.2

A

gent

s us

ed to

rev

erse

eff

ects

of

antic

oagu

lant

dru

gs

Age

nt w

hich

may

re

vers

e dr

ug

effe

ct o

r m

anag

e bl

eedi

ngB

rand

nam

eA

ntic

oagu

lant

af

fect

ed/u

seM

echa

nism

Ons

etPe

ak /

dura

tion

Dos

eC

linic

al n

otes

Vita

min

KM

ephy

ton

War

fari

nL

eads

to p

rodu

ctio

n of

fu

nctio

nal c

lotti

ng

fact

ors

II, V

II, I

X, a

nd

X

IV: 1

–2 h

PO: 6

–10

hPe

ak:

IV: 1

2–14

hPO

: 24–

48 h

Dur

atio

n:

depe

nden

t on

war

fari

n in

tens

ity a

nd

Vita

min

K

dose

giv

en

1–10

mg

IV o

r PO

×

1. R

eass

ess

for

repe

at d

ose

at le

ast

12 h

aft

er in

itial

do

se if

IN

R >

1.4

Subc

utan

eous

and

IM

rou

tes

not

reco

mm

ende

dC

anno

t be

used

as

mon

othe

rapy

in

life-

thre

aten

ing

blee

ding

due

to

slow

ons

et o

f ac

tion

Prot

hrom

bin

Com

plex

C

once

ntra

te

(PC

C)

Oct

aple

xB

erip

lex

Kce

ntra

Dir

ect t

hrom

bin

inhi

bito

rsFa

ctor

Xa

inhi

bito

rsW

arfa

rin

Rep

lace

s co

agul

atio

n fa

ctor

s re

duce

d by

w

arfa

rin

incl

udin

g fa

ctor

s II

, VII

, IX

, and

X

(4

fact

or P

CC

) in

a

conc

entr

atio

n 25

tim

es

that

in F

FP. F

acto

rs

have

to b

e ac

tivat

ed

in v

ivo

≤5

min

Dur

atio

n:6–

8 h

(up

to

24 h

ours

if

used

with

V

itam

in K

)

Dep

ende

nt o

n IN

R

(for

war

fari

n re

vers

al),

co

agul

atio

n ab

norm

ality

and

pa

tient

wei

ght

~10–

50 u

nits

/kg

per

dose

Firs

t-lin

e op

tion

in

patie

nts

with

lif

e-th

reat

enin

g bl

eeds

whi

le o

n w

arfa

rin

and

INR

>1.

4 sh

ould

be

com

bine

d w

ith

vita

min

K to

pr

olon

g re

vers

alSt

ored

as

a ly

ophi

lized

pow

der

at r

oom

te

mpe

ratu

re –

pr

even

ts d

elay

s in

ad

min

istr

atio

nM

ay c

onta

in

hepa

rin,

thus

not

an

optio

n fo

r us

e in

pa

tient

s w

ith a

hi

stor

y of

HIT

or

alle

rgy

to h

epar

in

(con

tinue

d)


326

Tabl

e 17

.2

(con

tinue

d)

Act

ivat

ed P

CC

(a

PCC

)FE

IBA

Dir

ect t

hrom

bin

inhi

bito

rsFa

ctor

Xa

inhi

bito

rsFo

ndap

arin

ux

Res

tore

s co

agul

atio

n fa

ctor

s th

at a

re

depl

eted

by

war

fari

n,

Fact

ors

alre

ady

exis

t in

an a

ctiv

ated

for

m (

VII

pr

imar

ily a

nd s

mal

l am

ount

s of

II,

IX

, and

X

)

≤5

min

Dur

atio

n:6–

10 h

20–5

0 un

its/k

g pe

r do

seU

sed

prim

arily

w

hen

PCC

is

inef

fect

ive

(e.g

., D

OA

C r

ever

sal)

or

not a

vaila

ble

in

life-

thre

aten

ing

situ

atio

nsC

once

rn a

bout

po

tent

ial

prot

hrom

botic

ef

fect

Rec

ombi

nant

A

ctiv

ated

Fac

tor

VII

(rV

IIa)

Nov

osev

en

RT

Nia

stas

e R

T

Fact

or X

a in

hibi

tors

, D

irec

t thr

ombi

n in

hibi

tors

,L

MW

HFo

ndap

arin

ux

Thr

ombi

n ge

nera

tion

via

tissu

e fa

ctor

and

ac

tivat

ed p

late

lets

≤10

min

Dur

atio

n:

3–4

h,10

–90

mcg

/kg

per

dose

(ro

unde

d to

ne

ares

t mg

or

who

le v

ial)

Som

etim

es

cons

ider

ed f

or

resc

ue th

erap

y bu

t co

st a

nd p

oten

tial

thro

mbo

tic

com

plic

atio

ns a

re

limiti

ng f

acto

rsR

ecen

t stu

dies

hav

e qu

estio

ned

effe

ctiv

enes

s fo

r N

OA

C r

ever

sal

Not

rec

omm

ende

d fo

r w

arfa

rin

reve

rsal

: rap

idly

co

rrec

ts I

NR

, cl

inic

al im

pact

on

blee

ding

unc

erta

in

Age

nt w

hich

may

re

vers

e dr

ug

effe

ct o

r m

anag

e bl

eedi

ngB

rand

nam

eA

ntic

oagu

lant

af

fect

ed/u

seM

echa

nism

Ons

etPe

ak /

dura

tion

Dos

eC

linic

al n

otes


327

(Fre

sh)

Froz

en

Plas

ma

(FFP

or

FP)

–W

arfa

rin,

oth

er

antic

oagu

lant

s in

pat

ient

s w

ith

mas

sive

bl

eedi

ng

Con

tain

s va

ryin

g am

ount

s of

mos

t co

agul

atio

n fa

ctor

s

1–4

h de

pend

ing

on d

ose,

type

and

m

agni

tude

of

antic

oagu

latio

n

Dur

atio

n:6–

8 h

(var

ies

for

spec

ific

coag

ulat

ion

prot

eins

)

15 m

l/kg

roun

ded

to th

e ne

ares

t uni

t. M

ultip

le d

oses

may

be

req

uire

d

Onl

y us

ed a

s se

cond

- or

thir

d-lin

e ag

ent w

hen

othe

r tr

eatm

ents

(e.

g.,

vita

min

K o

r PC

C)

not a

vaila

ble

Nee

ds ti

me

to th

aw

(not

idea

l in

an

emer

genc

y si

tuat

ion)

Hig

h va

riab

ility

in

prop

ortio

n of

co

agul

atio

n fa

ctor

s be

twee

n un

itsL

arge

vol

umes

may

be

req

uire

d fo

r re

vers

alPr

otam

ine

–H

epar

in,

LM

WH

Form

s a

stab

le s

alt i

n th

e pr

esen

ce o

f he

pari

n in

activ

atin

g its

an

ticoa

gula

nt

prop

ertie

s. W

ith

LM

WH

may

in

com

plet

ely

reve

rse

anti-

fact

or X

a ac

tivity

≤5

min

Dur

atio

n:

irre

vers

ible

an

d do

se

depe

nden

t

1 m

g of

pro

tam

ine

per

100

units

of

hepa

rin

(max

dos

e,

50 m

g) a

t a r

ate

not

exce

edin

g 5

mg

per

min

ute

Pote

ntia

l for

re

boun

d w

ith

subc

utan

eous

he

pari

n, L

MW

H

dose

s or

with

larg

e IV

hep

arin

dos

esA

dditi

onal

pr

otam

ine

may

be

indi

cate

d in

2–4

h

(con

tinue

d)


328

Tabl

e 17

.2

(con

tinue

d)

Cry

opre

cipi

tate

Fibr

inol

ytic

s/th

rom

boly

tics

Fibr

inog

en

supp

lem

enta

tion

≤10

min

Hal

f-lif

e:

100–

150

h10

uni

tsA

lso

cont

ains

von

W

illeb

rand

fac

tor,

fact

or V

III,

fac

tor

XII

I, a

nd

fibro

nect

inFi

brin

ogen

co

ncen

trat

e m

ay b

e an

alte

rnat

ive

if

avai

labl

eA

ntifi

brin

olyt

ics

Cyk

loka

pron

(t

rane

xam

ic

acid

)A

mic

ar

(am

inoc

apro

ic

acid

)

Fibr

inol

ytic

s/th

rom

boly

tics

Dir

ect t

hrom

bin

inhi

bito

rsFa

ctor

Xa

inhi

bito

rsL

MW

H

Bin

ds to

lysi

ne b

indi

ng

site

s on

pla

smin

ogen

2–5

min

Hal

f-lif

e:

2–4

hT

rane

xam

ic a

cid

1–2

g or

ε-

amin

ocap

roic

ac

id 4

–5 g

IV

(h

ighe

r do

ses

in

card

iac

surg

ery)

May

pre

disp

ose

to

re-t

hrom

bosi

s if

us

ed to

rev

erse

fib

rino

lytic

dru

gsC

omm

only

use

d as

a

gene

ral

hem

osta

tic

(pro

phyl

axis

or

trea

tmen

t) in

tr

aum

a, c

ardi

ac

surg

ery,

and

ob

stet

rica

l ble

edin

gH

igh

dose

s m

ay b

e as

soci

ated

with

se

izur

es in

car

diac

su

rger

y

Age

nt w

hich

may

re

vers

e dr

ug

effe

ct o

r m

anag

e bl

eedi

ngB

rand

nam

eA

ntic

oagu

lant

af

fect

ed/u

seM

echa

nism

Ons

etPe

ak /

dura

tion

Dos

eC

linic

al n

otes


329

Idar

uciz

umab

Prax

bind

Dab

igat

ran

Ant

ibod

y th

at b

inds

sp

ecifi

cally

to

dabi

gatr

an o

nly

ther

eby

neut

raliz

ing

its

antic

oagu

lant

eff

ects

Imm

edia

tePe

ak: 2

.5–4

hD

urat

ion:

24

h

5 gr

ams

IV b

olus

ov

er 1

0 m

in (

2.5

g IV

× 2

via

ls e

ach

over

5 m

in)

Use

d fo

r em

erge

ncy

situ

atio

ns o

f lif

e-th

reat

enin

g bl

eedi

ng f

rom

da

biga

tran

or

need

fo

r ur

gent

sur

gery

Cir

apar

anta

g(P

ER

977)

U

nder

clin

ical

de

velo

pmen

t

Dir

ect t

hrom

bin

inhi

bito

rsFa

ctor

Xa

inhi

bito

rsH

epar

in,

LM

WH

Fond

apar

inux

Bin

ds d

irec

tly to

a

vari

ety

of

antic

oagu

lant

s th

roug

h no

n-co

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the use of fondaparinux is contraindicated in patients with severe renal dysfunction (CrCl less than 30 mL/min), and it is not a commonly used in critically ill patients.

Currently, there are no agents available to specifically reverse the anticoagulation effects of fondaparinux. Both cryoprecipitate and FFP may be considered to manage adverse bleeding. The use of activated prothrombin complex concentrates (aPCC) is recommended, and rFVIIa can also be considered for severe or intractable bleeding (Table 17.2). Protamine should not be used to reverse the effect of fondaparinux [4].

Parenteral Direct Thrombin Inhibitors

Parenteral direct thrombin inhibitors (DTIs) block the action of thrombin by bind-ing to one (univalent) or two (bivalent) of its three domains. The parenteral direct thrombin inhibitors that are currently available include bivalirudin, desirudin, and argatroban [7]. Dabigatran is an oral DTI which is discussed later in this chapter.

Bivalirudin

Bivalirudin is a synthetic analogue of hirudin and is a polypeptide with a molecular weight of 4000 da. Bivalirudin reversibly binds to thrombin (Fig. 17.1). After bind-ing, the complex is slowly cleaved by thrombin, enabling return of thrombin activ-ity. Bivalirudin is approved as an alternative to heparin in patients with or without HIT undergoing PCI and percutaneous transluminal coronary angioplasty [8] and cardiopulmonary bypass [9]. Also more recently, it has been used as alternative for heparin for patients on ECMO [10].

Bivalirudin has a rapid onset of action and a half-life of only 25 min making it an option during PCI (Table 17.1). Although only 20% of the dose is cleared by the kidneys, the dose must be adjusted in patients with moderate to severe renal insuf-ficiency (CrCl <30 mL/ min). The main route of bivalirudin clearance is by proteo-lytic cleavage and hepatic metabolism, and unlike lepirudin, it is not immunogenic. Because of its safety profile and short half-life, bivalirudin is used as an alternative to heparin in patients with HIT undergoing cardiopulmonary bypass surgery.

There is no specific reversal agent for bivalirudin. However, in the case of signifi-cant bleeding that requires immediate treatment, the use of aPCC or four-factor PCC has been suggested (Table 17.2). The use of rFVIIa or FFP is not recom-mended [4].

Argatroban

Argatroban is a synthetic competitive univalent DTI with a small-molecular-weight of 500 da. The pharmacological effect is by binding to the active site of thrombin, forming a reversible complex (Fig. 17.1). Argatroban is approved for the prevention


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or treatment of HIT-associated thrombosis and as an alternative to heparin in patients with a history of HIT undergoing PCI [11].

Argatroban has a half-life of approximately 45 min and is metabolized in the liver via the CYP450 3A4/5 enzyme system. As a result, dose adjustments are nec-essary in patients with hepatic, but not renal impairment. Argatroban is given as a continuous infusion at an initial rate of 2 μg/kg per minute in patients with normal hepatic function and 0.5 μg/kg per minute in patients with hepatic insufficiency, heart failure, multiple organ system failure, severe anasarca, or after cardiac surgery (Table 17.1). The dose of argatroban is titrated to achieve a goal aPTT of 1.5–3.0 times the patient’s baseline. Activated clotting time can also be used to monitor its effect with a usual target >300 s [12].

Argatroban increases the INR, as well as other thrombin-dependent coagulation tests to a greater extent than other DTIs at therapeutic doses. This can create a chal-lenge when transitioning from argatroban to vitamin K antagonists [4].

There is no specific reversal agent for argatroban; however, in the case of signifi-cant bleeding, the use of aPCC or four-factor PCC has been suggested (Table 17.2). The use of rFVIIa or FFP is not recommended.

Desirudin

Desirudin (another recombinant hirudin analogue) is approved in the United States for the prophylaxis of DVT in patients undergoing elective hip replacement surgery. Of note, desirudin has also been studied extensively in patients with stable angina undergoing PTCA. Desirudin is primarily eliminated by the kidneys, so patients with renal impairment require monitoring, and activated partial thromboplastin time (aPTT) can be used. However, desirudin is not commonly used, especially with newer oral anticoagulation agents available [7].

Fibrinolytics

Fibrinolytic agents are drugs lyse thrombi through conversion plasminogen to plas-min, which then degrades fibrin. The first-generation fibrinolytics, streptokinase and urokinase, are fibrin nonspecific and cause systemic fibrinolysis. Therefore, they have disadvantages such as increased bleeding, allergic reactions, and limited efficacy. The newer-generation agents are fibrin specific (alteplase, reteplase, and tenecteplase) [13].

There are multiple uses for fibrinolytics, which include (1) acute ST-segment elevation myocardial infarction (alteplase, reteplase, and tenecteplase), (2) acute ischemic stroke (alteplase, reteplase-unlabeled use), (3) pulmonary embolism (alteplase, reteplase-unlabeled use), (4) peripheral arterial occlusion (alteplase, reteplase-unlabeled use), and (5) occlusion of a central venous catheter (alteplase, reteplase-unlabeled use).


332

Currently, there are no available antidotes for the fibrinolytic agents. All fibrino-lytic agents have short half-lives; however in the case of significant hemorrhage, the use of cryoprecipitate and tranexamic acid has been suggested [4].

Warfarin

Warfarin is an oral anticoagulant that exerts its therapeutic effect by inhibiting vita-min K epoxide reductase mediated activation of coagulation factors II, VII, IX, and X as well as proteins C and S. Warfarin has been the standard of long-term antico-agulation for over 50 years in managing a wide variety of thromboembolic compli-cations (both as prophylaxis and as treatment). Specifically, it is indicated for the treatment of venous thromboembolism and prevention of embolic complications in patients with atrial fibrillation or insertion of a nonbiological prosthetic cardiac valve.

The significant interpatient and intrapatient therapeutic variability of warfarin complicates its dosing. Concurrent medications, diet, coexisting disease states, genetic predispositions, alcohol intake, drug compliance, and body mass can all affect therapeutic activity. Warfarin activity is monitored by measuring the INR (international normalized ratio). The target INR for most indications is between 2 and 3. A higher INR of 2.5–3.5 is targeted in patients with certain types of mechani-cal heart valves or coagulation disorders. Peak concentrations are reached within 4 h; however, peak anticoagulant effects are only attained between 24 and 96 h as it takes several days to suppress the synthesis of the coagulation factors with longer half-lives (Table 17.1) [14].

The incidence of major bleeding in patients maintained on warfarin therapy is approximately 1.5% per year. The risk of bleeding is increased in patients with pre-existing bleeding disorders, liver or renal dysfunction, cerebrovascular disease, thrombocytopenia, concurrent antithrombotic therapy, or prior episode(s) of major bleeding.

A large proportion of patients maintained on warfarin at home who present to a critical care setting may need to be assessed for reversal of anticoagulant effect. This is to mitigate the risk due to limb or life-threatening bleeding or to facilitate invasive surgery or another procedure associated with a high bleeding risk.

Given the prothrombotic potential for some reversal agents, caution should be exercised when attempting to reverse the effect of warfarin, especially with PCC and rVIIa. A thorough risk versus benefit evaluation should be made prior to initiat-ing reversal in the following patients: intracerebral hemorrhage due to cerebral venous thrombosis, concurrent life-threatening thrombosis, HIT, disseminated intravascular coagulation, and acute ischemia.

The management of warfarin reversal is largely dependent on whether the patient is having clinically significant active bleeding and/or how quickly reversal is required. Vitamin K (phytonadione), PCC, aPCC, and rFVIIa can all be used as warfarin reversal agents (Table 17.2). While vitamin K monotherapy may be suffi-


333

cient in non-bleeding patients, additional agents, such as PCC, may need to be used in cases of major life-threatening bleeds. Figure 17.2 summarizes strategies to man-age warfarin in the critical care setting [15].

Novel Oral Anticoagulants

Novel oral anticoagulants (NOACs) produce their therapeutic effects by targeting specific serine proteases in the coagulation pathway. They are also known as DOACs (direct oral anticoagulants) or TSOACs (target-specific oral anticoagu-lants). The two main classes of NOACs in clinical use are direct factor Xa inhibi-tors and direct thrombin inhibitors. Due to the convenience and favorable balance of thrombotic and hemorrhagic outcomes, NOACs are increasingly being encoun-tered in the ICU.

NOACs have a high oral bioavailability and a wide therapeutic window that gen-erally does not require titration or monitoring. There is a reduced risk of pharmaco-kinetic interactions with other drugs compared to warfarin, although a potential still remains [16].

Studies comparing NOACs with conventional anticoagulants suggest NOACs are superior for the prevention of thromboembolic events (DVT and PE), and they reduce the risk of stroke in patients with atrial fibrillation with equal or more efficacy

No bleedingBleeding

Major bleed*

Patient presents to critical setting with warfarin exposure

• Hold warfarin• PCC 40-40 units/kg depending on INR

• Re-check INR 15–30 min then at 6 h

• Hold warfarin• Vitamin K IV 1–3 mg x 1

• Q6H INR monitoring until stable

• Lower or limit dose

• More frequent INR checks until stable• Resume at lower dose

• Omit 1–2 doses

• Daily INR until stable Resume at lower dose

• Consider low dose oral Vitamin K if high risk of bleeding^

Imminent Surgery

Urgent surgery (< 6 h)

PCC + Vitamin K IV Vitamin K IV alone sufficient

*Major Bleed: limb or life-threatening bleeding or active bleeding with hemodynamic compromise^Age > 70, liver disease, renal failure, thrombocytopenia, uncontrolled HTN, prior bleeding, recent major surgery,concurrent anti-platelets/NSAIDs#The IV should be used in emergent situations as it has a faster onset of action (avoid Subcut and IM routes ofadministration – erratic and delayed absorption)Abbreviations: PCC – Prothrombin Complex Concentrate, FFP – Fresh Frozen Plasma, INR: International Normalized Ratio

Delayed surgery (> 6 h)

• Hold warfarin

• Daily INR until stable

• Vitamin K 2.5–5 mg PO x 1

• Doses rounded to the nearest 500 units (20 mL vial), Max single dose = 3000 units

• lf INR unknown, give 2000 units (80mL)

• FFP 15ml/kg rounded to nearest unit, if PCC contraindicated (HIT or allergy)

• Vitamin K 10mg IV x 1#

(omit if < 6 h reversal required). Can be repeated in 12 h

Non-major bleed INR < 5 INR 5-9 INR > 9

Fig. 17.2 An approach to management of bleeding patients on warfarin in the critical care setting


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and reduced bleeding complications. All-cause mortality with NOACs is lower than with warfarin [17–21].

NOACs are contraindicated in patients with mechanical heart valves who require anticoagulation, as there is an increased risk of thromboembolic events and bleed-ing. Like many drugs, there is little experience with NOACs in the pregnant patient, and therefore, LMWH remains the mainstay of anticoagulation in this population.

Most NOACs are excreted by the kidneys, making them unsuitable in patients with severe renal impairment and less desirable in the hospital setting. With appro-priate dose adjustments, they can be used with caution in patients with less severe renal impairment [22, 24–27].

Direct Thrombin Inhibitors

Dabigatran

Dabigatran is the first of a class of oral direct thrombin inhibitors. It is a prodrug that is converted to its active form by nonspecific liver and plasma esterases. In the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial, dabiga-tran was superior to warfarin in preventing ischemic stroke in patients with non- valvular atrial fibrillation while lowering rate of life-threatening bleeding and intracranial hemorrhage [17]. Dabigatran plasma concentration peaks at 1.5 h, with maximal anticoagulant effect within 1–2 h (Table 17.1). In patients with normal renal function, the half-life is approximately 12–17 h. Being a substrate of the P-glycoprotein, dabigatran is subject to interactions with other drugs that induce or inhibit this system, resulting in diminished or enhanced anticoagulant effects. Dabigatran is predominately excreted unchanged by the kidneys and may be removed by dialysis, with up to 60% of the plasma concentration removed in 2–3 h. There is a theoretical risk of re-anticoagulation due to its high volume of distribution.

Dabigatran is used for the treatment and secondary prevention of venous throm-boembolism, pulmonary embolism, and prevention of embolic events in patients with non-valvular atrial fibrillation [22].

Due to predictable plasma levels, therapeutic drug monitoring is not necessary; however, a baseline platelet count and renal and coagulation profiles are recom-mended. The Hemoclot Thrombin Inhibitor assay and the Ecarin clotting time (ECT) assay can quantify the anticoagulant effects of dabigatran, but are not widely available (Table 17.3). Conventional coagulation tests will generally be prolonged, with thrombin time (TT) being particularly sensitive demonstrating a linear rela-tionship with dabigatran levels in the therapeutic range. It is less useful at supratherapeutic levels. Prothrombin time/international normalized ratio (PT/INR) should not be used to assess dabigatran effect.


335

Managing the Bleeding Patient on Dabigatran

Some coagulation tests may provide useful information in the bleeding patient on dabigatran. An elevated TT suggests an active dabigatran effect, and an elevated aPTT suggests recent (<12 h) administration. Management of bleeding in a patient on dabigatran should include usual resuscitative and supportive measures, and acti-vated charcoal can be given if ingestion occurred within 2 h. Antifibrinolytic treat-ment with tranexamic acid may also be considered. Prothrombin complex and high-dose fresh frozen plasma have been used in case reports. Dabigatran is the only NOAC that can be removed by hemodialysis (Fig. 17.3).

Idarucizumab (Praxbind) is a humanized anti-dabigatran monoclonal antibody fragment which is a direct and specific reversal agent of dabigatran used for emer-gency reversal of anticoagulation (e.g., imminent risk of mortality or major morbidity from dabigatran-associated bleeding or if lifesaving surgery is immi-nently required) (Table 17.2). The usual dose of idarucizumab is 5 g. It should not be required in those with a normal TT. Its use in combination with “procoagulant” reversal agents (e.g., aPCC) is unclear; the possible increased risk of thrombosis should be balanced against that of continued bleeding [23].

Table 17.3 Laboratory tests for detecting NOACs

Direct thrombin inhibitor (dabigatran)

Direct FXa inhibitora (apixaban, rivaroxaban, or edoxaban)

Preferred assays(quantitative; provide an estimate of anticoagulant drug levels)

HEMOCLOT dilute thrombin timeEcarin clotting timeAssays may not be available in the emergency setting

Anti-FXa assays (specifically calibrated for agent)Assays may not be available in the emergency setting

Alternative assays (qualitative; indicate the presence or absence of drug effect)

aPTT assay: ↑ aPTT suggests dabigatran

presence Normal aPTT does not rule

out the presence of dabigatran

TT assay: ↑ TT suggests presence of

dabigatran Normal TT suggests the

absence of dabigatran Viscoelastic test (TEG/

ROTEM) Clot initiation time may be

prolonged; normal result does not rule out presence of drug

PT assay obtained in seconds with sensitive reagentsPT assay: ↑ PT suggests presence of

FXa inhibitor Normal PT does not rule out

the presence of FXa inhibitor Viscoelastic test (TEG/

ROTEM) Clot initiation time may be

prolonged; normal result does not rule out the presence of drug

aEffect of apixaban on routine coagulation test is less pronounced than the effect of rivaroxaban. Adapted from Levy et al. [33, 35] and Thrombosis Canada [34]


336

Direct Factor Xa Inhibitors

Rivaroxaban

Rivaroxaban is a direct factor Xa inhibitor with a half-life of 7–17 h, prolonged in the elderly (Table 17.1). It has an oral bioavailability of 80–100% and plasma con-centrations peak at 2–4 h after intake. Rivaroxaban is metabolized by CYP3A4 in

Determine type and timing of oral anticoagulant administered

Routine and/or specialized coagulation testing

If actively bleeding: • local compression and/or surgical hemostasis • consider antifibrinolytics and/or other blood conservation options • guide line and/or protocol based transfusion • consult hematologist

If antidote not available +/- persistent and/or severe bleeding, reassess hemostasis

Transfusion support as indicated

Consider activated charcoal ≤ if 2 h

Dabigatran Xa Inhibitors (Rivaroxaban, Apixaban,

Edoxaban, Betrixaban)

Consider hemodialysis and maintain urine output and/or renal clearance

Reassess coagulation status & surgical and/or interventional options and consult hematologist

Consider activated factors (eg. aPCC, ?rFVIIa)

Antidote if available/approved(Andexanet alfa, ciraparantag)

(for life threatening bleeding or need for urgent surgery)

Antidote (Idaracizumab) if available (for life threatening bleeding or need

for urgent surgery)

If antidote not available +/- persistent and/or severe bleeding, reassess hemostasis

Transfusion support as indicated

4 factor PCC 4 factor PCC

Reassess coagulation status & surgical and/or interventional options and consult hematologist

Consider activated factors (eg. aPCC, ?rFVIIa)

Maintain urine output and/or renal clearance

Fig. 17.3 An approach to manage novel oral anticoagulant associated bleeding in the critical care setting


337

the CYP450 system and P-glycoprotein and may interact with other drugs. It is administered as a once daily dose with a reliable therapeutic profile and should be taken with food.

Rivaroxaban undergoes hepatic metabolism and is excreted by the kidneys (50%) and in the feces. A significant proportion is also excreted unchanged by the kidneys. In patients with renal impairment (CrCl 15–30 ml/min) or signifi-cant hepatic impairment (Child-Pugh Classes B and C with coagulopathy), the dose is reduced or avoided altogether. Rivaroxaban is highly protein bound (>90%) and cannot be removed via hemodialysis. Current indications for rivar-oxaban include stroke prevention in patients with non-valvular atrial fibrillation, venous thromboembolism prophylaxis after hip or knee replacement surgery and treatment, and secondary prevention of deep vein thrombosis and pulmonary embolism [24].

Apixaban

Apixaban has a high oral bioavailability (80%) and is unaffected by food intake. Maximal plasma concentrations are rapidly achieved within 0.5–2 h after ingestion, and it has a half-life of 8–15 h (Table 17.1). Apixaban is highly protein bound, pre-cluding hemodialysis removal. It is metabolized by the CYP3A4 in the CYP450 system. Apixaban has a favorable pharmacokinetic profile with minimal renal excretion and rapid spontaneous reversal. In the ARISTOTLE (Apixaban for Reduction in Stroke and Other thromboembolic Events in Atrial Fibrillation) trial, no dose adjustments were made for mild and moderate renal impairment without any significant bleeding complications [19].

Apixaban is superior to warfarin in preventing stroke in atrial fibrillation and venous thromboembolism prophylaxis, with lower rates of major bleeding and lower overall mortality (ARISTOTLE and AVERROES trials) [19, 20]. The ADVANCE 2 trial demonstrated the non-inferiority of apixaban to enoxaparin 40 mg daily for the prevention of deep vein thrombosis [21]. From indirect compari-sons, apixaban appears to have the lower risk of major hemorrhage compared to other factor Xa inhibitors.

Edoxaban and Betrixaban

Edoxaban is used for the prevention and treatment of venous thromboembolism and in stroke prevention in patients with atrial fibrillation, while betrixaban is used in the prevention of venous thromboembolism in hospitalized adult medical patients. Common to other NOACs, their plasma concentration are predictable and do not require monitoring [26, 27].


338

The half-life of edoxaban is approximately 10–14 h, while betrixaban is longer at 19–27 h (Table 17.1). Both agents undergo renal excretion and require dose adjustment or avoidance according to renal function. They are substrates for the P-glycoprotein system and may be subject to drug interactions. Patients with very abnormal renal function (15 mL/minute < CrCl > 95 mL/minute) should not receive edoxaban, as there is reduced efficacy in non-valvular atrial fibrillation.

Monitoring of Factor Xa Inhibitors

The plasma concentrations of direct factor Xa inhibitors are reliably predictable over their therapeutic range. Their anticoagulant effects can be monitored with anti- Xa assays with specialized calibrations, distinct from that used for LMWH monitor-ing (Table 17.3).

Direct factor Xa inhibitors may variably prolong the PT, limiting its usefulness. Rivaroxaban prolongs the PT in a linear dose-response manner, although the abso-lute values will vary according to the thromboplastin reagent. In contrast, apixaban has little impact on the PT, but its plasma levels do correlate with a diluted TT assay [28, 29].

Managing the Bleeding Patient on Direct Factor Xa Inhibitors

Andexanet alfa is a recombinant protein that rapidly and competitively sequesters direct factor Xa inhibitors (Table 17.2). In the ANNEX-A and ANNEX-R trials, andexanet alfa reduced anti- factor Xa activity by 94% and 92% and fully restored thrombin generation in 100% and 96% of patients treated with apixaban and rivar-oxaban, respectively, although a rebound increase in anti-factor Xa activity was seen after discontinuation of the infusion [30–32]. Andexanet alfa was recently approved by the FDA for reversal of rivaroxaban or apixaban anticoagulation in the setting of life-threatening or uncontrolled bleeding.

Ciraparantag (PER977) is a small, cationic molecule that nonspecifically binds to all factor Xa inhibitors, dabigatran and heparins, via hydrogen bonds and which is undergoing clinical trial evaluation [30, 31].

In hemorrhage or overdose, conventional coagulation assays may not be repre-sentative of the true anticoagulant effect. Management includes usual resuscitative and supportive measures, including transfusion, antifibrinolytics (tranexamic acid), and as indicated for bleeding. Ensuring adequate volume status and supporting renal function will facilitate drug excretion (Fig. 17.3).

The anticoagulant effects of factor Xa inhibitors can be treated with administra-tion of coagulation factors in the form of PCC and aPCC. Recombinant factor VIIa has been used for rescue therapy in unresponsive or massively bleeding patients. In refractory hemorrhage, renal impairment and/or severe overdose and extracorporeal


339

elimination via plasma exchange may be considered. Activated charcoal may be a beneficial adjunct if there is a history of recent ingestion (<2–6 h) [28, 29].

Conclusion

Patients in the ICU may be exposed to or require a wide range of anticoagulant drugs which may predispose them to bleeding complications. A variety of strategies are available to treat bleeding in these patients, and reinitiation of anticoagulant therapy should be considered as soon as clinically indicated. Understanding the physiology and pharmacology of this evolving field is important for optimal patient management.

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35. Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagu-lants. Nat Rev Cardiol. 2018 Jan 18;15:273. https://doi.org/10.1038/nrcardio.2017.223.


http://docs.boehringer-ingelheim.com/Prescribing Information/PIs/Pradaxa/Pradaxa.pdf

https://www.xareltohcp.com/shared/product/xarelto/prescribing-information.pdf

https://packageinserts.bms.com/pi/pi_eliquis.pdf

http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa&inline=true

http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa&inline=true



http://thrombosiscanada.ca/guides/pdfs/NOAC_Monitoring.pdf

https://doi.org/10.1038/nrcardio.2017.223


Chapter 18Therapeutic Apheresis for Hematologic Emergencies

Jori E. May and Marisa B. Marques

Introduction

According to the American Society for Apheresis (ASFA), apheresis is “a procedure in which blood of the patient or donor is passed through a medical device which separates one or more components of blood and returns the remainder with or with-out extracorporeal treatment or replacement of the separated component” [1]. Thus, apheresis is a broad term that includes a wide range of interventions which, when used for treatment, are referred to as therapeutic apheresis (TA).

In the intensive care setting, TA procedures allow for rapid correction of many hematologic emergencies. There are four types of TA that could be used in critically ill patients, which are defined by ASFA as follows [1]:

• Therapeutic plasma exchange (TPE): “A therapeutic procedure in which blood of the patient is passed through a medical device which separates plasma from other components of blood. The plasma is removed and replaced with a replace-ment solution such as colloid solution (e.g., albumin and/or plasma) or a combi-nation of crystalloid/colloid solution.”

• Red cell exchange (RCE): “A therapeutic procedure in which blood of the patient is passed through a medical device which separates red blood cells from other components of blood. The patient’s red blood cells are removed and replaced with donor red blood cells and colloid solution.”

• Cellular depletion: “A procedure in which blood of the patient or the donor is passed through a medical device which separates a given cell line, collects the selected cells, and returns the remainder of the patient’s blood with or without

J. E. May Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

M. B. Marques (*) Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAe-mail: [email protected]



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the addition of replacement fluid. This general term includes leukocytapheresis for removal of white blood cells, erythrocytapheresis for removal of red blood cells, and platelet apheresis for removal of platelets.”

• Extracorporeal photopheresis (ECP): “A therapeutic procedure in which the buffy coat is separated from the patient’s blood, treated extracorporeally with a photoactive compound (e.g., psoralens) and exposed to ultraviolet A light then subsequently reinfused to the patient during the same procedure.”

Although each TA modality has unique clinical applications, there are unifying principles that apply to them. This chapter will first explore the technical and patient-specific aspects of TA followed by hematologic indications in the intensive care setting.

General Considerations

Apheresis Technology

The separation of constituents of the patient’s blood can be achieved by two means: centrifugation or filtration. In centrifugation, the process is based on the specific gravity of plasma and the various blood cells; in filtration, the blood passes through a filter with variable pore sizes [2]. In the United States and Canada, all instruments approved for TA are centrifugation-based, while filtration is more commonly used in Europe and Asia.

In addition, TA can be performed via two methods of flow: continuous (most commonly used) or sequential/intermittent. In continuous flow procedures, blood is removed and processed inside the apheresis device, while the discarded component (i.e., plasma in TPE) is moved to a waste bag, and the remaining components returned to the patient mixed with a replacement fluid. In contrast, sequential/intermittent flow involves pulling a discrete volume of blood which is processed in the TA device and reinfused before any additional blood is drawn for further separation [2].

Vascular Access

An essential aspect of TA is appropriate vascular access. Considerations when selecting vascular access include the type of procedure and the acuity, frequency, and planned duration of the treatment series. There are also patient-specific factors to consider such as vascular anatomy and other active disease states [3]. Although peripheral venous catheters may be used in certain TA procedures in nonemergent situations, central venous catheters are recommended in the critical care setting [4]. Catheter size should be at least 11.5 F in adults, 10 F in children 20–40 kg, and 8 F in children <20 kg, and catheters should be non-collapsible to withstand the high negative pressure exerted by the device in order to collect the blood [2]. For the rare

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instances when intermittent flow is used, a single lumen catheter is sufficient, but dual lumens are required for continuous flow to allow for concurrent blood removal and reinfusion [5].

It is also essential that providers follow Centers for Disease Control (CDC) guidelines for proper sterile insertion of central access to avoid catheter-associated infections [6]. Non-tunneled catheters are preferable for emergent use due to ease of insertion at the bedside. They can be used safely for up to 2 weeks [3]. If catheter insertion is nonemergent and a longer duration of TA is expected, tunneled catheters are another option with the added advantage of a lower infection risk. The site of insertion depends on multiple factors including the patient’s anatomy and the pro-vider’s experience, but internal jugular placement is typically preferred over femoral or subclavian due to the risk of infection and subclavian stenosis, respectively [4].

Exchange Volume

The volume of blood processed and/or exchanged depends on the type of TA and patient’s specific parameters.

For TPE, the volume of plasma exchanged depends on the patient’s height, weight, and hematocrit which are used to estimate the plasma volume (PV) [7]. The target volume exchanged for most TPEs, with the exception of a new patient with thrombotic thrombocytopenic purpura (TTP), is 1 PV per session [7]. Removal of 1–1.4 times the PV decreases high-molecular-weight substances by 63–75% [8]. Larger volumes increase treatment duration, cost, and the risk of hypofibrinogen-emia and hemodynamic compromise.

In RCE procedures, the volume of red cells replaced with donor packed red blood cell (PRBC) units similarly depends on the patient’s height and weight but also takes into account disease-specific considerations. For sickle cell disease, the exchange volume must account for the baseline and target hematocrits and the per-centage of hemoglobin S pre- and post-RCE, while for severe malaria, the exchange volume must account for the percentage of infected red cells.

For cellular depletions such as leukocytapheresis, the goal of each procedure is to process at least two total blood volumes per session to achieve a clinically signifi-cant decrease in the number of leukemic circulating cells. Depending on the rate of synthesis in the bone marrow, more than one leukocytapheresis may be necessary.

In ECP, the volume of blood processed is set by the device and is the same for all adult patients.

Replacement Fluid

In order to maintain euvolemia, TA requires infusion of a replacement solution to compensate for the volume of plasma or cellular products removed. The type of fluid varies with the type of TA procedure as well as the clinical scenario: for TPE,

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it could be 5% albumin or donor plasma, and for RCE, PRBCs with or without 5% albumin. Saline alone is rarely used in TA, as it is hypotonic and extravasates from the vasculature resulting in edema and/or hypotension. Saline may be used during cellular depletions because the total volume removed is a small fraction of the patient’s blood volume, but 5% albumin is more often utilized. With the exception of treating a patient with TTP where plasma is essential to replenish ADAMTS13, plasma is avoided during TPE due to the potential risk of infection transmission and transfusion reactions.

Thus, 5% albumin is the preferred replacement solution for most TA procedures because it is isosmotic and only rarely leads to reactions. One serious reaction that may occur is severe hypotension due to the accumulation of bradykinin in patients taking angiotensin-converting enzyme (ACE) inhibitors (see section “Adverse events”). Rarely, patients may experience anaphylactic reactions to albumin, pre-sumably due to the formation of antibodies against polymerized albumin [8].

Another potential consequence of using 5% albumin as replacement fluid is hypofibrinogenemia and bleeding. In order to avoid this complication, it is advis-able to measure the patient’s fibrinogen prior to the first TPE, especially if there is concern for liver disease or transient hepatic dysfunction. Knowing that 63% of fibrinogen will be removed in each TPE, the post-TPE level can be predicted and a determination of the safety of using 5% albumin made. Furthermore, measuring the fibrinogen prior to starting all subsequent TPEs ensures that this risk is avoided. If necessary, the replacement fluid may be a combination of 5% albumin and plasma to replace fibrinogen. In patients with normal liver synthetic activity, the fibrinogen concentration is expected to return to the baseline value after 48 h. Of note, the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are not sensitive enough to detect low fibrinogen unless it is severely depleted and should not be used to guide the choice of replacement fluid [7].

In patients that necessitate weeks to months of TPE with 5% albumin, which is not usually the case in critically ill patients, hypoimmunoglobulinemia may also develop. For such patients, especially when a serious infection is diagnosed, intra-venous immunoglobulin (IVIG) infusion can be considered [8].

Type of Anticoagulant

In order to prevent extracorporeal clotting, TA requires anticoagulation with citrate (ACD-A) or unfractionated heparin. ACD-A, or Anticoagulant Citrate Dextrose Solution, Solution A, is a mixture of citric acid, sodium citrate, and dextrose in water and is the most commonly used agent. ACD-A prevents clotting by chelating ionized calcium which is necessary for many of the reactions in the coagulation cascade. The benefit of citrate is that it acts as an extracorporeal anticoagulant only, losing its anticoagulant ability when reinfused into the patient. Therefore, citrate has a lower bleeding risk compared to heparin. Heparin also carries a risk of heparin- induced thrombocytopenia (HIT) which makes it additionally less desirable com-pared to citrate. ACD-A is the recommended anticoagulant by most TA devices’ manufacturers.


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The primary limitation of citrate is the risk of plasma accumulation and severe hypocalcemia and hypomagnesemia. Because it is metabolized by the liver, this risk is particularly high for patients with hepatic dysfunction. If time permits, calcium and magnesium should be repleted to within normal limits prior to any TA proce-dure with citrate anticoagulation. The risk of hypocalcemia can be further reduced by slowing the TA flow rate, adding calcium to the replacement fluid, or providing prophylactic calcium administration throughout the procedure (most commonly intravenous 10% calcium gluconate in the critical care setting) [9, 10]. The risk of hypomagnesemia can be reduced by similar means, and replacement can be pro-vided as needed (most commonly intravenous magnesium sulfate, 1–2 g over 5–60 min) [11]. The risk of citrate toxicity is also influenced by the citrate content of the replacement fluid; for example, the risk of symptomatic hypocalcemia with plasma is 4.8% compared to 1.8% with albumin [12].

Even in the absence of risk factors for hypocalcemia, all patients must be moni-tored for its early signs, including perioral numbness, distal paresthesias, nausea, vomiting, abdominal cramping, and light-headedness. Special care should be taken in monitoring unresponsive patients, who may manifest toxicity with hypotension, arrhythmias (QTc prolongation), or agitation [2]. If there is concern for citrate tox-icity, the procedure should be stopped and electrolytes should be rapidly measured and repleted. After the necessary pause and management of the patient, the proce-dure can be restarted and proceed to completion.

In the critical care setting, heparin may be used in combination with citrate in patients requiring large volume leukocytapheresis to mitigate the risk of citrate tox-icity, as long as there is a protocol in place to do so [13].

Assessing Effectiveness

The assessment of response to TA depends on the condition being treated. For TTP, perhaps the most important diagnosis treated with TA considering that it is 90% fatal without TPE, monitoring the platelet count and signs of hemolysis is the stan-dard of care [14]. In RCE for acute chest syndrome, a post-procedure hemoglobin S percentage <30% is expected. In other TA procedures, a clinical endpoint is more appropriate (i.e., resolution of symptoms in a patient with hyperleukocytosis under-going leukocytapheresis). Prior to initiating treatment with any TA procedure, it is essential to define a clear clinical endpoint that can be assessed daily to ensure that continued treatment is appropriate, as well as to allow for adjustments in the treat-ment plan if necessary [15].

Adverse Events

Complications of TA are rare with most large case series reporting a rate of 5–12% [12]. Importantly, the risks associated with the insertion of large-bore catheters for adequate vascular access need to be considered among them [16]. The most


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common complications include hypocalcemia, as already described, and allergic reactions when plasma is used as replacement fluid. Although hypocalcemia is com-monly due to ACD-A, it can also occur independent of citrate [17].

An unusual but potentially severe reaction characterized by sudden hypotension and bradycardia may occur in patients taking an angiotensin converting enzyme (ACE) inhibitor and receiving TPE with 5% albumin [18]. It is hypothesized that the reaction results from activation of the kinin system, either due to the apheresis pro-cedure or excess prekallikrein activator in the albumin product, which accumulates in the plasma because of the drug inhibition of ACE. For this reason, ACE inhibitors should be held for at least 24 h prior to a TA procedure, unless the TA is emergently needed. If a reaction occurs, the procedure should be stopped immediately, and appropriate supportive measures should be instituted.

Indications

Since 2007, ASFA has published evidence-based guidelines for the use of TA every 3 years. Each indication is assigned a category ranking from I to IV to designate the role of TA in that disorder and a grade to indicate the quality of evidence supporting that recommendation.

Categories I and II refer to disorders for which apheresis is accepted as a first- or second-line therapy, respectively. Category III disorders are those in which the role of apheresis has not been definitively established, while category IV disorders have published evidence demonstrating that apheresis is ineffective or even harmful.

Each disorder is also assigned a grade 1 or 2, indicating a strong recommenda-tion or weak recommendation, respectively. Each grade is also given a letter desig-nation: A indicates high-quality evidence, B indicated moderate-quality evidence, and C indicates low- or very low-quality evidence.

The most recent guidelines published in 2016 include 89 diseases in which TA is a potential treatment modality, 19 of which are either primary hematologic disor-ders or conditions with secondary hematologic manifestations that may be encoun-tered in the critical care setting [1]. Four types of TA may be used for hematologic challenges in the intensive care unit: TPE, RCE, cellular depletion techniques (including leukocytapheresis and erythrocytapheresis), and ECP. Each of these modalities will be discussed in the context of the diseases to which they are applied, focusing on disorders with category I and II indications.

Therapeutic Plasma Exchange (TPE)

In TPE, the patient’s plasma is replaced with 5% albumin or donor plasma in a spe-cialized device [1]. TPE is commonly confused with plasmapheresis, which ASFA defines as the isolated removal of plasma without volume replacement, such as from normal volunteers for manufacturing of albumin, coagulation factor, IVIG, etc.


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TPE was first used to treat hyperviscosity in Waldenstrom’s macroglobulinemia by Skoog and Adams in 1959; it has since become the most commonly used TA modality [19, 20]. According to the 2016 ASFA guidelines, TPE may be indicated in the critical care setting to treat patients with 12 hematologic disorders. The dura-tion, frequency, and type of replacement fluid used in TPE can be adapted to meet the needs of the patient and their diagnosis. The therapeutic mechanism of TPE was originally thought to be its ability to remove pathologic substances from the plasma, but increasing evidence suggests that TPE may also affect T-cell function and cyto-kine production [21, 22].

Thrombotic Microangiopathies

Thrombotic microangiopathy (TMA) is a broad term for conditions characterized by systemic occlusive microvascular thrombi that result in microangiopathic hemo-lytic anemia, thrombocytopenia, and multi-organ injury [23, 24]. Although the severity of TMAs varies, patients are often critically ill at the time of presentation. Ten TMAs are listed in the latest ASFA guidelines, and three of them received cat-egory I designations for TPE: TTP, ticlopidine-induced thrombotic microangiopa-thy, and thrombotic microangiopathy with factor H autoantibodies (Table 18.1). When TMA is suspected, an attempt must be made to determine its etiology as quickly as possible, since it will influence responsiveness to TPE. However, it is often difficult to be certain of the diagnosis promptly. Thus, if there is any possibil-ity that a patient could have a TPE-responsive TMA, empiric therapy should be initiated pending the conclusion of diagnostic workup [25]. TPE can always be stopped if a non-responsive TMA is diagnosed, but delaying TPE initiation to con-firm a diagnosis could have fatal consequences.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) was originally defined by a clinical constellation of microangiopathic hemolytic anemia and thrombocytopenia, with or without renal or neurologic abnormalities and with exclusion of other potential eti-ologies [26]. In 1998, TTP was discovered to be caused by a congenital (rarely) or acquired deficiency of ADAMTS13, an enzyme responsible for cleavage of von Willebrand factor once secreted in the plasma [27, 28]. Nowadays, the standard definition of TTP is the presence of thrombocytopenia and microangiopathic hemo-lytic anemia without an obvious cause [29].

Emergent TPE is the first-line treatment for acquired TTP, which is due to an autoantibody against ADAMTS13. TPE removes these antibodies and replaces ADAMTS13 with donor plasma to avoid further accumulation of ultra-large von Willebrand factor multimers that induce systemic platelet-rich thrombi. Before TPE was available, patient survival was approximately 10%; now, it has increased to 80% with prompt initiation of TPE [30–32]. Therefore, TPE should be started immediately if there is clinical concern for TTP based on an intermediate or high


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Table 18.1 Hematologic indications for therapeutic plasma exchange according to the 7th edition of the American Society for Apheresis (ASFA) guidelines [1]

Category I indications (grade of recommendation)

Thrombotic thrombocytopenic purpura (TTP) (1A)Hyperviscosity in monoclonal gammopathies, symptomatic (1B)Ticlopidine-induced thrombotic microangiopathy (2B)Thrombotic microangiopathy with factor H autoantibodies (2C)Category II indications (grade of recommendation)

Catastrophic antiphospholipid syndrome (CAPS) (2C)Cold agglutinin disease, severe (2C)Category III indications (grade of recommendation)

Other thrombotic microangiopathies: MCP mutations (1C) Clopidogrel (2B) Calcineurin inhibitors (2C) Coagulation factor-mediated, THBD mutation (2C) Complement factor gene mutation (2C) Hematopoietic stem cell transplantation- associated (2C) Shiga toxin-mediated, severe neurologic symptoms, or Streptococcus pneumoniae (2C)Coagulation factor inhibitors, autoantibody (2C)HELLP syndrome, postpartum (2C)Henoch-Schönlein purpura, crescentic or severe extrarenal (2C)Heparin-induced thrombocytopenia and thrombosis (2C)Immune thrombocytopenia, refractory (2C)Posttransfusion purpura (PTP) (2C)Warm autoimmune hemolytic anemia, severe (2C)

MCP membrane cofactor protein, THBD thrombomodulin, HELLP hemolysis, elevated liver enzymes, low platelet countCategory I, first-line therapy; Category II, second-line therapy; Category III, role of apheresis not definitively established

PLASMIC score [25]. The diagnosis must be established with an ADAMTS13 level, but TPE should not be delayed pending laboratory confirmation since most institutions will send the test to a reference laboratory, with a turnaround time of days. If TPE is initially unavailable, simple plasma infusion may be used, while the patient is being transferred to a facility where TPE can be initiated [33]. The volume of plasma necessary to keep a patient with TTP from succumbing to the disease, however, may lead to transfusion-associated circulatory overload (TACO), which is another reason to arrange TPE emergently.

Until the diagnosis of TTP is confirmed and once it has been made, TPE should be continued daily until the platelet count is >150 × 109/L for 2–3 consecutive days [14]. Corticosteroids are often used in conjunction with TPE at 1 mg/kg/day, although evidence supporting this practice is limited [14, 34]. Rituximab can be added in patients with relapsed and refractory disease [35]. Patients with an ADAMTS13 activity level <10% are at high risk for relapse, but preemptive ritux-


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imab for these patients is not currently recommended [14, 32]. Importantly, since TPE will remove a portion of rituximab from the circulation, when concurrent use is required, rituximab should be infused immediately after TPE, and the interval until the next procedure should be increased to 18–24 h to allow rituximab time to bind to B cells [1].

Other Thrombotic Microangiopathies

Other TMAs can be divided into three additional categories: Shiga toxin-induced hemolytic uremic syndrome (ST-HUS), atypical hemolytic uremic syndrome (aHUS), and secondary TMAs.

ST-HUS, also referred to as typical HUS, is caused by infections with Shiga toxin-producing organisms (i.e., Escherichia coli, Shigella dysenteriae); patients often present with gastrointestinal symptoms as well as severe renal dysfunction that may require renal replacement therapy. The foundation of treatment is support-ive, as there is no convincing evidence of benefit with TPE and there is some sug-gestion that TPE worsens long-term outcomes [36, 37]. Nevertheless, given lack of treatment options, TPE may be considered in patients with severe neurologic symptoms.

Atypical HUS (aHUS) refers to TMAs due to congenital or acquired dysregula-tion of the alternative pathway of complement; among them, approximately 10% of patients have autoantibodies to complement factor H (CFH) [38]. TPE is beneficial in CFH autoantibodies-mediated aHUS since removal of these antibodies appears to facilitate TMA resolution. Conversely, there is a variety of congenital mutations that similarly result in complement dysregulation and increase aHUS risk, but these disorders are minimally responsive to TPE given they are not antibody-medi-ated. In such cases, treatment with eculizumab should be considered, as it inter-rupts the overactive complement pathway by inhibiting cleavage of C5 by C5 convertase [39].

Secondary TMAs refer to those triggered by a medication or another disease state. A systematic review published in 2015 reported 22 drugs with a proven causal association with TMA and another 56 with suspected association [40]. There is no definitive evidence to support the use of TPE in the majority of drug-induced TMAs, and treatment relies primarily on cessation of the offending agent. The exception is ticlopidine, an antiplatelet medication in the thienopyridine family, which causes a TTP-like syndrome with a detectable inhibitor of ADAMTS13 in the patient’s plasma. Clopidogrel, another member of the thienopyridine family, can also cause TMA, but ADAMTS13 levels remain normal, and the TMA rarely resolves with TPE. The efficacy of TPE appears to depend on the timing of exposure to the thi-enopyridine based on a review of 128 cases – when TPE is used for a TMA that started more than 2 weeks after thienopyridine initiation, there is significant survival advantage compared with treatment for a TMA less than 2 weeks after thienopyri-dine initiation [41]. In secondary TMAs not responsive to TPE, treatment with ecu-lizumab can also be considered [42].


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Hyperviscosity in Monoclonal Gammopathies

Patients with monoclonal gammopathies can develop increased serum viscosity due to high immunoglobulin concentration resulting in a clinical syndrome that may include headache, visual impairment, somnolence, congestive heart failure, and respiratory compromise [43]. Hyperviscosity most commonly occurs due to excess IgM (i.e., Waldenstrom’s macroglobulinemia or multiple myeloma) because of the large size of this immunoglobulin, but it can also occur with IgG3, IgA, or light chain myeloma due to aggregation and formation of immunoglobulin polymers [44]. The viscosity threshold at which a given patient becomes symptomatic is vari-able, but symptoms rarely occur until the serum viscosity exceeds 4 centipoise, which corresponds to an IgM, IgG, and IgA level of 3 g/dL, 4 g/dL, and 6 g/dL, respectively [43]. The diagnosis is based on the symptomatology and/or evidence of retinal venous engorgement (“sausaging”) on fundoscopic exam.

If there is clinical suspicion for hyperviscosity syndrome, emergent TPE should be initiated. A single TPE treatment can reduce serum viscosity by 20–30% [45]. TPE should be continued daily until symptoms resolve, which generally occurs with 1–3 treatments [1]. In addition to TPE, patients must receive treatment for the underlying plasma cell dyscrasia to prevent recurrence. Importantly, treatment with rituximab in Waldenstrom’s macroglobulinemia can cause a spike in immunoglobu-lin levels with an acute increase in serum viscosity. Therefore, patients may require TPE prior to rituximab infusion if immunoglobulin levels are above the aforemen-tioned thresholds [46].

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia is a broad designation for diseases in which hemo-lysis occurs due to the presence of red cell autoantibodies [47, 48]. It can be subdi-vided based on the temperature in which antibody binding is optimal: 37 °C in warm autoimmune hemolytic anemia (WAIHA) and 4 °C in cold autoimmune hemolytic anemia (CAIHA). CAIHA most commonly occurs due to cold agglutinin disease (CAD). WAIHA is typically caused by IgG while CAD is due to IgM directed against I/i antigens on red cells. Diagnosis of autoimmune hemolytic ane-mia is confirmed with a positive direct antiglobulin test (DAT or Coombs test), which detects IgG and/or C3 bound to the patient’s red cells in vivo.

WAIHA can occur due to a variety of triggers including lymphoproliferative disorders, autoimmune conditions, and medications (tacrolimus, cephalosporins) but can be idiopathic in an estimated 35% of cases [49]. CAD itself is now consid-ered a lymphoproliferative disorder, although a similar syndrome of CAIHA may occur as a result of an infection (Mycoplasma pneumoniae in adults, Epstein-Barr virus in children).

WAIHA is treated primarily with high-dose corticosteroids (prednisone 1–1.5 mg/kg/day or 60–100 mg daily) [50]. Second-line therapies include rituximab and splenectomy. Refractory cases can be treated with IVIG or other immunosup-


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pressive medications (vincristine, azathioprine). The foundation of treatment for CAD is avoiding cold temperatures. However, severe disease may necessitate treat-ment with rituximab to suppress IgM production, although the response rate is only 45–55%. Fludarabine can be added to rituximab in refractory cases, with response rates approaching 75% [48]. Unlike WAIHA, corticosteroids and splenectomy are ineffective in CAD.

WAIHA is a category III indication for TPE and rarely utilized in practice, although it could provide a therapeutic bridge as immunosuppressive drugs take effect. Since CAD is due to IgM, which is mostly intravascular, it is a category II indication for TPE in patients with brisk hemolysis. Importantly, if TPE is per-formed in CAD, the thermal amplitude of the autoantibody must be taken into account, and the patient’s room temperature must be kept as close to core body temperature as feasible to avoid antibody binding and hemolysis as the blood crosses the extracorporeal circuit of the TA device. Although 5% albumin is the preferred replacement fluid for patients with AIHAs, plasma may be considered to provide haptoglobin to bind free hemoglobin when hemoglobinemia is massive (in which case the removed plasma will be dark), since it leads to hemoglobinuria that is nephrotoxic [51]. Evidence of the benefit of TPE in these conditions is inconsis-tent in the literature, and no large-scale studies exist [16].

Catastrophic Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune disorder defined by one or more thrombotic event or pregnancy morbidity in the presence of antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and/or anti-beta2-glycoprotein I). Catastrophic APS (CAPS) is a severe form of APS with thrombosis affecting three or more organ systems simultaneously or within a week [52]. CAPS manifestations are a result of vessel occlusion and include renal insufficiency, acute respiratory distress syndrome, stroke, myocardial infarction, skin necrosis, and other poten-tially fatal complications.

CAPS occurs in less than 1% of patients with APS but has a mortality rate of over 30% [53, 54]. Up to 60% of episodes of CAPS have a clear precipitant, most com-monly infection, but also malignancy, surgery, and cessation of anticoagulation may be implicated [55].

Because of the severity of CAPS, early intervention is essential. Any possible trig-gering infection should be promptly treated with appropriate antimicrobials. Anticoagulation with heparin should be started to control the ongoing thrombosis, and high-dose glucocorticoids (methylprednisolone 1 g IV for 3–5 days) are also indicated to suppress cytokine production. TPE may be used as first-line therapy in addition to heparin and steroids based on observational studies that suggest a survival benefit by removing antiphospholipid antibodies [56]. However, the grade of evidence for the role of TPE is low, and CAPS is a category II indication for TPE (Table 18.1).

According to the ASFA guidelines, daily or every other day TPE for 1–3 weeks may be planned [1]. Plasma has classically been used as the replacement fluid, as it


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is thought to replete anticoagulants such as antithrombin, protein C, and protein S. However, there have also been case reports that successfully used albumin instead [57]. Ultimately, the guidelines suggest that their combination could maximize repletion of necessary proteins and minimize risks from plasma. IVIG is often incorporated into the treatment, in which case infusions should be timed after TPE to prevent wastage.

Red Cell Exchange

Red cell exchange (RCE), also called exchange transfusion, is primarily used to treat complications of sickle cell disease, although it can also be necessary for severe babesiosis and malaria (Table 18.2). Patients with sickle cell disease possess an abnormal sickle hemoglobin (HbS) due to a missense mutation in the beta-globin gene. HbS polymerizes upon deoxygenation, altering the conformation of the red cell and causing occlusion of the microvasculature. As a result, patients present with a wide array of acute and chronic consequences of hypoxia and tissue infarction [58].

During a RCE, the device removes patient’s red cells containing HbS and replaces them with normal PRBCs. In addition to ensuring that the donor PRBCs are not from someone with sickle cell trait, some institutions make an effort to use antigen-matched (Rh and Kell, most commonly) units to avoid the development of alloantibodies. However, if the RCE is emergent, antigen matching is secondary unless the patient has already developed one or more alloantibody(ies). According to the ASFA guidelines, the RCE target hematocrit should be 30 ± 3% and the HbS concentration <30% [1]. Utilizing the calculations outlined previously in this chap-ter (see section “Exchange volume”), a single exchange transfusion is sufficient to reach these goals.

Under the umbrella of sickle cell disease, there are five indications for RCE in the critical care setting: acute stroke, acute chest syndrome, splenic or hepatic

Table 18.2 Hematologic indications for red cell exchange according to the 7th edition of the American Society for Apheresis (ASFA) guidelines [1]

Category I indications (grade of recommendation)

Acute stroke in sickle cell disease (1C)Category II indications (grade of recommendation)

Acute chest syndrome, severe (1C)Babesiosis, severe (2C)Category III indications (grade of recommendation)

Malaria, severe (2B)Multi-organ failure in sickle cell disease (2C)Splenic/hepatic sequestration; intrahepatic cholestasis in sickle cell disease (2C)Erythropoietic porphyria, liver disease (2C)

Category I, first-line therapy; Category II, second-line therapy; Category III, role of apheresis not definitively established


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sequestration, intrahepatic cholestasis, and multi-organ failure that will be discussed below.

Acute Stroke

Without appropriate preventative measures (including transcranial Doppler screen-ing and blood transfusions), 10% of children with sickle cell disease will have an overt stroke, and approximately another 20% will have a silent infarction before the age of 20 [59, 60]. Adults also have a high risk of both ischemic and hemorrhagic strokes. Although there have been no studies comparing RCE with simple transfu-sion, expert opinion recommends prompt RCE when there is radiographic evidence of an acute stroke [61]. In hemodynamically unstable patients or those that may not tolerate an exchange transfusion for other reasons, simple transfusion may be ben-eficial. In such instances, the hematocrit should be maintained below 33–36% to avoid hyperviscosity. In children, exchange transfusions have also been shown to decrease the risk of stroke recurrence when compared to simple transfusions [62].

Acute Chest Syndrome

Acute chest syndrome is a leading cause of morbidity and mortality in patients with sickle cell disease [63]. Episodes are most commonly triggered by infection (Chlamydia pneumoniae, Mycoplasma pneumoniae, respiratory syncytial virus, among others) or bone marrow fat embolism, but in many patients the inciting etiol-ogy is unknown [64]. Acute chest syndrome is difficult to differentiate from pneu-monia because the symptoms include shortness of breath, cough, chest pain, and fever, while the chest radiograph reveals a multilobar infiltrate [64].

Initial management of acute chest syndrome includes antibiotics, respiratory support (target oxygen saturation >95%), and simple transfusions if the hemoglobin concentration is >1 g/dL below the patient’s baseline and <9 g/dL. Studies compar-ing simple versus RCE have been small and retrospective and have produced con-flicting results [65, 66]. However, if a patient exhibits signs of severe disease or rapid progression, including hypoxia (oxygen saturation <90%) while receiving oxygen supplementation, increasing respiratory distress, worsening pulmonary infiltrates, or decline in hemoglobin despite PRBC transfusion, emergent RCE is recommended [61].

Splenic/Hepatic Sequestration, Intrahepatic Cholestasis, and Multi-Organ Failure

Sickle cell disease can also cause acute, emergent manifestations in other organs besides the brain and the lungs. Splenic sequestration refers to the acute trapping of red cells in the spleen causing very painful splenomegaly and a rapid drop in


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hemoglobin (2 g/dL or greater) that can be fatal. In patients with homozygous sickle cell disease (HbSS), splenic sequestration typically occurs during childhood because by the time they reach adulthood, their spleens have often undergone autoinfarction and involution. In comparison, patients with heterozygous hemoglobinopathies such as hemoglobin SC disease (HbSC) and hemoglobin S beta-thalassemia (HbSβ+) may develop splenic sequestration later in life. Treatment involves aggressive vol-ume resuscitation with crystalloids and transfusion for symptomatic anemia. Since there have not been any head-to-head comparisons of simple versus exchange trans-fusion, RCE is often reserved for refractory cases. Importantly, anemia should only be partially corrected with PRBCs, as patients can experience an “autotransfusion” as red cells are ultimately released from the spleen, resulting in a potentially fatal hyperviscosity syndrome. Sequestration can also occur in other organs, including the liver, with similar consequences and recommended management.

Intrahepatic cholestasis is an emergent complication of sickle cell disease in which acute vaso-occlusion of the hepatic sinusoids results in parenchymal isch-emia and bile stasis. Patients develop right upper quadrant pain and hepatomegaly similar to hepatic sequestration, but they also have extreme hyperbilirubinemia and acute hepatic failure. Published case reports suggest benefit of RCE over simple transfusion for all causes of acute hepatopathy in patients with sickle cell disease, but no formal comparison has been conducted [67, 68]. Nevertheless, given the high risk of fatality in this disorder, emergent RCE should be considered.

Acute multi-organ failure is another life-threatening complication of sickle cell disease that is defined by simultaneous failure of three organs: lung, liver, or kidney. Similarly, evidence of benefit of RCE in acute multi-organ failure is lacking, but given its high mortality, this condition is a category III indication according to ASFA (Table 18.2). Some authors suggest that in multi-organ failure, a lower HbS target of <20% and a lower hematocrit target of 28% should be used in an effort to decrease blood viscosity and improve tissue oxygenation [69].

Bone Marrow Necrosis with Fat Embolism Syndrome

Close to 90% of cases of bone marrow necrosis are due to malignancies, although certain medications, infections, and heterozygous hemoglobin S states may also be implicated [70].

In addition to the loss of hematopoietic cells and medullary stroma, bone marrow necrosis may precipitate the release of fat from the marrow space into the blood-stream as fat emboli. These emboli have devastating systemic consequences and can result in multi-organ failure [71].

An increasing number of case reports of bone marrow necrosis and fat embolism in patients with heterozygous hemoglobin S states suggests that this is likely an under-recognized clinical entity [72–74]. In several published case reports, treat-ment with RCE was based on the theoretical premise that decreasing HbS concentra-tion would decrease the red cell sickling responsible for the microvascular occlusion


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and resultant infarction in the marrow. Indeed, the literature suggests that when initi-ated promptly, RCE can allow for full recovery from an otherwise fatal disease [72–74]. This syndrome is not yet recognized in the ASFA guidelines as an indication for RCE but should nevertheless be considered in critically ill patients with multi-organ failure, hypoproliferative anemia, and thrombocytopenia. In fact, fat embolism syn-drome may be confused with TTP, but the degree of thrombocytopenia is much less severe, schistocytes are rare, and the reticulocyte count is low [75].

Cellular Depletions

Cellular depletion techniques, including leukocytapheresis and erythrocytapheresis, involve removal of a selected cell type (most commonly blasts) with reinfusion of the remainder of the blood components into the patient, with or without the addition of a replacement fluid. In the critical care setting, the ability to rapidly decrease a specific blood cell population via apheresis can be lifesaving.

Hyperleukocytosis

Hyperleukocytosis is strictly defined as a white cell count (WBC) >100,000/μL and can cause a pathologic syndrome called leukostasis due to microvasculature occlu-sion, tissue hypoxia, and multi-organ dysfunction. Patients with leukostasis may present with varying degrees of neurologic and respiratory compromise, from head-ache and mild dyspnea to coma and severe hypoxia [76]. The WBC count threshold for symptomatic hyperleukocytosis is variable, as myeloid leukemias can cause symptoms with counts as low as 50,000/μL, while patients with lymphoid leuke-mias may remain asymptomatic with counts as high as 500,000/μL [76].

Initial treatment in symptomatic patients should focus on rapid cytoreduction, which can be achieved by medication (i.e., induction chemotherapy with hydroxy-urea), leukocytapheresis, or both. The ASFA guidelines assign symptomatic hyper-leukocytosis a category II, grade 1B indication for apheresis intervention. A single leukocytapheresis is often sufficient to emergently reduce the WBC count by 30–60% and resolve symptoms, but repeat sessions may be required as the leukemic cells quickly re-accumulate and symptoms return. Importantly, leukocytapheresis is only a temporizing intervention, and definitive management with chemotherapy is subsequently required.

Leukocytapheresis is contraindicated in patients with acute promyelocytic leu-kemia as it can result in worsening of disease-associated coagulopathy [77]. Also, prophylactic leukocytapheresis in patients with asymptomatic hyperleukocytosis is not routinely recommended, as it has not been proven to provide additional benefit over chemical cytoreduction, even in patients with tumor lysis syndrome [78, 79].


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Polycythemia Vera and Secondary Erythrocytosis

Erythrocytosis, or absolute polycythemia, is defined as a hematocrit >60% in males or >56% in females. Erythrocytosis can be either primary (due to an acquired or inherent red cell mutation) or secondary to an external factor that stimulates eryth-ropoiesis (such as chronic hypoxia, testosterone injections, or erythropoietin- secreting tumors) [80]. Primary erythrocytosis most commonly refers to polycythemia vera (PV), a myeloproliferative disorder that results in excess red cell production due to an activating mutation in the Janus kinase 2 (JAK2) gene in >90% of cases. Patients can present with more benign sequelae of their erythrocytosis including erythromelalgia and pruritus, but they can also develop emergent compli-cations including hyperviscosity, hemorrhage, thrombosis, and congestive heart fail-ure. The cornerstone of PV treatment is lowering the hematocrit to <45% as it has been shown to decrease the risk of cardiovascular death and major thrombosis [81]. Simple phlebotomy and chemotherapy (chlorambucil, hydroxyurea, 32P) is often sufficient in nonemergent scenarios, but erythrocytapheresis is preferred in patients with hyperviscosity, thrombosis, or congestive heart failure because it can more rap-idly and efficiently lower the hematocrit to the desired target (ASFA category I, grade 1B) [82, 83]. Apheresis has additional utility in PV patients with thrombocy-tosis, as concurrent erythro- and thrombocytapheresis can be performed [84].

Emergent complications are much less likely in secondary compared to primary erythrocytosis. Although there is no evidence to support or refute the use of eryth-rocytapheresis in secondary erythrocytosis, a therapeutic trial can be considered if a patient presents with hyperviscosity or thrombosis.

Extracorporeal Photopheresis

Extracorporeal photopheresis or ECP was first developed in 1987 by Dr. Richard Edelson for the treatment of cutaneous T-cell lymphoma [85]. Its use has since been expanded to treat other disorders, including acute graft versus host disease (aGvHD). Unlike the other TA techniques discussed herein, no blood component is discarded. In ECP, a portion of the patient’s circulating white blood cells (the “buffy coat”) is collected in a satellite bag attached to the ECP device, mixed with a photoactive compound (8-methoxypsoralen), exposed to ultraviolet A light, and reinfused into the patient [86]. ECP is considered a cell-based immunomodulatory therapy, but a complete understanding of its mechanism of action remains unknown. Growing evidence suggests that ECP induces dendritic cell activity, which in different clini-cal settings can have either immunotolerizing (e.g., aGvHD) or immunizing (e.g., lymphoma) effects [87]. In aGvHD, both in vitro and in vivo studies suggest that various sessions of ECP increase the number of regulatory T cells in the circulation, which modulate the overactive immune response [88, 89].


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Acute Graft Versus Host Disease

As a potentially serious complication of allogeneic hematopoietic cell transplant, aGvHD is caused by donor immune cells (T cells) that identify recipient histo-compatibility antigens as foreign and mount an immune response against the patient [90]. It is associated with significant morbidity and mortality, most com-monly secondary to skin (81%), gastrointestinal tract (54%), and/or liver (50%) involvement [91].

According to the National Institutes of Health consensus criteria published in 2015, classic aGvHD occurs within 100 days of transplantation, but the disease can also manifest later, often due to withdrawal of immunosuppression [92]. Therefore, the distinction between acute and chronic disease is not based on time of presenta-tion but rather on the constellation of symptoms.

Since aGvHD is a category II, grade 1C indication for ECP, it is more often employed after failure of standard immunosuppression with corticosteroids. In a prospective phase II trial by Greinix et al., 38 patients with steroid-refractory aGvHD were treated with weekly ECP with significant response. Complete reso-lution of disease occurred in 82%, 61%, and 61% of patients with cutaneous, liver, and gut involvement, respectively. Overall survival at 4 years was 47% of all patients that received ECP, with significantly higher survival of patients with complete response (59%) as compared to those that did not respond (11%) [93]. Since the optimal interval for ECP treatments has not been established, the schedule used by Greinix and colleagues is commonly followed. In their study, ECP was performed on 2 consecutive days at weekly intervals until maximal response was achieved. The median number of cycles in the study was 4, ranging from 1 to 13 [93].

Because transplant patients are prescribed immunosuppressive medications that cause hypomagnesemia, special care should be taken to replete electrolytes prior to the procedure to decrease the risk of citrate toxicity, unless heparin is used as the anticoagulant.

Summary

• Multiple modalities of TA are indicated in critically ill patients, including TPE, RCE, cellular depletions, and ECP.

• Most conditions treated with TA still lack definitive studies for its exact role, but evidence-based guidelines exist and should be consulted prior to proceeding with TA.

• Several technical and patient-specific parameters must be decided upon in con-junction with an apheresis-trained physician in order to achieve the best treat-ment response and avoid complications.


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Chapter 19Intravenous Oxygen Therapeutics: A Revolution in Medicine Yet to Be Realized?

Bruce D. Spiess

Introduction

Medicine has lo ng searched for the “best” intravenous fluid with many that have proven to be imperfect. In designing fluids, it is important to think about the func-tions for which they are asked to work. Crystalloid fluids are purely, and imper-fectly, volume resuscitators [1–3]. Each crystalloid fluid has problems in that they are not maintained intravascularly for long periods of time, as well some, such as saline, can cause hyperchloremic metabolic acidosis [1–4]. They do offer the advan-tage of being inexpensive which is probably why they are first-line choices. Colloids, although being more effective for filling, and maintaining intravascular volume, hence cardiac preload, may have in vitro and in vivo coagulation alterations as well as are far more expensive [5–8]. Controversy exists regarding the use of protein or synthetic starch or gelatin fluids as to how research has been conducted, whether the protein fluids cause lingering fluid retention after trauma (particularly) in lung and brain tissues, other side effects, anaphylaxis, as well as cost issues. A potential advantage of colloids is that they open the microcirculation whereas crystalloids may not improve perfusion after hemorrhagic shock [9]. As well, there may be enough oxygen (O2)-carrying capacity in retained erythrocytes such that resuscita-tion is most dependent upon opening the microcirculation. Giving an O2-carrying drug without being able to get the arterioles and capillary beds flowing may be wasted therapy.

The one factor that none of the existing intravenous fluids today have is the capa-bility of carrying significant O2 content. Whole blood has thousands of functions, including O2-carrying capacity/delivery. In the past, the pursuit of O2-carrying intra-

B. D. Spiess, MD, FAHADepartment of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USAe-mail: [email protected]



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venous fluids has been misnamed as well as misdeveloped to be “blood substitutes.” Today, we have realized that just by this misnomer a great disservice to mankind developed for what might otherwise be a tremendous revolution in medicine. The reason one should consider this misnomer a mistake is that by taking that name—“blood substitute”—so many other research designs, pharmaceutical development algorithms, and financial decision trees were based upon trying to create fluids that competed with banked blood. In so doing, the pharmaceutical industrial base was responding to a potential multibillion-dollar prize—taking away cash flow from the blood banking industry. This pursuit was historically based upon the human immu-nodeficiency virus (HIV) infectivity of the developed nations’ blood supplies [10].

Lay public outcry to the fact that transfused blood was causing the spread of HIV led to fear of transfusion and an overall reduction in allogeneic blood usage [10, 11]. Pharmaceutical houses explored aggressively becoming the first to market with an “artificial blood.” The concept and the nomenclature were wrong, but we could not know that until hundreds of millions of research dollars had been spent and a num-ber of promising appearing compounds or formulations had been tried and failed due to inherent toxicities. Although most of the agents that were developed during the period wherein there was pursuit of a “blood substitute” are now in pharmaceu-tical graveyards, others have made it into use in various forms and in some countries [12]. The compassionate use of certain hemoglobin-based oxygen carriers (HBOCs) is still active today in the United States [12]. This author has saved lives with the HBOCs as compassionate usage agents, yet it appears we are years away from hav-ing a viable US pharmacopeia approved single or class of IV agents that are O2 carriers.

To understand some of why failure has been more prominent than success, one needs to explore what we assume, i.e., believe about O2 delivery, but is perhaps not true.

Oxygen Delivery to Tissues

Every breath inhaled into our lungs is 21% oxygen and approximately 79% nitrogen at a partial pressure varying upon elevation of the person above or below the sea level. The basic physiology of respiratory mechanics and O2 binding to hemoglobin is not the subject of this chapter. However, medical teaching has been very hemo-globin centric in terms of how O2 is carried, delivered, and regulated within the body. That focus upon hemoglobin as “nature’s molecule” for O2 transport has led to basic assumptions, including the development of a whole class of pharmaceuti-cals known as hemoglobin-based oxygen compounds (HBOCs). Hemoglobin is an iron-based globular protein with four different active sites. Iron, to bind O2, must be in reduced form. It is the fact that metals share electrons with oxygen that allows iron to be effective in binding and, to a much smaller extent, releasing O2. Other transition metals bind O2 including copper, which is the blood-binding metal for some invertebrates, as well as manganese—found in some enzymes and cobalt.

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Evolution has created a large series of metalloproteins based mostly upon reduced (Fe2+) or ferrous iron. Iron with 3 electrons is known as oxidized iron and is unable to participate in the reactions needed for clinical metabolism. In medicine we know it as methemoglobin. When the Earth first formed, O2 was not available in gaseous form. Although oxygen was then and still is today the most common ele-ment on the Earth’s surface, the atmosphere 4 billion plus years ago was only 0.2% oxygen. Interestingly, the atmosphere was extremely high in gaseous hydrogen per-oxide, a powerful oxidizing free radical. When the earliest life forms began repro-ducing and metabolizing, they were obligate anaerobes living in deep seas and near sources of sulfur as well as heat. They metabolized sulfur to move electrons produc-ing energy. Today, those same anaerobes exist, still in the deep oceans, but in and around geyser basins still metabolizing sulfur, as well as in our gut where sulfur is often liberated. With the atmosphere containing large amounts of hydrogen perox-ide, it is thought that the very first iron-based metalloprotein to evolve was catalase. Interestingly, catalase, the cytochromes, and so many other iron-based proteins involved in electron transfer probably evolved very early in eukaryotic cells [13]. Indeed, these and sulfur-based proteins are the basic machinery for photosynthesis. Cyanobacteria harvested the sun’s photons by photosynthesis to split water creating energy and releasing dioxygen as a toxic by-product. Dioxygen (O2) is toxic if you are an obligate anaerobe [13, 14].

The earliest forms of hemoglobin evolved in cyanobacteria on Earth as metallo-proteins capable of detoxifying oxygen. The point of this discussion is to show that hemoglobin did not evolve de novo on the planet for the purpose of transporting O2 in multicellular highly complex organisms such as mammals. Cyanobacteria became cells that cooperated more and more developing into someday the precur-sors of our mitochondria and the cellular machinery that contains myoglobin doing energy production through the Krebs cycle [14]. Indeed, the Krebs cycle is analo-gous to running photosynthesis in reverse (way oversimplified but many enzymes are the same). Hemoglobin eventually evolved in multicellular organisms providing the function that it did in anaerobes- binding O2 [14].

In so binding O2 hemoglobin is highly important. The four different heme moi-eties in each hemoglobin molecule interact and change the allosteric reaction of the three-dimensional structure of the protein. We know the point at which hemoglobin is 50% saturated with oxygen to be the P50. Different hemoglobin preparations have different P50s, and it is instructive to note that fetal hemoglobin has a P50 of 14.4 mmHg compared to normal hemoglobin A which is 26 mmHg. The lower the P50, the tighter the O2 is bound to hemoglobin. Medicine has thought that by manip-ulating the P50 and the allosteric binding of O2 to hemoglobin, they might create a medical therapy which when infused would release large amounts of oxygen. The drug RSR-13 was created and trialed in animals all the way to humans. It worked, O2 was released from hemoglobin, but patients died and vascular spasm resulted. This drug (RSR-13) should be a cautionary tale to all that are pursuing O2-carrying IV compounds. Excess O2 is toxic and leads to vascular spasm, i.e., myocardial infarctions and lower organ blood flow. Hemoglobin evolved inside of a cell

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membrane for survival reasons, and we would do well to embrace the concept that hemoglobin evolved to stabilize and buffer the O2 levels in the microcirculation.

The P50 of hemoglobin has been the center of debate amongst pharmaceutical houses wishing to create HBOCs [12–15]. Some have argued for a normal P50, being that it is what evolved in nature, whereas others have argued that the P50 should have a higher number so that the HBOC would donate its O2 more readily to tissue. Still others have argued the exact opposite [14–18]. To date, we do not know the answer and no HBOC has made it to FDA approval yet, no matter what its P50. We can say that allosterically altering P50 led to patient deaths and myocardial infarctions, as you will see later, the same effect as giving HBOCs [12, 16, 17]. Yet some still believe that manipulating P50 in critically ill patients holds promise [17]. The argu-ment persisting means that medicine to date does not fully understand oxygen deliv-ery and hemoglobin’s evolution. In tumors it appears these may be an advantage to shifting P50 [18–20].

All this academic fluster means is that we don’t know the right answer and that the concept of free hemoglobin and O2 delivery is still a scientific mystery only partially understood [14]. However, we do know that hemoglobin binds oxygen 5000 to 100,000 times tighter than it releases it. That fundamental characteristic of hemoglobin has evolved, to do what it did in cyanobacteria, bind up excess O2 [14]. There are 300,000,000 molecules of hemoglobin in each red blood cell and 4,000,000 erythrocytes per cc of blood with 4 binding sites on each hemoglobin for four O2. The capacity to bind O2 is immense. The capacity to release it is far less so! The balance is what has evolved in nature.

It appears from evolution that hemoglobin arose on Earth’s surface to be an O2 buffer and to protect cells from too much O2. We have worshipped hemoglobin, and the industry of allogeneic blood banking, as a result of our fascination and misun-derstanding of hemoglobin, has carried it to being the number one medical interven-tion in the world. One can carry the thought that hemoglobin circulates in our body as an O2 buffer through to its correct conclusions. If one understands the microcir-culation and how O2 travels from hemoglobin into the plasma and then from the plasma, across the various cell membranes and cytosol of cells, it is clear that hemo-globin is only the bit part of transport getting O2 molecules from the lungs to the plasma [21]. Plasma, cytosol, and cell membranes are differential resistors to O2 movement. Cell O2 partial pressures are constant and at surprisingly low levels. Mitochondrial O2 levels are around or below 1 mmHg [14, 21]. The circulation functions as a just-in-time O2 delivery system wherein partial pressures of O2 are constant but flux and flow of plasma is highly variable. Hemoglobin functions as a bank of chemically bound O2 to supercharge and constantly decay O2 off of it to create the constant dissolved amounts in the plasma. There is no direct movement of O2 from a hemoglobin molecule to a target cytochrome in the Krebs cycle. Everything is dependent upon overcoming the resistance of water-based plasma, the fats of lipid cell and mitochondrial membranes (more O2 permeable than plasma and cytosol), and cytosol. Medicine, in its hemoglobin worship, has taught thou-sands of people that dissolved O2 does not matter and that only hemoglobin-based bound O2 matters. In reality, the exact opposite is true: dissolved O2 is the only O2

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used in energy production and it is hemoglobin-bound O2 that gets O2 from the lungs to the microcirculation. The O2 content equation, again taught to every junior medical student, is real but only a small part of the story.

The release of O2 from hemoglobin is driven by hydrogen ion concentration and by 2,3-diphosphoglycerate (2,3-DPG) as well as chloride ion. When hemoglobin is taken outside of the red cell, we really have very little basic understanding of the factors driving O2 delivery. To simply assume that a P50 of 26 is “best” because that is what is seen inside the red cell is almost certainly a flawed position. High vascular O2 partial pressures create vasoconstriction. This fact has been shown in a number of experiments including ones with isolated heart preps. The fact that high partial pressure of O2 in some part regulates vascular smooth muscle triggering vasocon-striction has led some HBOC groups to believe that low P50 values (tight holding of O2) make sense [14]. Vasoconstriction/hypertension and myocardial infarction (MI), are side effects of HBOCs and allosteric modifiers, that have blocked develop-ment. But perhaps we should learn from that fact alone and realize that perhaps free hemoglobin next to endothelial cells has evolved to not occur in mammals for evolu-tionary survival reasons. That one evolutionary fact has not been gripped by the phar-maceutical development companies that continue to forge forward with HBOCs of any number of different formulations. Perhaps yet, we can overcome our failures in HBOC development [12, 14].

No matter, there does exist a worldwide need for intravenous solutions that can supply some level of tissue enhanced O2 delivery.

The Unmet Need

Volume expanders, crystalloids or colloids, cannot fulfill the needs for tissue perfu-sion with enhanced O2 delivery [9]. Perhaps what is truly needed are special solu-tions that trigger the microcirculation to open otherwise closed channels after shock, thereby increasing functional capillary density [4, 9, 21]. Fresh whole blood does perform so many functions when hemorrhagic shock is encountered. Fresh warm whole blood was available in some battlefield situations during World Wars and was just recently revitalized by NATO troops during the second Gulf War and the Afghanistan conflict. Banked blood stored at 4°C for up to 42 days is far inferior to fresh warm whole blood [31–33]. Although authors like myself may believe that fact, banked blood is what is the standard for medicine today. It is the most widely utilized therapeutic in Western medicine. But transfusion therapy is not always available.

To most physicians who work in high-tech modern centers, the possibility of not having immediately available cross-matched banked blood is frightening. But that does happen. Blood shortages have become relatively commonplace. During natural and man-made (e.g., September 11, 2001) disasters, blood banking in the normal manner can and was limited [34]. Hurricanes, earthquakes, large fires, and wars cre-ate civil stress that can result in temporary periods where blood banking cannot


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supply needs. Countries that have had to deal with terrorism have realized that and have stockpiled blood. Israel and Great Britain maintain a far larger inventory of banked blood and can therefore withstand a cutoff of supply-sided input of fresh harvested blood as compared to the United States [35, 36]. Israel may have up to a 10-day supply, whereas the United States has a 1.4-day supply with temporary regions of supply/demand inequality always occurring just during normal operating conditions. The holiday season when blood donations decrease puts real stress upon the blood banking industry in the United States [35, 36]. The problems of supply/demand inequality have been recognized by government agencies and have been labeled as a homeland security issue.

Rural hospitals may well have more of a blood supply issue as compared to more urban centers. Some parts of what we consider to be very high-tech academic medi-cal centers such as Dartmouth-Hitchcock in New Hampshire still are supplied by blood suppliers out of state in Massachusetts. Should the interstate road system be blocked by a blizzard, a common occurrence there, issues of blood supply become acute. What about rural Western Texas, North Dakota, Wyoming, Montana, or Alaska? Often such far-removed places are the sites of major automotive trauma.

Efforts are underway to study putting blood components, particularly fresh fro-zen or thawed plasma, on first responders’ vehicles or medevac helicopters. The challenges herein are many simply to extend the blood transfusion paradigm for-ward from the emergency department out to the point of first contact. We undertook a study of doing exactly that and had to stop the study because of logistical chal-lenges that could not be met. The presence of an O2 therapeutic that could be uti-lized by first responders or in situations when blood is simply not available or is delayed would by itself be a huge advance.

The military need for such an O2 therapeutic cannot be overstated. The US mili-tary has funded the studies to find logistic ways to put plasma on first responder’s vehicles. However, even with such a program, if it was effective, it will not have red cells and not type and crossed red cells. For the military to have a pharmaceutical that could be utilized by medics/corpsmen within the first few minutes of trauma might well prove lifesaving. We simply do not know how effective that pharmaceu-tical will be because to date such a scenario has never been studied. A conference in February 2017 was convened by the Department of Defense, the National Institutes of Health, the Food and Drug Administration, as well as the Biomedical Advanced Research and Development Authority (BARDA) to explore the state of the art of O2 therapeutics as well as the unmet need of their existence when blood was simply not an option. The Biomedical Advanced Research and Development Authority (BARDA), an agency not known to many, is tasked with deciding what is needed if the United States undergoes a crippling event such as a nuclear attack [30]. The conclusion for the 2-day conference was that this is a huge unmet need that requires government funding for focus to success.

A smaller but very real need is to supply a viable O2 carrier to those patients who either cannot receive blood or refuse blood transfusion on either religious or per-sonal grounds [37]. There are approximately 5.3 million Jehovah’s Witnesses in the United States, and although some might take blood transfusions, it is fundamentally

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against their belief to do so. Perhaps several million other people for reasons of either very rare blood type or antibody presence are a challenge to find compatible red cell units. Others, and extremely rarely, have autoantibodies leading to severe life-threatening hemolytic anemias for which blood transfusion in itself serves to worsen a near mortal condition. The compassionate use of HBOCs has been done for each of these clinical scenarios. O2 therapeutics would in these cases increase the therapeutic options for not only life-threatening conditions but perhaps to nor-malize otherwise risky surgery and care.

Eighty percent of the world’s population does not have access to pathogen-free blood for transfusion [38–40]. Malaria remains the single largest infectious killer of mankind with 200–267 million new cases per year [41]. Infectious contamination of blood in endemic areas wherein the blood supply is thought (at least by the native populations) to be completely infected by malaria affects huge portions of mankind. In sub-Saharan Africa, for example, the societal acceptance of blood transfusion is diametrically different than the developed world [38–40]. Blood transfusion in these countries is viewed by the population as a kiss of death, not a lifesaving inter-vention. In South America, blood availability by modern transfusion service is highly variable and quite different between even neighborhoods in urban centers to Andean, Amazonian, and meso-American medical systems [42]. Even in places where some blood is available, “family replenishment” is required before a transfu-sion is released. Other situations require payment of cash prior to transfusion.

The burden of HIV on the blood system is high—just not in the developed world. In North America, Europe, Australia, New Zealand, and Japan, the risk of HIV from the blood supply is thought to be approximately 1 unit infected per 1–4.5 million units transfused. In Uganda, Senegal, Nigeria, Ghana, and others, the range of HIV presence in units surveyed is from 1.4% to 12.3% of all units collected [43, 44]. In Benin City of Nigeria, 12.3% of all blood contains HIV [45]. Overall in Nigeria, the seroconversion rate to HIV positivity after transfusion is 7.6%. In Zimbabwe, from 2002 to 2003, the seroconversion rate was 0.48% with a program to get underaged high school students to donate blood because they have the lowest HIV rate in the country [44]. Dengue fever is present in much of the tropical world and that alone is a major problem with the blood supply in the Pacific Islands [46, 47].

The development of an oxygen therapeutic for use in the developing world might well be a great advance. Indeed, HBOCs have been utilized in South Africa but have been very limited because for the cost per unit and their lack of widespread avail-ability [48]. One has to ask the ethical question of whether the developed world owes a moral obligation to test/create a pharmaceutical to relieve the burden pres-ently imposed by the unsafe blood supply endemic for 80% of the world’s popula-tion. Pharmaceutical houses and the US FDA have no regulatory or financial incentive/obligation to answer this question nor does it even influence their thought process.

The last and perhaps largest unmet need in the developed and developing world as well for that matter is the treatment of tissue hypoxia with oxygen therapeutics. Red blood cells are limited in their ability to supply oxygen when perfusion is lim-ited. Atherosclerosis is the leading killer in the developed world and it kills by acute


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tissue ischemia leading to low flow or no flow of blood in the heart and brain. Acellular oxygen therapeutics have shown both animal lab and human trial suc-cesses [49–57]. Indeed, HBOCs and PFCs have both been extensively tested in models and some human trials of critical tissue ischemia. Acellular O2 supply per-haps can salvage tissue during periods of low flow/no flow states. Acute coronary blockage is most often due to a fractured plaque that triggers an acute thrombosis. Some trickle of plasma may get through a thrombus, or some bits of tissue may be partially supplied by collateral flow. If the plasma trickling to these areas of dying tissue were otherwise empowered to carry enhanced O2 either with an HBOC or a PFC, it is possible that critical tissue could be salvaged. Even if tissue could be salvaged until definitive therapy, that would be a great advance. Until recently, phar-maceutical development had been focused only upon competing with banked blood, not treated tissue ischemia.

The most wonderful human demonstration of this effect was accomplished dur-ing the evolution of balloon dilatation for coronary atheroma. Fluosol-DA-20% (a first-generation PFC) was utilized in a pivotal trial for coronary balloon angioplasty, and in persons wherein PFC was instilled intravenously prior to balloon inflation, the MI rate and death rate were cut. In so doing this one series of human trials, the drug achieved FDA approval, but far more importantly it proved that the proper use of these compounds should be in ischemic treatment. The burden of disease caused by vascular occlusion, diabetes, traumatic brain injury (a microvascular dysfunction after the initial brain tissue death due to the trauma itself), stroke, myocardial infarc-tion, etc. is huge. Even temporary use of these compounds to salvage tissue until definitive therapy can be carried out would in itself be a monumental advance. Take the all-too-frequent occurrence of a transient ischemic attack of the brain heading toward a full stroke. If on first contact emergency medical personnel could adminis-ter an oxygen therapeutic and it salvaged some or all of the brain tissues while clot- busting therapy was being undertaken, that would be a tremendous medical advance. Perhaps it would even lengthen the window of time to getting victims into an angi-ography suite for the clot-busting tissue plasminogen activator therapy. Data exists in animal studies showing this seems probable. Today, we are even seeing success in increasing tissue O2 delivery so that cancer radiation therapy can succeed by using PFCs [58]. Yet and unfortunately in the 1990s and early part of this millennium, oxygen therapeutic companies refused to put research dollars into this line of clini-cal trials, instead focusing their wasted energy on competing with banked blood.

Hemoglobin–Based Oxygen Carriers (HBOCs)

Two main lines of oxygen therapeutics have been in development for a very long time. One is based upon human, mammalian, or other animal (earthworm, sea worm, etc.) hemoglobin [30]. Man-made oxygen carriers (perfluorocarbons (PFCs)) are based upon carbon skeleton molecules that have been hydrogen substituted with halogens [55]. Mostly, the halogen utilized has been fluorine and the resulting sets

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of molecules carry oxygen by enhanced solubility. HBOCs, of course, carry O2 by molecular binding. HBOCs have the longer history beginning with early efforts to utilize stroma-free hemoglobin.

Hemoglobin has been regarded by doctors and physiologists as the molecule leading to O2 transport in the blood. In cells, hemoglobin is a tetrameric protein with two sets of alpha and beta subunits. It is cooperative in terms of the binding and release of O2 as the sets of globin molecules take up oxygen they create a con-formational change in the next to or surrounding globulins, leading to a sinusoidal oxyhemoglobin dissociation curve. Each of the proteins is further structurally influ-enced by chemical modulators of certain residues so that oxygen binding/release is affected. Chloride ion, hydrogen ion (pH), and 2,3-DPG all shift the dissociation of oxygen, making it either more or less tightly bound. For example, a more acid pH, more hydrogen ion, causes the hemoglobin to less tightly bind, or more easily release O2. That would make physiologic sense in that tissues that are acidotic could well be O2 starved, i.e., being more dependent upon anaerobic metabolism and lead-ing to creation of bio-acids. The release of hydrogen ion would then provide a feedback to more easy release of O2 to such anaerobic tissues. These physiologic events, of course, are all predicated upon the study of hemoglobin inside the erythrocyte.

Therefore, the natural conclusion is that if one were to create a pharmaceutical fluid that would supply O2 to tissues, it should/could contain hemoglobin. Early efforts at HBOCs used lysed erythrocytes created by simple low-tonicity hydrolysis of cells, some filtration and precipitation of cellular debris, followed by the resus-pension of the resulting hemoglobin in saline. In the 1930s, this was first done and stroma-free hemoglobin was injected into hemorrhagic shock created cat models [59]. The cats recovered from the hemorrhagic shock, thought to be due to the infused stroma-free hemoglobin, but died fairly soon afterward with renal failure and hypertension. Dogs injected with bovine hemoglobin from lysed cells had simi-lar fates [30, 60, 61]. The hypertension was thought to be due to “an unknown pres-sor response” in conjunction with colloidal imbalances drawing in free water [61]. The conclusion was that the hemoglobin worked to treat the shock but that the impurities in the stroma-free slurry were such that cellular debris was clogging the renal tubules. At that time, no one knew of the renal toxicity of hemoglobin.

This early group of cat experiments did not deter efforts to create cell lysed hemoglobin from being injected into humans [30, 23]. In the 1950s, experiments in humans with blood loss had the same outcomes as in the cats. Fifteen patients were given this slurry of material suspended in lactated Ringer’s solution, and this led to cardiac dysfunction, hypertension, and renal failure as well as some deaths. The developers of HBOCs were yet undeterred [23]. One should note that some of these same early problems are the ones plaguing investigators today, yet the worship of and pursuit of hemoglobin-based oxygen carriers is gaining a rebirth.

There were nausea, vomiting, chest pain (angina described as tightening of the chest), back pain, and groin pain along with fevers if injections were more than 10 gms of free hemoglobin. The earlier researchers were puzzled that icterus and jaun-dice seemed to not occur.


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A single case reported in 1949 is instructive of these early efforts to use hemoglobin- saline solutions. A 22-year-old female with postpartum hemorrhage was in extremist situation and pulseless when she was given all the plasma and whole blood available in a hospital. Those infusions brought her back to having an 80 mmHg systolic pulse, but her uterine postpartum hemorrhage continued, and the team requested the use of an experimental hemoglobin-saline solution because no more type and crossed blood could be obtained [23]. The patient received a total of 2300 cc of the solutions containing up to 250 gm of hemoglobin. She developed blood pressures above 140/90 and then began speaking and thinking. Her early function looked good except she had a temperature to 103 and 104 F sustained for hours on end. By the second day “kidney block” with urine output below 5 cc/hr. developed and “neurologic block (unconsciousness) by day 5 ensued. On the 9th day she expired in uremic shock with complete heart block, followed by cardiac arrest [23].

The worship of hemoglobin as a savior went on! This group went on to inject 77 patients with their solution, only one in hemorrhagic shock as described above. They described common renal dysfunction and failure but thought it could be over-come by giving “alkaline” fluids to shed the hemoglobin through the kidney. Somehow they continued to conclude that the use of hemoglobin-saline solutions improved oxygen delivery, yet no techniques of blood gases or tissue oxygenation had yet been invented [23]. There were no direct or indirect measures of O2 delivery, yet they steadfastly noted increased O2 delivery. We can marvel or rale at the lack of protections of human subjects at that time, but the belief in the “goodness” of hemo-globin still persists today.

No one at that time had conceived of nitric oxide (NO) as a vasodilator nor did anyone know of the effects of free hemoglobin extravasation from the vasculature through tight junctions between endothelial cells. The knowledge that methemoglo-bin was important was known but not appreciated to be a problem with these fluids. Hemoglobin outside of red cells is devoid of antioxidant buffers, very quickly and in large percentage converts to methemoglobin (no longer able to participate in oxygen transfer). The tetramers of hemoglobin when free in plasma rapidly break down into dimers and monomers. Free heme is highly toxic with the body having a very complex series of proteins for binding free hemoglobin and hemin (haptoglo-bin, ferritin, etc.). It turns out that free hemin is itself highly reactive for the reticu-loendothelial system as well as macrophages. The upregulation of inflammation in macrophages filled with heme along with the deposition of free hemin in the liver, spleen, and kidneys is highly toxic. Once research had begun to conclude some of these findings that breakdown of the tetramers was a problem and that potential endothelial absorption or movement of the stroma-free hemoglobin out of the plasma into the immediate perivascular space was likely to occur, then a movement began to change the stroma-free hemoglobin. The effects of binding NO away from the perivascular smooth muscle were simply not known back in the 1940s and 1950s [23]. But it quickly became evident that hemoglobin needed to stay intact as a tetramer. If the molecular structure of the hemoglobin were such that it would stay intact and molecules could not diapadese through the tight junctions. If tetramers

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and larger hemoglobin could be created intravascular dwell time in the plasma would be lengthened as well perhaps some of the toxic side effects would be less-ened. But as that was done, each one was again another experiment into something nature has never made.

In the 1960s to 1970s, work proceeded with Department of Defense grants and Baxter pharmaceutical to produce diaspirin cross-linked hemoglobin [30, 59, 61]. Hemoglobin can be cross-linked rather easily with glutaraldehyde. In some of the early cross-linked hemoglobin, the first step was to use pyridoxal phosphate (similar to 2,3-DPG) to stabilize the glutaraldehyde linkage between amino acids. Once this first step with glutaraldehyde had been accomplished, then other specific (and pro-prietary) different cross-linkers were utilized by different companies [30, 59, 61].

The product produced by Baxter used α subunits of human hemoglobin har-vested from outdated human blood which was then acetylated with bis(3,5- dibromosalicyl) fumarate [22–25, 28, 29, 61, 62]. The linkage was highly specific for the Lysineα199 residues which are internalized inside the globins. Diaspirin is not related to aspirin, the drug, at all. This lysine cross-linked tetramer was therefore highly resistant to being broken into dimers and monomers.

Early work was conducted in hemorrhagic shock rat models wherein the animals were maintained for up to 30 min at a blood pressure of 35–40 mmHg leading to acidosis and dramatic changes in key organ perfusion. Brain perfusion was decreased by 26% and the kidney had a 65% decrease [23, 30, 61]. Resuscitation with crystalloids did not improve either brain or renal blood flow. However, in this immediate and short-term (time) study, brain perfusion increased 112% (compared to lowest) with the diaspirin cross-linked hemoglobin solution, while the kidney perfusion rose 178%. Early animal studies led to larger animal studies including a specific swine study commissioned by the Army in preparation for the first Gulf War [23, 30, 61].

That swine study was meant to mimic hemorrhagic shock with a delayed time to rescue from the battlefield [63, 64]. Animals were made dehydrated, as a soldier might be going into battle in the desert. This was followed by a 50% blood volume shock removal of blood. The animals then were randomized to receive 5% albu-min, Ringer’s lactate, or one of the two hemoglobin solutions including the DCLHb. A period of time then ensued to simulate waiting time for evacuation with no further resuscitation efforts made. Both hemoglobin components increased blood pressure much better than crystalloid or colloid, but did not increase survival or other key factors. In reality, the hemoglobin components drove the vascular resistance very high, but the cardiac output, already low due to hemorrhagic shock, fell further or did not improve to the same level seen with either Ringer’s lactate or albumin [24, 25, 28, 63]. The lack of increased cardiac output, hypertension, and severe vasoconstriction led the Army to back off further development. The Army then took a much more passive role as they watched the human trials unfold with Baxter leading the way.

Baxter led the trials then into various groups of patients, many of which, like all too many pharmaceutical trials, are not published [23–28]. The trials were not all aimed at hemorrhagic shock. Indeed, some were focused upon brain and heart


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ischemia for which they postulated acellular O2 delivery might well be a great pharmaceutical treatment. In stroke a phase II increasing dosage trial of 25, 50, and 100 mg/kg DCLHb infused within hours of acute stroke diagnosis was under-taken [24, 25]. So this was a trial looking at tissue ischemia as mentioned prior in terms of unmet needs. There were at least 8 patients in each arm (the 100 mg/kg arm had 11 patients) and 26 placebo patients were also randomized. In terms of blood pressure and endothelin- 1, renin, catecholamine, etc., this study was aimed at trying to understand more of the hypertensive responses to HBOCs. Normally after stroke, there can be a hypotensive response (central nervous system shock), but in those who received the DCLHb, there was a severe hypertensive response, the worst being in the group with the highest treatment. Endothelin-1 increased in response to increasing dosages, tripling in the highest group. Hypertension and plasma endothelin-1 correlated. In an overlapping clinical trial of 85 patients, patient outcomes were worse with the DCLHb, noting that more serious adverse events and deaths occurred with the use of the HBOC. One might well have postu-lated that early use of an intravenous method to increase O2 tension as well as perfusion in penumbral regions of the brain at risk would salvage brain and improve outcome. Two patients in the highest dose of DCLHb had fatal brain and pulmo-nary edema. Pancreatic and renal insufficiency or failure was another problem encountered.

A trial in cardiac surgery wherein increased hemoglobin and O2 delivery would be postulated to improve outcome was carried out. Almost 2000 patients were screened, yet only 209 had excessive bleeding meeting the criteria that they would require a blood transfusion [30, 61, 62]. They were randomized to either DCLHb (104) up to three 250 ml infusions or packed red blood cell transfusion (105) with a primary outcome being avoidance of transfusion overall. As one could predict from the design of the study, far fewer in the DCLHb were transfused (only 19%), whereas 100% of the controls were transfused. The mortality was not different. Unlike other work, renal failure was not different in these cardiac surgery patients, but the ones who received DCLHb hypertension, jaundice, hyperbilirubinemia, and liver enzyme elevations were noted in the group with DCLHb. Of note, the stroke work mentioned had not been matched against an equal amount of red blood cell transfusion. The study in cardiac was heralded as a success because the number of red cell units transfused was reduced; however, the authors did note that with the DCLHb cardiac output values decreased along with the elevation in blood pressure, not the other way around. The work continued.

In yet another study with 24 patients slated to have surgery at high risk for major blood loss, groups were randomized to get either packed RBCs or DCLHb up to 1000 mg/kg with an assessment of vital signs and organ functions. Orthopedic and general surgery cases predominated, and the blood loss was between 27 and 31 ml/kg during surgery. During surgery there were far fewer PRBCs administered in the DCLHb group, but after that time period in the ICU and later the numbers of trans-fusions were no different. In the DCLHb group, 4 of 12 patients avoided transfusion all together [30, 61]. There were no MIs, strokes, or pulmonary edema events with the DCLHb, but the ones who got the DCLHb had a higher (deemed better) blood

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pressure than the transfused group. Three of the DCLHb patients had prolonged ileus, and two of these had elevated liver enzymes. No differences were seen in creatinine clearance. The study was deemed successful, although those that received the HBOC were more jaundiced than the transfused patients [30, 61].

The determination to follow HBOCs as a treatment compared to standard of care (large-volume crystalloid) turned to acute trauma, both blunt and penetrating. Two parallel studies in the United States and Europe were carried out with 219 patients wherein patients were randomized to get either normal saline or DCLHb in resusci-tation. Those who got the DCLHb had higher blood pressures at several time points, and their lactate levels were for some reason higher in the US centers than in European centers. Also the shock severity index was higher in the US centers than in European centers (perhaps reasoning for higher lactates) [30, 61]. What ulti-mately stopped further work on this HBOC was that in these trials there was a 72% increase in mortality with the DCLHb compared to saline. Subgroup analysis between US and European centers was debated for some considerable amount of time, but that is probably of little importance [23–28].

Baxter had invested heavily in creating a manufacturing plant in Europe for DCLHb. With the bad outcomes from this one trial that investment was scrapped as was other investment by Baxter in perfluorocarbons, they were sponsoring to go through human trials. Therefore, the failure of the HBOC trial had implications for the future development of a PFC and indeed all oxygen therapeutics. One has to wonder if these problems could have been foreseen from the rat as well as early stroma-free hemoglobin studies. One has to also wonder if the entire future develop-ment of oxygen therapeutics has been overshadowed by these trials and the business decisions. “Wall Street” money has decreased and the sector has had bad press in one form or another ever since.

Other pharmaceutical houses picked up from the diaspirin failures or overlapped with different methods to increase the size of the molecules of hemoglobin. Somatogen Inc. from Boulder, Colorado, genetically engineered bacteria or yeast to turn out great amounts of human α-chain hemoglobin [30, 61]. They cross-linked the monomers with glycine recreating tetramers of hemoglobin after first glutaral-dehyde fixation creating a product called Optro. This group thought the biggest problem for pharmaceutical development might well be the limited supply of out-dated hemoglobin, but they did not solve the basic problems of hemoglobin toxicity to the microvasculature. They have similarly gone bankrupt with similar hyperten-sion and cardiovascular toxicity.

Hemogen Inc. from Canada used O-raffinose to cross-link their human out-dated blood harvested hemoglobin (HemoLink), and Biopure Inc., Cambridge, MA, took the approach to use cow harvested hemoglobin, then cross-linking it with glutaraldehyde (HBOC-201) [30, 61, 65]. Northfield Laboratories used human hemoglobin also to create Poly Heme, a much larger molecular HBOC [66]. All three of these companies had different sized polymers with the idea that the larger the molecules, the longer they would stay intravascularly circulating to carry O2. Each had similar effects upon blood pressure though the larger molecules seemed to have less vascular constriction than did the diaspirin cross-linked


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HBOC. Through a myriad of animal projects, these three companies competed to get into clinical trials [30, 61].

Hemogen Inc. did a pivotal human trial in CABG surgery in 24 medical centers across Canada and Great Britain [65]. The goal was to use the HBOC as a way to extend O2 delivery with aggressive hemodilution. These studies were carried out at a time when the transfusion world focus was upon the risks of HIV transmission by blood transfusion. Hemogen targeted their outcome variable to be reduction in allo-geneic transfusion with the implied idea that the use of allogeneic transfusion by itself was bad, i.e., the risks of HIV transmission. In retrospect, one can critique all of this research in that it was focused upon avoidance of an already flawed therapy (allogeneic blood transfusion) and played upon the fear factor of HIV to be a future reason for marketing. In the HemoLink study, they achieved their goal of having fewer patients who received the HBOC get human allogeneic transfusion. However, in 2003, further development was stopped on the product when further CABG stud-ies showed that those who received the HBOC had worse degrees of hypertension, increased gastrointestinal distress, myocardial damage, as well as renal toxicity. Again these were the same types of findings hinted at from the very beginning with stroma-free hemoglobin and diaspirin cross-linked hemoglobin [30, 61].

Biopure was eventually approved for use in South Africa for uncontrolled hem-orrhage, and perhaps several thousand patients have received it. It is extremely expensive in that country, so the usage is rather minimal [30, 61, 48]. A derivative of it (Oxyglobin, HbO2 Therapeutics, USA) is available for veterinary usage, again being expensive and underutilized. Biopure filed for bankruptcy and was purchased by OPK Biotech, and they have continued research in a product called HBOC-201 [30, 61]. Unlike other companies, OPK has encouraged transparency with public disclosure and scientific publication of results [67, 68]. Noncardiac surgery with expected significant blood loss was the center of that study published in 2014. In that study, patients were randomized, not blinded, to get either up to 7 units of HBOC-201 or allogenic blood for noncardiac surgery, and 83 received the HBOC while 77 received blood [68]. The odds ratio for avoidance was 0.43 in favor of HBOC [68]. Serious and adverse events were not different in the HBOC or alloge-neic transfusion group nor were there differences in mortality or length of stay in the hospital. The study was not powered for these differences but was focused on reduc-tion in transfusion. As the focus in transfusion complications has shifted away from viral transmission to immunosuppression, organ dysfunction, and length of hospital stay, there exists a great debate upon such complications from allogeneic blood and particularly that transfusion in light of length of storage. So to design a superiority or a properly designed non-inferiority study of any HBOC to allogeneic blood trans-fusion still remains a huge logistical as well as statistical nightmare. Even a phase III trial using 150 plus patients does not prove equivalency or non-inferiority. The lack of large differences in HBOC-201 in a series of cases where blood is not avail-able is intriguing [68].

The Northfield Poly Heme trials are worthy of study not only because of their outcomes but in terms of the debate they created and how they opened the research world to human trials without informed consent [68]. In phase II trials in CABG

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surgery, just as others had shown, the use of an HBOC could reduce the use of allo-geneic transfusion [61, 68]. Why pharmaceutical houses thought that reduction in allogeneic transfusion would sway the FDA is now in retrospect a moot point. In the pivotal Poly Heme trauma study, patients were randomized to in-hospital allogeneic blood or prehospital resuscitation with crystalloids or crystalloids plus HBOC. They could then receive further HBOC in hospital before being switched to allogeneic blood. The study showed that those who got Poly Heme received fewer PRBCs [30, 61–68]. Mortality was not largely different so the forward in time use of Poly Heme did not improve outcome over standard therapy. There were more adverse events in the Poly Heme group, and perhaps that reflects some of the earlier findings from animal and other human studies. There were some fascinating process variables col-lected such as tissue oxygen delivery and inflammatory markers. These actually looked significantly better in the group that received Poly Heme and less allogeneic transfused blood. But the FDA does not approve pharmaceuticals based upon inter-leukins, or tissue oxygenation. Of interest in post hoc analysis, there was an improvement in survival in the very low-hemoglobin group with entry Hgb below 5.3 gm/dl who had received Poly Heme. The authors have since noted that the use of Poly Heme functioned well when blood was not an option; however, that is not how they designed the study. The thought that might have hampered the study from having better separation in favor of Poly Heme was that the average time from first EMT contact until hospital entry was only 26 min. Although this had been touted as a civilian way to investigate battlefield injury, the immediacy of contact and entry to a level I trauma center made it such that limited amounts of Poly Heme and time had occurred before definitive therapy was administered [68].

The Poly Heme study and other human trials were all evaluated in a meta-analy-sis of human trials [69]. In the meta-analysis, 5 different products were evaluated from over 70 different human trials. The N was 3711 patients with varied patient populations in different medical conditions including prehospital usage. No single individual trial or product stood out to have either a spike in mortality or myocardial infarctions, but rather the adverse events were spread across the entire pharmaceuti-cal group. When fixed effects models were conducted, death was found to have a statistically higher odds ratio in the HBOC group (OR, 1.30; 95% CI, 1.01–1.61), and the OR for MI was raised as well rather dramatically at 2.71 (95% CI, 1.67–4.40). That meta-analysis essentially shut down HBOC future human trials wherein HBOCs were to be compared as “superior” to banked blood. It did not however stop all HBOC research, but it has certainly refocused that research into the use of HBOC for when blood is not available as well as retooled basic thinking about the side effect profiles of HBOCs in terms of NO binding, oxygen release, excess tissue oxygenation [69].

In one effort to make HBOCs less toxic, it was thought that by using polyethyl-ene glycol (pegylation) enlarging particles of heme that circulating dwell time could be increased as well that hypertension and extravasation would be stopped. Sangart produced a low P50 pegylated Hgb (Hemospan) and performed trials in orthopedic surgery. Other pegylated HBOCs by Enzon USA as well as Apex Biosciences with low P50 have been produced [30]. These agents have undergone European trials


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wherein these seem to be plagued with rises in pancreatic enzyme profiles. In a phase III European trial, Hemospan showed improved oxygen delivery, but renal and cardiovascular dysfunctions still exist [30].

The next set of focus was to make these modified Hgb molecules become less potent as NO sinks. A wide range of biochemical schemas have been attempted to either saturate the hemoglobins with nitrates with S-nitrosylation of cysteine resi-dues or perhaps through some enzyme changes to make hemoglobin act as an NO donor [30, 61, 68, 70]. Furthermore, some have attached specific antioxidative enzymes into their macromolecular complexes including superoxide dismutase or even to get 2,3-DPG, glutathione, and even adenosine into the structures. All of these efforts are, of course, to try to recreate in a pharmaceutical what nature has packed into erythrocytes wherein mammals have evolved to simply have hemoglo-bin away from endothelial and organ cells. Under preclinical investigations now are OxyVita which uses a pegylated Hgb with nitrate donors and SynZyme with a cata-lytically caged NO. Whether these or others like them will make it into late-stage clinical trials is hard to say [30, 61, 70].

Other routes of creating a hemoglobin-based artificial oxygen carrier have now focused on larger and larger hemoglobin moieties. In Europe, nonmammalian hemoglobins are being tested. Earthworm hemoglobin and sea worm, annelid, hemoglobin are being harvested. HEMOXYCarrier being developed by Hemarina, France, is utilizing polychaete annelid worms grown in large shallow seawater ponds, allowing farming of these unique creatures [30]. These complex molecules have 3600 plus KDa sizes, interesting NO donor and CO binding capabilities. To date, the literature shows only animal experiments with this huge molecular com-plex hemoglobin in which less vasoconstriction is demonstrated. How such foreign proteins will behave in larger mammals and humans is yet to be tested. Hamster cheek pouch experiments with animals top-loaded with the worm hemoglobin did not exhibit arteriolar vasoconstriction that has been seen in the same labs with other HBOCs.

In earthworm (Lumbricus terrestris) hemoglobin studies, rat studies show it to be fairly well tolerated [30]. Using earthworm (Lumbricus terrestris) hemoglobin, rat studies to interact with other hemoglobin in that the earthworm one has a large num-ber of O2 binding sites with different redox potentials. It functions as an NO donor, and therefore and perhaps the use of this unique biologic hemoglobin might well function as an HBOC. Again there is a great deal of development and human testing before these worm globins might be useful for human anemia and resuscitation.

And the research industry has developed to create encapsulated hemoglobin that in so many ways mimics erythrocytes. Natural red cells are biconcave discs with estimated 300,000,000 hemoglobin molecules. They average 7–8 um in diameter the greatest dimension with a central diameter of perhaps 1–2 um. The biconcave disc has unique properties in that it allows for folding and flexibility unique in nature, allowing these small cells to travel down capillaries that are 3–5 microns in diameter. The red cells stack in capillaries leading to a stable and unchanging capil-lary hematocrit of 15%. Those red cells that are deoxygenated have poor flexibility due to hemoglobin structural changes as well as the cytoskeletal spectrin changes

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with deoxygenation [30]. To try to mimic a natural red cell is, of course, completely unreasonable. But the industry is trying to chaise this goal.

Different materials as well as microparticle production techniques are being tried. One uses a technique of overlaying lipids over a core and dissolving the core once it is laden with hemoglobin. Another system has used polyethylene glycol along with a hydrogel which can control particle size by the molecular aspects of cross-linking the hydrogels. Some of these hydrogel discs can be molded to bicon-cave shapes with similar sizes to human erythrocytes. In such techniques, human hemoglobin is added later. How they perform is yet to be tested. Surface charge is important. Erythrocytes carry a negative surface charge, repelling each other lead-ing to a natural resistance to aggregation. How to put surface charge onto these particles is yet another challenge. However, some of the liposome-encapsulated hemoglobin particles have shown in animals up to a 72 h half-life. Just as the best P50 is not known for free or large polymerized HBOCs, the half-life, particle size, and best surface charge of the particle are not known. Also not known is if it is important to put antioxidants, 2,3-DPG, glutathione, etc., all in the mix and to what concentrations. Are there other enzymes that are normally found inside an erythro-cyte that should be included? The more we try to recreate natural erythrocytes, a potential solution, the more the cost.

ErythroMer is a polyethylene imine particle that is treated with palmitic acid into a donut shape called toroidal [30]. These have been tested in some early animal work showing promise that they carry and release O2 but the size is 200 nm which may well be an advantage or potentially make them targets for reticuloendothelial scavenging, hence inflammatory upregulation perhaps [30]. None of the encapsu-lated hemoglobin particles are yet into human trial. Will they be trialed head to head against allogenic blood or for the other indications noted in this article?

One technology one needs to examine is the microencapsulated pure O2 with particle sizes of about 2 um [30]. Microencapsulated O2 systems make sense but would probably need continuous infusion. With a 1 h or less half-life the lipid load-ing, micro-capsular load on the RES again may well trigger a number of adverse events. Perhaps such infusion could work for, several hours, limited life periods or limbsaving events. But at this stage, such a technology does not seem to hold appeal for a widespread universal oxygen therapeutic [30].

HBOCs for Patients for Whom Blood Transfusion Is Not an Option

It is impossible to design a clinical trial of HBOCs or PFCs for use in persons who cannot or will decline to receive blood [30, 68]. The compassionate use (now termed “expanded access” by the FDA) of HBOC-201 has been ongoing for a number of years with accumulated case series [68]. Perhaps this bespeaks to a niche utilization of these compounds. In severely anemic and bleeding patients, when the Hgb drops


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below 7 gm/dl and a patient is hemodynamically unstable if blood is not adminis-tered, there is an incremental increase in mortality with each gram drop in Hgb. For JW patients the mortality figures have been well described by several authors sur-prisingly with very similar survival curves. Below 4–5 gm/dl the curve of survival drops dramatically, and although case reports exist of patients as low as 0.8 gm/dl surviving the imputed survival curve below 3 gm/dl shows less than 50% survival. In a 2016 expert meeting at Ft. Detrick presenting updated work with HBOCs, the conclusion of the assembled experts was that randomized trials could not be per-formed in patients who decline transfusion.

In 2017 Weiskopf et al. compared Kaplan-Meier survival curves for those non-transfused JW patients in surgical and “all comers” medical conditions to both an orthopedic trial of HBOC-201 and expanded access, previously known as compas-sionate use HBOC-201 [68]. Two databases of JW survival were examined and combined since little difference was seen in survival over a 20-year period in surgi-cal patients. It is therefore interesting to note that survival has not changed in 20 years when severe anemia occurs perioperative. A total of 593 patients herein were compared to 350 elective orthopedic cases where HBOC-201 was utilized and nadir Hgb was noted prior to HBOC-210. Survival was greater in the HBOC-201 patients compared to the historical surgical non-transfused severely anemic patients [68].

Perhaps this is not an appropriate comparison because the two JW surgical data-bases had emergency, trauma, cardiac, neurosurgery, and multiple other cases, not simply elective, and selected orthopedic surgeries. One has to take the conclusions with some critical eye.

However, when “all comers” medical JW cases were reviewed in the same arti-cle, the relationship to survival was quite a bit less clear cut. The “all comers” group had a higher nadir Hgb at death than did those with surgical cases perhaps meaning that 132 patients who had largely medical admissions as well as severe anemia were more ill, more sepsis, more respiratory failure, etc. than a surgical group. When that 132-patient “all comers,” severe anemia group was compared to 102 “all comers” nonsurgical severely anemic patients treated with HBOC-210, those receiving the HBOC did indeed show a better Kaplan-Meier survival curve. In the group that received the HBOC-201, the median number of HBOC units infused was 6 with 36% of patients receiving 10 or more units over multiple days. The time to death in all the severely anemic patients was 10 days or longer, meaning that often severe anemia does not kill right away. The authors noted that in all of these databases treated or untreated, there was little assessment of nonfatal but important organ hypoxia [68].

The data from the 102 HBOC-201 expanded access patients are important, but far-reaching safety and efficacy generalizations to battlefield, trauma, or emer-gent surgical cases wherein blood is not available cannot at this time be enough for licensing [68]. They are encouraging and should spur further expansion of such programs. Unfortunately, no such data has been gathered for any contempo-rary PFC.

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PFCs

Perfluorocarbon emulsions or PFC microbubbles (NuVox) are completely different technologies than are HBOCs. HBOCs have garnered more attention from govern-ment funding agencies and from scientific and medical communities simply because medicine is so hemoglobin centric. PFCs are man-made organic molecules of dif-ferent length carbon backbones. Straight chain, branching, and cycle hydrocarbon parent molecules are electro-substituted with halogens for hydrogen. The most common and probably the most important bond is the carbon fluoride bond. The carbon fluoride bond is perhaps the highest energy carbon bond in nature [53].

Carbon hydrogen molecules are polar oils. Nonpolar respiratory gases do not dissolve well in polar liquids. Water is a perfect example of a highly polar molecule; hence, O2, CO2, and N2 do not dissolve well in plasma. We transport a great deal of O2 because of hemoglobin bonding and CO2 is highly soluble in blood because it is buffered with bicarbonate as well as hemoglobin is the highest binder of CO2. At high pressures and cold temperatures in the deep sea, some fish have circulatory systems without hemoglobin because enough O2 can be dissolved in the plasma that no other gas-carrying capacity is necessary [53].

One should realize that all metabolic O2 is dissolved O2. If an additive to plasma (e.g., PFC emulsion) functionally changed plasma so that O2 was much more highly soluble, a number of useful characteristics might well change. All O2 carried in PFCs dissolved is immediately available for metabolic processes. The O2 moves out of the PFC particles based only upon partial pressure diffusion gradients. When PFC particles are injected, they intersperse with the RBCs circulating. The PFC particles therefore form a third gas transport compartment, the others being Hgb and dissolved O2 in plasma. Equations for that gas-carrying capacity have been written based upon the solubility coefficient of gases within the PFC.

PFC dissolved O2 rapidly equilibrates with the surrounding tissue and blood par-tial pressure of gas. There is no dissociation curve for O2 from PFC as there is for O2 from Hgb. Acidosis, 2,3-DPG, chloride, and other factors affecting Hgb do not affect PFC. However, temperature dramatically affects gas solubility. The colder the temperature, the more gas dissolved. That may well be important in future usages of these compounds if cold PFC infusions might be utilized as organ preservation solu-tions, cardioplegia, or even central cold resuscitation solutions for brain cooling after cardiac arrest. The PFC emulsions have a very high cooling potential.

If a hydrocarbon, such as benzene, is halogenated, it changes. With half the hydro-gens removed the cyclic hydrocarbon becomes an anesthetic, although highly hepato-toxic. It has no increased O2 solubility. When all hydrogens are substituted with fluorine, the molecule becomes highly nonpolar and has up an O2 gas- carrying capability of 60 volume%. Whole blood can carry only 21 volume % O2 [53].

Perfluorocarbons are oils. As such, they are immiscible with water-based fluids, i.e., plasma. The challenge in making a perfluorocarbon emulsion has been to create an emulsion particle that is stable, has a high enough concentration of perfluoro-


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carbon to enhance gas solubility and to have an emulsion method that is nontoxic as well as one that has a decently long plasma half-life. Furthermore, particle size may well be important and stability of particle size over time in storage is particularly important. If PFC emulsions are stored with time, a process known as Ostwald’s ripening occurs wherein particle coals join and grow larger. It is therefore important to use fairly fresh PFC emulsions, and each product has different characteristics, making it at times difficult to draw conclusions [53].

The PFCs were first developed by the Japanese in the 1960s and led to the pro-duction of a first-generation product name, Fluosol-DA-20%. This agent was uti-lized in an unknown number of cases in Japan and was introduced into the United States by Green Cross Corporation. They established a regulatory series of human studies for treatment of surgical anemia as well as tissue ischemia. Their pivotal trial should be instructional for how these compounds could be utilized. At the time that the study was conducted, early balloon catheters for coronary atherosclerosis were being employed. These catheters did not have flow-through capabilities; therefore, whenever they were inflated, obligatory coronary ischemia resulted. If Fluosol-DA-20% was infused prior to inflation of the balloon and therefore obstruc-tion of a major coronary artery, the myocardial infarction rate and death rate were reduced. Fluosol-DA-20% was given FDA clearance for coronary ischemia, and it should be noted that it is the only oxygen therapeutic yet to gain regulatory approval in the United States [53].

Fluosol-DA-20% was supplied frozen, needed to be thawed, and then re- sonicated to assure particle size was uniform. It was used in only 15,000 coronary angioplasties because that process was labor and time consuming. Today, Perftec/Perftoran is marketed in Russia, Kazakhstan, and Mexico. It is based upon Fluosol’s parent structuring, but the Russian compound has a more modern emulsion chemis-try. There is an extensive literature, in Russian, testifying to its utility as well as downplaying any toxicity issues. It is utilized in trauma in Russia and has been uti-lized by the Soviet army during their invasion of Afghanistan [71]. Some entrepre-neurial persons have tried, as yet unsuccessfully, to bring it to the United States for testing and approval.

Second-generation, US-produced PFC emulsions were tested from the mid- 1990s to present day [53, 72, 73]. Alliance Corporation, San Diego, created an egg- yolk/lecithin phospholipid emulsion of perfluorooctyl bromide and perfluorodecalin. This was known as Oxygent. It underwent extensive animal preclinical testing as well as trials in orthopedics and heart surgery. In orthopedic surgery, it demon-strated that when anemia due to hemodilution was encountered, the use of Oxygent meant a higher mixed venous oxygen level, connoting better tissue oxygen delivery than in patients not receiving the infusion. In both heart surgery and orthopedics trials of Oxygent were able to demonstrate that less allogeneic blood was transfused when elective autologous hemodilution was carried out in operating theater using Oxygent as an adjuvant [53]. The failure of this agent in a final phase III human cardiac surgery trial has set the entire pharmaceutical sector back for years, but that will be discussed later. It is important to note that the Alliance Corporation did not heed the lessons instructed from Fluosol-DA-20% in that these agents could be

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utilized to treat tissue ischemia. Rather, the administrative oversight of Alliance pursued the contemporary view that oxygen therapeutics could compete with allo-genic blood.

Other second-generation PFC compounds were tested, including one by Hemagen Inc., St. Louis, MO. That compound appeared very promising and was backed financially by Baxter Inc. [53] Hemagen took a different view that indeed not only could PFCs carry O2 but they had a huge solubility for N2. N2 microbubbles are a constant threat to neurologic tissues during and after cardiac surgery. In animal work it had been demonstrated that up to 95% of the bubble load from the bypass machine could be absorbed if PFC was present in the circulation [74–78]. A phase II human trial was underway in the United States and Great Britain when Baxter withdrew support from all “blood substitute”/oxygen therapeutic development after the diaspirin cross-linked HBOC failed. That withdrawal of support by Baxter ended development of a potentially winning PFC to be used for a creative niche need. Hemagen’s PFC still exists, as do patents for its production, but no pharma-ceutical group has taken up further development [53].

Synthetic Blood International had yet another two PFCs. One was a highly con-centrated (up to 80 plus % PFC to emulsifier) that ended up being utilized only in animal-based research [53]. The other emulsion (Oxycyte) which is 60% perfluoro-cyclohexane was further tested in animals, and the company changed its name to Oxygen Biotherapeutics. Oxycyte was utilized for a trial in nine severe traumatic brain injury patients (unpublished data, abstract only) with very low Glasgow coma scores. TBI is, after initial impact, a problem of swelling and microcirculation dys-function leading to a viscous cycle of decreased brain tissue partial pressure, further ischemia, and more swelling. In animal experiments with the PFC, and others, treat-ment shortly after brain impact can preserve brain tissue. Oxygen Biotherapeutics was caught up in the FDA anxiety/caution after the failure of the Alliance phase III pivotal trial in heart surgery. However, that product (Oxycyte) is now being tested by a different pharmaceutical firm for treatment of cerebral ischemia in acute stroke in Scotland. No data is yet published but some work in animals had showed that this approach ought to be effective. If one interprets the data from the Fluosol trials, the use of PFCs in ischemic tissues wherein vascular flow is limited is very rational [53, 78, 79].

Our laboratories have demonstrated that the use of PFC emulsions can supply O2 to tissues with very little blood flow [53]. The enhanced diffusion of O2 in plasma containing PFC has been demonstrated by others [80]. A 10–50 fold increase in plasma O2 diffusion occurs when PFC is present. Data from our microcirculation laboratories showed that when the feeder arterioles are occluded either with an air embolism or by external compression if PFC has been infused, then tissues down-stream can maintain cellular O2 delivery [53, 74]. That one single finding could make the use of PFC revolutionary in medicine. As such, the use of these com-pounds in all types of tissue ischemic diseases would represent a breakthrough. But such work does not in itself prove utility of PFCs as O2 carriers for the instance when blood is not available. To this author’s knowledge there is no present-day ongoing project to use PFC for trauma when blood is not available.


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The failure of Alliance’s pivotal phase III cardiac trial should be instructive in terms of how not to do this research going forward. The study was designed with unequal technologies to severely hemodilute patients prior to cardiopulmonary bypass. The focus was upon using PFCs as a “blood substitute” allowing for more extensive hemodilution prior to surgery if PFC was infused. There was an increased stroke rate in patients who received the PFC as compared to controls (just hemodi-luted with colloid) [53]. The stroke rate was statistically higher in the PFC group but this and the control group had lower stroke rates than any otherwise published stroke rate for heart surgery. Some researchers who had been involved in a phase II previous trial noted and hypothesized that the PFCs might well be activating plate-lets and creating a nidus for embolisms to the brain. They based this on the fact that in their phase II trials they had used a transcranial Doppler technology to follow cerebral blood flow. With the infusion of PFC a sudden and striking rate of cerebral embolic counts was noted by the TCD. This phenomenon had been noted before by our laboratory and by many others as the PFC is itself and echo contrast and it is therefore expected that it will create echogenic foci especially when first infused. No other animal or human experiment had ever shown an increase in neurologic dysfunction or emboli. Indeed, in a large swine bypass model, the use of Hemagen’s PFC dramatically protected the brain from stroke. The FDA required that PFC com-panies prove that their infusions did not activate platelets and thereby create a stroke risk. That work is now being completed but the answer regarding the adverse events seen in the Alliance trial will need to be closely monitored for years in the future if further human trials are forthcoming.

A unique PFC formulation stands alone. NuVox Corporation has developed an emulsion of perfluoropentane, a very short-chain and therefor volatile PFC [81]. The boiling point of that PFC is below human body temperature. When the emul-sion is injected, the emulsion swells as the perfluoropentane partially vaporizes inside the emulsion envelope. Because of its short chain length it is rapidly elimi-nated from the body by the lungs. The ultrasmall particle size as well may be a plus in that the reticuloendothelial system seems not to scavenge the PFC particles. Tissue O2 delivery is enhanced with this PFC and the company is now pursuing tri-als in stroke and sickle cell crisis and is trying to get preclinical work done on TBI.

This NuVox product has a short half-life, which in the past has been critiqued by the HBOC community. The HBOC community has also criticized PFCs as a phar-maceutical class because the calculated O2-carrying capacity of the PFC is such that to get a whole body O2 utilization supplied by PFC they have felt the patients must breathe 100% fiO2. That viewpoint has led the PFC development companies to increase concentration of active fluorocarbon inside the emulsion particles to the point that these emulsions have become viscous and difficult. Historically one should remember that Fluosol worked well and was approved by the FDA for tissue ischemia. Fluosol is a 10% w/v emulsion whereas some of the 2nd generation ones are up to 80% w/v. It is too bad that the pharmaceutical companies were so influ-enced by the hemoglobin centric thinking rather than embracing and understanding the effects of PFC upon microcirculation and diffusion rather than following the whole blood total O2 content equations. HBOC, not PFC, experts appearing as

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speakers and writers have at times pronounced the death of PFCs yet work is ongo-ing, they are utilized in countries around the world including Russia, China and Mexico. The only place that an HBOC has been approved is in South Africa and its sale there has now been curtailed.

The Future

It is clearly hard to see into the future. However, there seem to be places for both HBOCs and PFCs in medicine’s future. The days of focus upon these agents as “blood substitutes” should be forgotten. Newer expanded contemporary thinking about tissue O2 requirements taking advantage of the unique aspects of each phar-maceutical class makes scientific sense. Because the HBOC industry has competed and in some ways worked to defeat the PFCs, there has been little liberal thinking of how the two classes might work synergistically. Combined infusions are rarely approved by regulators, but it makes sense that smaller amounts of each might work well to reduce toxicity from either class and enhance O2 delivery to tissues in a complimentary way. At the present time, there are no investigative efforts to explore this yet we truly need a “best” IV fluid. No radical improvement in intravenous therapy has been created in 50 years. Work with altered albumin, particularly poly-ethylene glycol linked albumin, may reopen the microcirculation after hemorrhagic shock. Could such a fluid with an enhanced O2 delivery agent be of great use for battlefield situations? We don’t know and it is probably true that simply using an enhanced O2 delivery agent without reopening the microcirculation is incomplete therapy. Clearly a great deal of work remains to be done.

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https://doi.org/10.1097/SHK


Chapter 20Role of Blood Bank, Transfusion Services, and Pharmacy in ICU Patients with Hematologic Challenges

Joseph E. Cruz, Jeffrey Nemeth, and Ana Burga

Evolving Roles in Healthcare

Pharmacists and laboratorians, especially those in transfusion services, have emerged as integral members of the care team in the hospital setting. The migration of pharmacy practice from being solely based on medication preparation and dis-pensing toward a more patient-centered practice model has been ongoing for decades [1] and continues to advance as technology improves [2]. Medication dis-tribution functions are still largely carried out by pharmacists and pharmacy techni-cal staff, but the emergence of clinical pharmacist practitioners as direct care collaborators, particularly in the ICU setting [3], has been well documented and endorsed by key stakeholders in the medical community across various care settings [4–7]. The recently re-branded Pharmacy Practice Advancement Initiative (PAI) by the American Society of Health-System Pharmacists (ASHP), for example, is aimed at building a new pharmacy practice model to meet this forthcoming need [8].

The field of transfusion medicine as a subspecialty of pathology or hematology has been undergoing similar fundamental changes over the recent years. Pathologists are increasingly taking on a more proactive and essential role in patient care due to a similar shift from the traditional product-centric model of care to one that focuses on individual patients. This evolution in roles comes as no surprise given the increas-ingly complicated nature of health problems, an aging population, and the expand-ing number of therapeutic agents used to manage disease. Indeed, pharmacists and laboratorians, along with other healthcare practitioners, have been tasked with improving the quality of patient care and achieving better outcomes in a financially judicious manner (the essence of modern healthcare reform) [9]. Transfusion medi-cine has begun to recognize allogeneic blood transfusion as a de facto tissue trans-plant with multiple corresponding risks and complexities. The core clinical question

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of whether or not to transfuse a patient has become complicated – a greater focus is now being place on what else can be done to reduce the need for transfusion while still achieving desirable outcomes. As these roles continue to evolve moving for-ward, it is imperative that pathologists and pharmacists have the proper resources and training necessary to carry out practices core to the ideals of Patient Blood Management (PBM) [10].

Patient Blood Management at the Intersection of Pharmacy Practice and the Blood Bank

The Society for the Advancement of Blood Management (SABM) defines PBM as the application of evidence-based practice to “maintain hemoglobin concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient out-come.” Strategies used in PBM to achieve this goal include (1) managing anemia, (2) optimizing coagulation and hemostasis, (3) interdisciplinary blood conservation techniques, and (4) patient-centered clinical decision making [11, 12]. While PBM does seek to minimize the use of blood transfusions indiscriminately, it does support the judicious, evidence-based use of allogeneic blood transfusions when appropri-ately indicated and when they cannot be avoided by using other therapies with simi-lar or better risk-benefit profiles [13, 14].

The concept of employing a truly evidence-based approach to care is not foreign to pharmacy practice – pharmacists have favorable attitudes toward the core tenets of evidence-based medicine (EBM) [15] and routinely use EBM to make clinical interventions, guide appropriate medication dosing, and affect policy change through pharmacy and therapeutics (P&T) committees at the institutional level. Medication use throughout an institution is governed by P&T, and pharmacists can participate in developing policies governing storage, ordering, preparation, and administration of high-risk and expensive therapies. Likewise, laboratorians can help to maximize the benefits of therapeutic modalities through their participation in blood utilization committees. Maintaining governance of medications and blood components under the watchful eyes of pharmacies and blood banks allows for rig-orous analysis of usage and appropriateness, ultimately with the goal of improving patient care and better outcomes. Laboratory and pharmacy staffs have experience with the use of technology and decision support systems, which have demonstrated effectiveness in improving utilization of blood components and promoting PBM measures [16]. As a result, both disciplines must actively participate in and spear-head implementation of these initiatives.

To be able to take on these important roles, pharmacists and blood bankers (transfusion services) must recognize the need to expand their knowledge base and commit to taking the necessary steps to bridge their potential knowledge gaps with additional education, mentoring, and board certifications (for pharmacists either board certification in pharmacotherapy [BCPS] or board certification in critical care pharmacy [BCCCP]). It is important that both pharmacists and pathologists under-

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stand the medications and products used in PBM, why they are used, the difference between them, and their storage requirements. Additionally, both disciplines will need to have the ability to review physician orders for appropriateness, ensure pro-tocol compliance, and troubleshoot any issues related to product preparation and dispensation. With PBM being increasingly adopted as standard of care given its role in improving the outcomes of patients [17], its inclusion is timely and appropri-ate in initiatives aimed at transforming pharmacies and blood banks to prepare them for practice in a new clinical environment.

Medications, Factors, Concentrates, and Other Agents

A growing number of medications have been used or considered for use as part of PBM strategies. The field of so-called pharmacologic alternatives to transfusion has the potential to transform traditional approaches to anemia, bleeding, and related issues. Here, we provide a review of several therapeutics, although diligence in maintaining clinical knowledge in the field will be necessary due to the ever- changing nature of the field.

Hematinic Agents

Hematinics stimulate and support the hematopoietic capability of the bone marrow, which can increase red blood cell (RBC) count and hemoglobin levels. Erythropoietin-stimulating agents (ESAs) have been studied and used clinically to manage anemia in the perioperative setting, following bone marrow ablative che-motherapy for cancer, and anemia due to chronic kidney disease. Clinical trials have consistently supported the efficacy of ESAs in treating anemia and reducing the need for allogeneic blood transfusions. There have been reports of increased risk of thromboembolic events, cardiac events, stroke, malignancy progress, and death associated with the use of ESAs, resulting in the revision of the labeling of the ESAs to include a black box warning [18]. It has been suggested that these risks may have been related to the pre-existing conditions of the studied patients, lack of prophylac-tic anticoagulation, lack of consistent iron replacement therapy, and treatment using escalating doses of ESAs to achieve arbitrary hemoglobin levels in patients with timid hematopoietic response. Hence, it appears that the risk is lower when short courses of ESAs are used for certain patients and indications, such as anemic patients undergoing elective surgery [19].

Despite ESAs relatively consistent effects on increasing the concentrations of hemoglobin and hematocrit, their effect on other clinical outcomes, such as number of units of blood transfused, has varied in trials evaluating critically ill patients. In one randomized trial, administration of 300 units/kg/day of recombinant human erythropoietin for 5 days, followed by every-other-day dosing, resulted in a 45%

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reduction in the total amount of blood transfused in critically ill patients [20]. A subsequent trial in critically ill patients in long-term acute care facilities showed similar benefits, with fewer blood transfusions required in patients treated with recombinant human erythropoietin [21]. However, a larger trial involving epoetin alfa administration to critically ill medical, surgical, and trauma patients failed to show a reduction in the number of patients requiring transfusion and the amount of total transfusions used. While patients did achieve increased hemoglobin concentra-tions when treated with ESAs, there was also a corollary increase in the rate of thrombotic events [22]. Based on these studies and other conflicting data, along with the Food and Drug Administration (FDA) warnings surrounding ESA use, there has been some resistance to the use of this therapy outside of very narrow indications. Judicious use of these medications as part of a multifaceted PBM strat-egy should be considered in lieu of abandoning them entirely, and new data may actually elucidate further patient populations that could benefit from ESA use in anemia despite their inherent risks [23].

Iron deficiency anemia is a common condition that can increase the risk of trans-fusion and negatively affect the outcomes of patients [19]. Anemia is a multifacto-rial condition, but iron deficiency is often a contributing factor even if it is not the main causative factor. When patients are in inflammatory states, regulatory mecha-nisms, such as the action of hepcidin, can inhibit the absorption of iron from the gastrointestinal (GI) tract [24]. Reduced bioavailability of iron may also occur dur-ing phases of rapid hematopoiesis (e.g., following treatment with ESAs), causing “functional” iron deficiency. Oral iron formulations are slow to exert their therapeu-tic effect due to absorption from the GI tract being a rate limiting factor in their utility. Patient intolerance and subsequent nonadherence can also lead to poor out-comes [25].

Intravenous (IV) formulations of iron act faster since they do not require enteral absorption. Modern preparations of IV irons are typically much safer than the tradi-tional dextran-based formulations [26]. Using IV iron concomitantly with ESAs has been shown to increase the effectiveness of treatment and can help to reduce the required dose of ESAs to achieve desired results [27]. Expert opinion has high-lighted IV iron as a treatment modality in critically ill patients with existing iron- deficient anemia, but it is important to acknowledge the potential risks associated with its use as well [28]. In a recent study, anemic critically ill patients treated with IV iron were observed to have increased hemoglobin levels by the time of their hospital discharge. There was no statistical difference in the number of transfusions needed between the IV iron and control group, but an absolute difference in RBC transfusion totals was observed (97 units in the IV iron vs. 136 units in the control). The authors of this study noted that there were methodological limitations which may have resulted in an underpowered analysis, so further research is required before dismissing the role of IV iron in this patient population [29].

Treatment with hematinic agents is often supplemented with ascorbic acid, vita-min B12, vitamin B6, and folic acid to provide theoretical advantages in supporting hematopoiesis. These vitamins and other supplements used in conjunction with

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hematinics are relatively inexpensive and safe when prescribed at typical doses. There is some evidence that androgens may have a role in the treatment of anemia, but a stronger evidence base is needed to establish the efficacy of this treatment before its use can be widely recommended [30].

Hemostatic Agents

Minimizing blood loss is key to employing a successful PBM strategy. The coagula-tion cascade is rapidly activated when bleeding occurs and the formation of a fibrin clot can subsequently work to effectively arrest blood loss. At the same time, fibri-nolysis begins to occur to keep the fibrin formation regulated and to prevent exces-sive clot formation [31]. While the fine balance between these two mechanisms is paramount, pharmacologic agents can be used to modulate the balance of this pro-cess in one direction or the other, at the local or systemic level, in order to achieve hemostasis. Hemostatic agents act by promoting fibrin formation or can inhibit its degradation at the sites of bleeding to reduce blood loss [32].

Antifibrinolytic agents act by inhibiting the fibrinolytic action of plasmin, which results in longer persistence of fibrin clots at the site of bleeding. Two available thera-pies, ε-aminocaproic acid (EACA) and tranexamic acid (TXA), prevent the conver-sion of plasminogen to plasmin and its binding to fibrin [33, 34]. Despite its demonstrated effectiveness in reducing blood loss and transfusion, another antifibri-nolytic therapy, aprotinin, was withdrawn from the US market in 2007 based on reports of increased mortality and serious complications associated with its use [35]. Some evidence suggests a parallel increase in transfusion (e.g., in cardiovascular surgery) following market withdrawal of aprotinin [36]. Nonetheless, TXA and EACA are still in use, and studies have validated their effectiveness in reducing blood loss and transfusion while still supporting their overall safety [37]. Notably, early treatment with TXA has been found to be associated with reduced risk of death from bleeding in trauma patients [38]. Antifibrinolytics are also effective as topical hemostatic agents. Studies indicate that these agents can reduce over 200 mL of post-operative bleeding, subsequently avoiding the need for transfusion of 1 unit of blood on average in cardiac surgeries [39]. Topical administration of EACA and TXA comes with the advantage of maximizing their concentrations at their desired sites of action without the associated risk of complications with systemic exposure [40].

The list of topical hemostatic agents has been growing. These products can reduce and arrest bleeding by their direct mechanical action (sealing), by providing a scaffold for clot formation or by delivering procoagulant compounds like throm-bin and fibrinogen to directly promote clot formation [41]. Studies have generally supported the effectiveness of these products in establishing hemostasis and reduc-ing bleeding and transfusions [42]. Concerns have been raised on the possibility of emergence of inhibitory antibodies (particularly against thrombin when bovine thrombin is used), but this risk appears to be low and practically eliminated with


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the use of recombinant (human) formulations [43, 44]. When injected locally, vasoconstrictors such as epinephrine have been used as highly effective hemostatic agents, but their use requires special precaution to minimize the risk of systemic exposure, particularly in susceptible patients such as those with history of cardiac disease [45, 46].

Desmopressin has been used clinically in patients with hemophilia A or type I von Willebrand’s disease [47]. Desmopressin is primarily known as a long-acting vasopressin agonist and seems to act in diverse (and somewhat contradictory) path-ways such as increasing the levels of von Willebrand factor and factor VIII, improv-ing platelet function, inducing the production of nitric oxide (a vasodilator), and increasing the level of tissue plasminogen activator (tPA), which increases the pro-duction of plasmin and promote fibrinolysis [48]. Desmopressin has been used as a hemostatic agent in surgeries associated with high blood loss such as cardiac, spi-nal, and orthopedic procedures, and some studies have shown a modest effect on decreasing blood loss and transfusion [48]. With that said, concerns over its safety have also been raised [49].

Factors and Concentrates

The approved indications of recombinant activated factor VII (FVIIa) include treat-ment or prevention of bleeding episodes in congenital hemophilia A or B with inhibitors to factors VIII or IX, congenital factor VII deficiency, and acquired hemo-philia. Additionally, it has been widely used off-label for control of bleeding in other settings. Examples of these off-label uses include spontaneous intracranial hemorrhages (ICH) in patients on warfarin and uncontrolled bleeding in trauma and cardiovascular surgery. The former indication has been supported by reports of improvement of international normalized ratio (INR) following administration of factor VII, but evidence to support improvements in clinical outcomes is largely lacking [50, 51]. Studies have shown that the use of recombinant factor VII is asso-ciated with increased risk of thromboembolic events, particularly arterial events. This is especially a concern in older patients and those who had received higher doses [52].

Prothrombin complex concentrate (PCC) is a heterogeneous family of factor concentrates derived from human plasma. The PCCs primarily contain vitamin K-dependent coagulation factors. Three-factor PCCs supply factors II, IX, and X at “therapeutic” levels, while some others additionally supply factor VII, protein C, protein S, and small amounts of heparin and antithrombin III (these are known as four-factor PCCs). These concentrates are mainly used for rapid reversal of warfarin and other vitamin K antagonists in patients with bleeding [53–55]. Similar to FVIIa, PCCs have been used to control bleeding in other clinical settings such as liver dis-ease, but more studies are needed to establish the safety and efficacy of these treat-ments. Off-label use of PCCs for managing bleeding due to other anticoagulants is discussed further later.

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Artificial Oxygen Carriers

The search for artificial oxygen carriers that can safely and reliably replace or sup-plement blood has been ongoing for decades. Despite some promising advances, issues over safety and efficacy remain with these products. Ideally, these therapies would come with advantages such as potentially eliminating the risk of transmitting infections, the need to cross match, the requirement of complicated distribution and storage process, and the concerns over limited shelf-life and dwindling supplies [56, 57]. Unfortunately, to date, none have managed to gain market approval for use outside of investigational settings.

Some artificial oxygen carriers rely on hemoglobin molecules or other deriva-tives to carry oxygen and are known as hemoglobin-based oxygen carriers (HBOCs). The hemoglobin used in HBOCs can be from animal blood or expired/unused human allogeneic blood units. Others can be synthesized de novo (e.g., recombinant hemoglobin). Examples of products that have been studied include Hemopure (OPK Biotech, Cambridge, MA), Sanguinate (Prolong Pharmaceuticals, South Plainfield, NJ), HemAssist (Baxter, Deerfield, IL), and PolyHeme (Northfield, Evanston, IL), with the latter two currently abandoned and no longer under development [58–60]. At this time there are no HBOCs that have attained FDA approval in the United States, and their use is largely limited to expanded access (aka compassionate use) programs and ongoing investigational research.

Hemopure (HBOC-201) contains polymerized hemoglobin from bovine blood. In a large orthopedic surgery study, the use of Hemopure effectively eliminated the use of allogeneic blood transfusion but came at the price of increased risk of com-plications [61]. Another study was terminated due to safety concerns. Hemopure has been utilized through compassionate use in severely anemic patients for whom blood transfusion is not an option. Sanguinate is based on bovine carboxyhemoglo-bin conjugated with polyethylene glycol (“PEGylated”) and was designed to mini-mize extravasation, vasoconstriction, and production of oxygen radicals while still transferring oxygen and releasing carbon monoxide (CO). It has been shown to limit the size and impact of cardiac infarct and cerebral ischemia and accelerate recovery from ischemia in animal studies, and preliminary clinical trials have had promising results [62].

Other types of artificial blood components are based on fluids that have large capacity to dissolve oxygen, namely, perfluorocarbon (PFC) emulsions [63]. Similar to HBOCs, the efficacy of these products was repeatedly shown in animal and clini-cal studies, but issues related to their side effects have precluded their use in humans [18]. No PFC products are currently available in the United States.

A recurring theme in the clinical experience with HBOCs and other artificial oxygen carriers is that these products may be effective in reducing the use of allo-geneic blood and, in some cases, replacing it altogether. Unfortunately, their use has also been associated with increased risk. Most side effects of HBOCs studied to date are related to vasoconstriction, hypertension, and renal, cardiac, liver, and pancre-atic injury [64, 65].


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When allogeneic blood is readily available and can be used, there is little justifi-cation for substituting it with HBOCs. In settings where blood is not available (e.g., desolate areas) or in patients for whom allogeneic blood transfusion is not an option (e.g., those of Jehovah’s Witness faith), these products may have some utility [66]. There have been reports of patients surviving hemoglobin levels as low as 2 g/dL who received HBOCs as part of their management, acting as a so-called oxygen bridge [66–68].

Drug Adverse Effects and Interactions

An important aspect of PBM and transfusion medicine is to understand and mitigate drug interactions and side effects which might increase the risk of patients to lose blood or develop anemia. Pharmacists can play a key role in this arena as they are often positioned as the “medication experts” on multidisciplinary teams, especially in the critical care setting. To this end, adjusting the doses or discontinuing antico-agulants and antiplatelet agents in anticipation of a procedure with high risk of bleed loss are among the strategies by which pharmacists can participate actively in PBM [69, 70]. Additionally, there has been a growing list of medications implicated in RBC disorders which can exacerbate anemia [71]. As the ultimate gatekeepers for medication use, pharmacists have an important role in monitoring for the poten-tial drug-drug interactions and reactions that could adversely affect the patient’s outcome. A number of drug-induced RBC disorders and medications linked to these conditions are listed in Table 20.1.

Table 20.1 Examples of drug-induced RBC disorders [69]

Disorders Medications commonly associated with the disorders

Anemia Hemolytic, immune Cephalosporins, cefotetan, ceftriaxone, methyldopa, penicillin derivatives, piperacillin, nonsteroidal anti-inflammatories (NSAIDs), diclofenac, ibuprofen, antineoplastics, fludarabine, quinine/quinidine

Hemolytic, non-immune

Primaquine, phenazopyridine, nitrofurantoin, sulfa medications

Megaloblastic Methotrexate and other antimetabolite chemotherapeutic agents, alkylating agents, metformin, oral contraceptives, phenobarbital, phenytoin, primidone, pyrimethamine, sulfasalazine, triamterene, trimethoprim/sulfamethoxazole

Sideroblastic Isoniazid, penicillamine, triethylene tetramine dihydrochloride, chloramphenicol, linezolid, tetracycline, progesterone replacement, phenacetin, busulfan

Aplastic Azathioprine, carbamazepine, chloramphenicol, erythropoietin, isoniazid, procainamide, sulfonamides, valproic acid

Polycythemia Erythropoietin-stimulating agents (ESAs), anabolic steroids

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Anticoagulant Reversal Agents and Antidotes

Timely, targeted reversal of anticoagulation therapies can serve as another method to reduce blood loss and, theoretically, the need for additional transfusion. While it is important to consider the repercussions of reversing anticoagulation (e.g., poten-tial for thrombosis), clinical necessity and circumstance will dictate how urgently reversal agents must be administered for medications like warfarin, heparin, low- molecular- weight heparin, fondaparinux, dabigatran, apixaban, rivaroxaban, and edoxaban [72]. Blood components such as fresh frozen plasma (FFP) have been commonly and historically used to reverse warfarin-associated bleeding [54]. With the advent of more modern therapies such as the aforementioned PCCs, and newer targeted reversal agents like idarucizumab [73], pharmacist oversight and interven-tion during the reversal process will be key to ensuring safe and appropriate medica-tion therapy. Likewise, clinicians involved in transfusion medicine must be knowledgeable on the different reversal agents as they may be used in place of blood components traditionally procured from blood banks during coagulopathic hematologic emergencies. Working in conjunction with pharmacy and transfusion medicine staff will ensure that patients get the correct reversal agent for the specific anticoagulant, at the right dose, with appropriate follow-up and monitoring. A brief overview of pharmacological anticoagulant reversal agents is included in Table 20.2.

Vitamin K Antagonists

The gold standard reversal agent for vitamin K antagonists such as warfarin is sim-ply orally or intravenously administered vitamin K [74]. Blood components such as FFP have also been used historically, though there are some limitations to the use of

Table 20.2 Preferred pharmacological anticoagulant reversal agents [54]

Anticoagulant Antidote/reversal agent

Warfarin Four-factor PCC (dose based on INR and weight)25 units/kg (if INR: 2 to <4) max 2500 units35 units/kg (if INR: 4–6) max 3500 units50 units/kg (if INR: >6) max 5000 unitsVitamin K 5–10 mg IV

Heparin Protamine 1 mg/100 units of heparin administered in the previous 2–3 hLMWH Protamine 1 mg/1 mg enoxaparin if given within 8 h

Protamine 0.5 mg/1 mg enoxaparin if given >8 h priorProtamine 0.5 mg/1 mg enoxaparin if bleeding persists beyond 4 h

Fondaparinux Four-factor PCC50 units/kg (max 5000 units)

Dabigatran Idarucizumab 50 mgApixabanEdoxabanRivaroxaban

Four-factor PCC50 units/kg (max 5000 units)


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these treatment modalities due to short shelf lives, logistical barriers like thawing and matching blood type, and the potential for transfusion-related acute lung injury (TRALI) [55]. The PCCs have also been studied specifically for the reversal of warfarin-induced bleeding, exert their effects quickly, and carry labeled indications for this use [75, 76]. The most recent CHEST guidelines recommend the use of four-factor PCC over FFP for the reversal of warfarin-related bleeding. The appro-priate dose of vitamin K and PCCs can be influenced by a host of patient-specific factors such as their weight, presenting INR value, clinical severity of their coagu-lopathy, and urgency of the need for reversal. Due to its longer onset of action, vitamin K should always be administered after PCC administration when using these products to reverse a warfarin-related bleed [74–76].

Heparin and Low-Molecular-Weight Heparins (LMWH)

When administered intravenously, protamine sulfate can rapidly reverse the antico-agulant effects of heparin and can partially neutralize low-molecular-weight hepa-rins (LWMH) [77]. Protamine sulfate binds to heparin and forms a stable salt which quickly eliminates the anticoagulant effect of the medication. The correct dose of protamine depends on the amount of heparin or LWMH given in the hours preceding the need for reversal – Pharmacist involvement in care and policy devel-opment is important to ensure proper dosing of protamine is used in practice. The aPTT levels measured after protamine administration can be used to determine if neutralization was successful. Protamine sulfate can cause rare, but serious, side effects such as hypotension and bradycardia. The risk of these adverse effects developing can be lowered by administering the medication slowly, though patients with previous protamine exposures and other risk factors can also develop hyper-sensitivity reactions. If a patient is known to have a protamine allergy, but still requires reversal of heparin therapy, they should be pretreated with corticosteroids and antihistamines [77].

Fondaparinux

Fondaparinux is a synthetic analogue based on the antithrombin-binding penta-saccharide structure found in heparin and LWMH. There is no direct reversal agent, though recombinant factor VIIa may have some effect in controlling fondaparinux-related bleeding [77]. Some reversal strategies for fondaparinux- related bleeding call for the use of four-factor PCCs [78]. Without strong research and primary literature support, these modalities should be reserved for clinical situations where the potential benefits far outweigh the treatment-associated risks.

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Direct-Acting Oral Anticoagulants

The newest anticoagulant agents are the direct-acting oral anticoagulants (DOAC). Unlike heparin, LMWH, and fondaparinux, the DOACs exert their anticoagulant effect independent of antithrombin III by inhibiting factor IIa (dabigatran) or factor Xa (apixaban, edoxaban, rivaroxaban, betrixaban) through direct binding. The DOACs do not rely on inhibition of clotting factor synthesis like warfarin does, so their effects are immediate. There are potential benefits to the DOACs over tradi-tional anticoagulants such as lack of need for routine lab monitoring (e.g., INR), fewer drug-food and drug-drug interactions than warfarin, and well-described safety and efficacy profiles [79–81].

The first DOAC targeted reversal agent to gain US approval was the humanized monoclonal antibody idarucizumab (Praxbind®) in 2015. In clinical trials idaruci-zumab has been shown to completely rapidly and completely reverse the anticoagulant effects of dabigatran [82, 83]. At the time of this writing, there are no other targeted antidotes for the DOACs that inhibit factor Xa (apixaban, edoxaban, rivaroxaban). There is some data to suggest that four-factor PCC may have utility in controlling DOAC-associated bleeding [84–86], but this remains an off-label use despite routine administration in clinical practice. Current guideline consensus calls for PCC to be used for the reversal of apixaban, edoxaban, or rivaroxaban until a targeted antidote makes its way into the medication armamentarium [87]. Due to its recent FDA approval, there is a paucity of data to guide the reversal of betrixaban- related bleeding. As clinical experience builds with this newly available anticoagulant therapy, it is likely that best practices will emerge that are similar to those of the other oral factor Xa inhibitors.

A recently FDA-approved therapy, andexanet alfa, mimics the protein structure of factor Xa in order to attract binding of circulating factor Xa inhibitors. Once bound to the “decoy” factor Xa, the anticoagulants can no longer exert their clinical effects. In a clinical trial, andexanet alfa reduced anti-factor Xa activity by more than 90% [88]. Andexanet alfa theoretically should not promote clotting since it is catalytically inactive, but the labeling of the product includes a black box warning for thromboembolic risks, ischemic risks, cardiac arrest, and sudden death.While promising as a targeted reversal agent of factor Xa inhibitors, availability of andex-anet alfa is currently limited to a small number of institutions in the United States. Its clinical role has yet to be determined and will likely rely on dissemination of real-world experience and additional clinical trial data.

Conclusion

Pharmacists, blood bankers, and transfusion services have proven in the past that they can leverage their expertise to take on a more active role in disease manage-ment, influence standardization of medication use, eliminate variability in care, and influence what clinical laboratory tests should be or should not be ordered in


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different clinical settings. Pharmacists are familiar with the development and imple-mentation of policies, procedures, and protocols on medications approved through P&T committees based on the indications of the medications, their costs, and best clinical practices [89]. Pathologists and transfusion experts are increasingly inte-grating themselves into blood utilization committees and should take on a larger role in policy-making for the judicious usage of blood components [90].

In order to contribute to hospital PBM programs, an awareness of the implica-tions of transfusion medicine and increased knowledge of hemostasis, coagulation cascade, and blood/drug components used will help pharmacists and pathologists as they increase their involvement with PBM policy development. Bridging the gap between modern transfusion medicine and pharmacy practice through educational initiatives and interdisciplinary collaboration, especially in critically ill patients, will allow for better patient care as the healthcare field continues to evolve. A prac-tice model that enforces traditional work isolated in the confines of pharmacy departments or blood banks can no longer answer the needs of our patients, espe-cially as blood collection and transfusion continue to decline in the United States [91]. Greater education, training, and subsequently, collaboration, among all health-care practitioners will help to facilitate the paradigm shift in patient care that PBM seeks to employ across disciplines – some advances have already been made on this forefront through inpatient pharmacy-driven stewardship programs that oversee the utilization of blood components [92, 93].

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67. Greenburg AG, Light WR, Dube GP. Reconstructing hemoglobin-based oxygen carriers. Transfusion. 2010;50(12):2764–7.

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69. Shander A, Moskowitz DM, Javidroozi M. Blood conservation in practice: an overview. Br J Hosp Med (Lond). 2009;70(1):16–21.

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71. Shander A, Javidroozi M, Ashton ME. Drug-induced anemia and other red cell disorders: a guide in the age of polypharmacy. Curr Clin Pharmacol. 2011;6(4):295–303.

72. Holzmacher JL, Sarani B. Indications and methods of anticoagulation reversal. Surg Clin North Am. 2017;97(6):1291–305.

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79. Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance for the prac-tical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41:206–32.

80. Schaefer JK, McBane RD, Wysokinski WE. How to choose appropriate direct oral anticoagu-lant for patient with nonvalvular atrial fibrillation. Ann Hematol. 2016;95:437–49.


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https://doi.org/10.2146/ajhp140722


Chapter 21Patient Blood Management in Critically Ill

Suma Choorapoikayil, Kai Zacharowski, Christoph Füllenbach, and Patrick Meybohm

Patient Blood Management

Patient Blood Management (PBM) is an interdisciplinary diagnostic, behavioural and therapeutic concept, which, taking into account the latest medical knowledge and techniques, reduces or avoids unnecessary blood loss and focuses on the ratio-nal handling of blood components and thereby strengthens patient’s own blood resources. The use of PBM in clinical practice is mainly based on three pillars (Fig. 21.1):

1. Comprehensive anaemia management. 2. Minimization of iatrogenic (unnecessary) blood loss. 3. Establishment of a rational management of haemotherapy.

The individual PBM components are intended to intensively support the patient even before admission to the hospital and to accompany the patient during and after any surgical or medical intervention. So far, more than 100 PBM individual mea-sures have been defined based on the broad interdisciplinary fields (anaesthesia, surgery and central laboratory) and temporal application (pre-, intra- to postopera-tive) [1]. The advantage of the extensive PBM measures is that the selection can be dynamically adapted to the individual financial and personnel capabilities as well as the respective focus of each hospital.

S. Choorapoikayil · K. Zacharowski · C. Füllenbach · P. Meybohm, MD (*) Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germanye-mail: [email protected]; [email protected]; [email protected]; [email protected]







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History of Patient Blood Management

Allogeneic blood transfusion is one of the major advances of modern medicine in an attempt to compensate life-threatening blood loss but is also simultaneously marked as one of the top five overused procedures in clinical practice [2]. In fact, assessment of current transfusion practice in hospitals shows that the handling of blood components is firmly anchored in daily life. The overall assumption “blood must be good” has permeated medical practice without supportive data and remains without critical challenge the default in treating anaemia in all hospitalized patients and especially those in the ICU. Allogeneic blood transfusion has always been associated with potential risks and adverse events. Continuous improvement in the safety of blood donation and processing reduced but not eliminated the risk of transfusion- transmitted infections to an all-time low level. For example, transfu-sion with hepatitis B, hepatitis C and HIV-contaminated blood components is with a risk of about 1:300,000, 1:1,000,000, respectively, and 1:4,000,000 extremely low now. Based on this notion and the constant reassurance that “donor blood is safer than it has ever been” might have led to the increase in “liberal” transfusions. It is noteworthy that this statement generally refers to the risk of transfusion-trans-mitted infections and not the influence on postoperative outcome. During the last decades, it has become increasingly clear that red blood cell (RBC) transfusion delays and moreover hinders patient’s recovery. In addition, clinicians are often uncertain about the clinical benefits of RBC transfusion and therefore the appropri-ate indication for RBC transfusion. Although transfusion guidelines exist, many clinicians still ignore or are unaware of them and rely on eminence-based transfu-sion practice. Based on the possibility to preserve patient’s own blood resources and to enable safe handling of donor blood, the World Health Assembly (WHA) has endorsed PBM, requesting the World Health Organization (WHO) to provide its member states with training on the safe and rational use of allogeneic RBC transfusion as well as implementation of transfusion alternatives – PBM – in 2010 (WHA63.12) [3].

Rational managementof haemotherapy

Minimization ofiatrogenic

(unnecessary) bloodloss

Comprehensiveanaemia

management

PatientBlood Management

A clinical concept to improve patient safety

Fig. 21.1 Three pillars of Patient Blood Management

S. Choorapoikayil et al.

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Impact of Anaemia and Transfusion on Outcome

The WHO has defined anaemia with haemoglobin (Hb) level of <13 g/dl for men and <12 g/dl in women [4]. The Global Burden of Disease Study 2013 (GBD-2013) revealed that only 4.3% of the world’s population were healthy and not affected by injury, injury sequelae or disease. About 1.9 billion individuals had anaemia, repre-senting almost 27% of the global population [5].

Anaemia is associated with a reduced oxygen-carrying capacity of blood and often develops gradually. Symptoms such as fatigue or weakness in concentration are of unspecific origin and therefore often attributed to stressful everyday life or age. Acute anaemia that occurs in the operating room or ICU alerts the clinician for immediate intervention. In contrast, preoperative anaemia is often accepted among clinicians and is considered a surrogate marker of the underlying disease [6]. The deleterious effects of (preoperative) anaemia on (postoperative) ICU outcome are supported by a growing body of evidence (summarized in Table 21.1) and leave one to question why anyone would regard anaemia as “normal”.

Scrascia and colleagues estimated the incremental value of preoperative anaemia in 4594 cardiac surgical patients with subsequently ICU stay performing logistic regression analysis including European System for Cardiac Operative Risk Evaluation (EuroSCORE) II. They found that in-hospital mortality was 7.7% for mild and 15.7% for moderate and severe anaemic patients (p < 0.001) [10]. A recent study by von Heymann and colleagues investigated the role of anaemia on the out-come of 4494 patients undergoing coronary artery bypass grafting and subsequent ICU stay. In average, non-anaemic patients stayed 4 days in the ICU, whereas mild and severe anaemic patients stayed 6 (p < 0.001) and 10.5 (p < 0.001) days, respec-tively. Furthermore, investigation of long-term survival showed a significant interac-tion between preoperative anaemia and RBC transfusion in that transfused non-anaemic patients had the same risk of death as non-transfused mildly anaemic patients. The study by von Heymann and colleagues emphasized the fatal role of anaemia during ICU stay. Compared with age, type of surgery, duration of cardio-pulmonary bypass, age, creatine, ejection fraction score, chronic pulmonary disease, coronary artery disease, diabetes mellitus, atrial fibrillation, peripheral vascular dis-ease, and even transfusion, severe anaemia was the strongest risk predictor for worse outcome including mortality and implication for postoperative ICU stay [15].

Taken together, preoperative anaemia even to a small extent is independently associated with increased risk of 30-day morbidity, transfusion rate, mortality and prolonged length of stay on ICU [9, 11, 16]. Anaemia is extremely common in patients admitted to the ICU affecting 60–80% of patients and is present at intensive care discharge in about 75% of patients [17, 18]. Furthermore, anaemia is the stron-gest predictor of RBC transfusion that, as mentioned above, is associated with worse patient outcome. Although RBCs are seen as a pharmaceutical agent, as a biologic agent, each blood unit consists of millions of foreign and viable cells and

21 Patient Blood Management in Critically Ill

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proteins, which are transplanted into a disease compromised patient. Such intervention interferes not only with the patient’s immune system but is also associ-ated with impeding the patient’s recovery. As opposed to the low infectious risks discussed above, the noninfectious hazards of transfusion (transfusion-associated circulatory overload, transfusion-related acute lung injury, acute or delayed haemo-lytic transfusion reaction, transfusion-related immunomodulation and allergic reac-tions) are the primary focus in current clinical practice. Concerns regarding the transfusion- associated risks and the different transfusion practices between coun-tries but also within a country, led to not only examine this practice but to look at changing it. Remoortel and colleagues conducted a methodologic quality assess-ment of RBC transfusion guidelines with restrictive transfusion thresholds published

Table 21.1 Impact of anaemia on ICU outcome (a selection)

Publication Patients (n) Study design Observation

Fowler et al. Br J Surg 2015 [7]

949,445All type of surgery

Meta-analysis Anaemia was associated with increased mortality (p < 0.001), acute kidney injury (p < 0.001), infection (p = 0.01) and increased risk of transfusion (p < 0.001)

Lasocki et al. Eur J Anaesth 2015 [8]

1534Orthopaedic surgery

Observational study

Postoperative complications were more frequent in anaemic patients (p = 0.009)

Baron et al. Br J Anaesth 2014 [9]

39,309Noncardiac and non- neurological surgery

Secondary analysis of a prospective study

Patients with anaemia had higher mortality rate, length of stay (p < 0.001) and admission to ICU (p < 0.001)

Scrascia et al. Ann Thorac Surg 2014 [10]

4594Cardiac surgery

No information available

Preoperative anaemia was strongly associated with death in surgical patients. EuroSCORE II model including anaemia provides clinicians with an accurate tool to predict hospital death in patients with anaemia

Hung et al. Anaesthesia 2011 [11]

2688Cardiac surgery

Prospective study

Anaemia was associated with increased transfusion (p < 0.001), death (p < 0.001) and prolonged ICU stay (p < 0.001)

Musallam et al. Lancet 2011 [12]

227,425Noncardiac surgery

Retrospective cohort study

Preoperative anaemia was associated with an increased risk of morbidity and mortality

Sakr et al. Crit Care 2010 [13]

5925ICU patients

Retrospective study

Anaemia was common in surgical ICU patients and was associated with increased length of stay and higher morbidity and mortality

du Cheyron et al. Intensive Care Med 2005 [14]

206ICU patients with acute renal failure

Prospective observational cohort study

Multivariable analysis revealed three variables as independent predictors for death: Age, SOFA score and anaemia at ICU admission. Cumulative observed survival rate of acute renal failure patients with Hb > 9 g/dl was 57% compared to 32% in patients with <9 g/dl


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between 2004 and 2014 using the AGREE II tool [19]. In total, 13 guidelines were evaluated of which six were developed by organizations in the United States [20–25], two by organizations located in the United Kingdom [26, 27], two by European organizations [28, 29], one by an International European and American committee [30], one located in Italy [31, 32] and one located in the Netherlands [33]. The analysis revealed that the methodological quality is highly variable, and sometimes the guidelines also recommend contradictory transfusion thresholds for the same intervention. For example, the transfusion threshold for acute coronary syndromes ranged from 7 to 10 g/dl [34]. Thus, the results highlight the persistent uncertainty regarding the appropriate indication for RBC transfusion.

Another controversial aspect is whether a liberal or restrictive transfusion regime should be applied in clinical routine. Anaemia might increase myocardial oxygen demand because a higher cardiac output is required to maintain sufficient oxygen delivery [35]. In particular, patients undergoing cardiac surgery display limited car-diovascular reserve and are exposed to intraoperative haemodilution. Thus, Hb-level decreases and in turn the risk of anaemia-induced tissue hypoxia increases. In this respect, several trials have been conducted comparing the outcome of restrictive versus liberal transfusion practice in the last years. Holst and colleagues performed a meta-analysis including 9813 randomized patients of 31 trials. No differences, except transfusion rate and applied RBC units, in outcome (morbidity, myocardial infraction and mortality) could be observed between a restrictive and a liberal trans-fusion strategy [36]. Recently, Mazer and colleagues conducted the TRICS III trial comparing primary composite outcome of death, myocardial infarction, stroke or new onset of renal failure in high-risk cardiac surgical patients receiving either a restrictive or liberal transfusion practice. In this study, analysis of 4860 patients with ICU stay revealed that a restrictive transfusion strategy was non-inferior to a liberal transfusion strategy [37]. Till date, it is evident that a restrictive transfusion threshold is generally recommended, but current studies also indicate that the dogma “one size fits all” is outmoded. In fact, transfusion regime must be adapted to the individual patient’s need and underlying disease pattern. For example, patients with traumatic brain injury may require a more liberal transfusion practice to pre-vent cerebral ischaemic events because the injured brain may not be able to com-pensate for a decreased oxygen delivery [38]. In contrast, patients with severe acute upper gastrointestinal bleeding mey benefit from a restrictive transfusion strategy since a liberal transfusion strategy increased portal-pressure gradient and thereby promoted acute variceal bleeding [39].

Comprehensive Anaemia Management

Anaemia is a common, independent and modifiable risk factor for many postopera-tive outcomes. Erythropoiesis is often altered in critically ill patients and further-more challenged through phlebotomy-induced blood loss. Almost every second, a patient is anaemic and undergoes elective scheduled surgery without preoperative


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anaemia management, and therefore it is not surprising that the majority of the patients admitted to the ICU have Hb-values below 12 g/dl. Strengthening patient’s blood volume preoperatively will tolerate surgical blood loss without the need for compensation with allogeneic blood and thus prepare the patient at the best for admission to the ICU.

PBM provides a comprehensive anaemia management that especially covers patients in the preoperative and postoperative phase. Unless of an existing primary disorder of the bone marrow or therapy impacting on marrow function, most anae-mias are correctable within a period of 2–4 weeks. IDA is the most common under-lying cause and simple to diagnose and to medicate. Parenteral iron has been shown to effectively reverse anaemia in iron-deficient patients [40–44] and is frequently used now due to the development of newer formulations with less side effects [45]. Total-dose infusions of iron can be administrated in as little as 15–30 min under monitoring. However, the use of iv iron in critically ill patient is controversially discussed. A systematic review by Shah and colleagues identified five randomized controlled trials including 665 ICU patients investigating the effect of iron supple-mentation and RBC transfusion rate. Overall, there was no significant change in RBC transfusion requirement, mean Hb concentration, mortality rate or length of stay upon iron administration. However, a trend could be observed in that iron- treated patients required less RBC transfusion [46]. It is notable that most effective increments of Hb-levels (∆Hb of 1.9, 2.2 and 3.9) were detected between 2 and 4 weeks after iron administration and may explain the lack of Hb increase in ICU patients with a stay shorter than 7 days [40, 43, 47]. These data are in line with the recently published results of the IRONMAN trial reporting an increase of haemo-globin of 0.7 g/dl in anaemic patients admitted to the intensive care unit [48].

Similarly, a controversial debate exists about the administration of erythropoetin (Epo) during ICU stay. Corwin and colleagues conducted three trials applying epo-etin alfa to critically ill patients with partly opposing results [49–51]. The first two trials including 1462 patients in 1999 and 2002 showed that administration of epo-etin alfa was associated with reduced numbers of RBC transfusion and increased Hb-level [50, 51], whereas in the latest trial in 2007, involving 1450 patients, only a change in Hb-level but not in transfusion rate could be detected [49]. The authors suggested that a change in transfusion practice over the years might have led to the opposing results. Interestingly, a reduced mortality rate was detected among patients treated with epoetin alfa compared with those who received placebo sug-gesting that anaemia might possess a higher impact on adverse outcome than trans-fusion with blood. It is noteworthy that an increase in Hb-level in patients receiving Epo is apparent after 1 week. Furthermore, Epo’s ability to stimulate erythropoiesis is highly dependent on the availability of iron which might be decreased in anaemic patients but may increase the risk of infection. For comparison, transfusion of one RBC unit will produce an immediate increase in Hb-level by ∼1 g/dl but also increased free iron [52].

Taken together, the use of iron and Epo in critically ill patient is still under inves-tigation, and consequently the intensive care medicine already begins preopera-tively with an adequate anaemia management (Fig. 21.2).


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Minimization of Iatrogenic (Unnecessary) Blood Loss

Critically ill patients have multiple confounding conditions that make them prone to bleeding due to inherited or acquired coagulopathy. Patients admitted to the ICU after complex surgical procedures, traumatic injuries and/or medical conditions show a variety of pathophysiological changes. PBM compiles several interventions to minimize surgical blood loss – a perioperative risk stratification including bleed-ing history, judicial use of anticoagulants and antiplatelet medications that are essential to prevent (iatrogenic) blood loss.


The pathophysiology of ICU blood loss is multifactorial and includes, for example, (hyper-)fibrinolysis, anticoagulation medications, plasma dilution, volume shifts and hypothermia. So far, allogeneic blood transfusion has traditionally been consid-ered the primary management strategy for bleeding. However, a thought-out algorithm- based coagulation management represents a significant evolution and a promising alternative to the current nondirected component therapy. Maintenance of a balanced physiology to aid optimal coagulation is essential and includes body temperature above 35 °C (avoiding hypothermia), pH > 7.2 (avoiding acidosis) and maintaining ionized calcium >1.0 mml/l (avoiding hypocalcaemia) [53]. Anticoagulant and antiplatelet medications are often used, and an individualized assessment of the thrombotic risks of stopping these drugs must be evaluated against the risk of bleeding. Substitution or bridging therapy of long-acting with short- acting anticoagulants might be indicated. In case of hyper-fibrinolysis or bleeding stemming from increased fibrinolytic activity, a serine protease inhibitor such as tranexamic acid (TXA) should be administered. TXA appears to have a clot- stabilizing effect by inhibiting clot-bound plasmin. This pro-haemostatic effect may explain why TXA significantly reduces bleeding-induced lethality in traumatized patients, without the risk of side effects such as vascular occlusion due to

Patient with no anaemia

Patient with anaemia and iron therapy

Patient with anaemia

Before surgery/admission intensive care unit

Hae

mog

lobi

n [g

/dl]

12/1

3

Surgery

High probability for RBC transfusion* **

*RBC transfusion

PBM anaemia management

Fig. 21.2 Haemoglobin progression with and without anaemia management during hospitalization


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thromboembolic complications. Van Haren et al. investigated whether administra-tion of TXA increases venous thromboembolism and whether its effect on fibrino-lysis can be identified with thromboelastography (TEG). In total, 121 trauma patients with a high-risk assessment profile during ICU admission and with sus-pected life-threatening haemorrhage received TXA within 3 h of admission. Analysis of data of patients with and with no thromboembolic complications was compared. The authors found that TXA was associated with reduced fibrinolysis. Moreover no association was found between TXA administration and occurrence of any thromboembolic event in this high-risk cohort of trauma patients [54].

Diagnostics with Point-Of-Care Testing

Point-of-care testing (POCT) such as thromboelastograph or thromboelastometer (viscoelastic parameters) have become increasingly attractive because they provide a more complete picture of the actual haemostatic system and yield a more rapid result (15–30 min) than standard clinical laboratory testing [55, 56]. Derangement of the coagulation system including thrombocytopenia, prolonged clotting times and/or complex haemostatic defects, such as disseminated intravascular coagula-tion, is a common phenomenon in critically ill patients. Abnormal clotting times and thrombocytopenia occur in about 30–40% of ICU patients [57–59]. Furthermore, platelet function analysers assess platelet functions after administra-tion of various pharmacological platelet inhibitors which seems to be an effective diagnostic tool in critically ill patients [60]. Although adequate powered studies demonstrating a significant impact on clinical outcomes are rare [61–63], the cur-rently available studies and the National Institute for Health and Care Excellence (NICE) indicate that POCT enables an appropriate use of haemostatic agents and blood components [45].

Prevention of Iatrogenic Blood Loss

Extensive monitoring of vital organ functions makes diagnostic blood losses in ICU patients inevitable. However, an individual designed treatment plan including only laboratory parameters that are actually relevant for the therapy prevents unneces-sary routine blood tests and protects the patient’s own blood volume. When sam-pling blood, phlebotomists should use the smallest collection tube size that is practical for the required analysis (Fig. 21.3). Furthermore, the use of closed inva-sive pressure measurement devices provides several advantages such as a contamination- free blood collection, reducing unnecessary blood loss, elimination of manual open flushing and reducing the risk of contamination with patient’s blood [64–66].


415

A recent study implemented a comprehensive “blood-saving bundle” on ICU. Measures included the use of closed arterial systems, smaller amounts of blood for blood gas analysis (1 ml), 2.7 ml (instead of 5.5 ml) standard lithium heparin serum tubes, pulse oximeters, capnometry and blood glucose “sticks”. On average, blood loss was significantly reduced from 43 to 15 ml. Furthermore, the daily discard of 19 ml of blood could be prevented by using closed arterial systems, and about 10 ml of blood could be saved by drawing smaller volumes of blood. Both the number of transfused units of RBCs (from 7 to 2) and the length of ICU stay (from 13 to 10 days) could be significantly reduced [67].

Taken together, by customizing diagnostic laboratory requirements, rational blood draws instead of standard orders, and using blood-saving methods in ICU patients, both the frequency and volume of diagnostic blood draws can be dramati-cally reduced without compromising treatment quality.

Management of Ongoing ICU-Related Anaemia and Coagulopathy

Anaemia is common in surgical intensive care patients and is associated with higher rates of morbidity and mortality. The causes of anaemia in these patients are likely to be multifactorial and are referred to as “anaemia of inflammation” or “anaemia of

Fig. 21.3 Three different tubes with a larger vs. smaller collection tube size


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chronic disease” [68]. Transfusion with RBCs is often considered as the ultimate and only option to treat anaemia. However, the avoidance of unnecessary RBC transfusion is of high importance due to the risks associated with allogeneic blood components. Therefore, determining safe postoperative transfusion thresholds is imperative. The decision to transfuse should not be based exclusively on Hb-levels, since Hb concentration reflects only the oxygen-carrying capacity of blood but not the actual level of tissue oxygenation, volume status, haemodynamic status, dynamic of bleeding, overall symptoms and status of the patient where all of them need be considered, too. In contrast, anaemia is also associated with worse outcomes creat-ing thereby a dilemma for the clinician at the bedside who needs to decide whether anaemia outweighs the risks of transfusion and vice versa. The risks associated with anaemia are mostly correlated to myocardial ischaemia. The ability to tolerate sup-pressed oxygen supply depends on how quickly anaemia develops and to which degree compensatory mechanisms, including increasing cardiac output, blood flow redistribution to vital organs and increased oxygen extraction, might be activated in the morbid patient. Therefore, the benefit and risks of transfusion must be assessed in each individual patient.

Phlebotomy is one of the biggest predictors for hospital-acquired anaemia; how-ever, drugs administered in critically ill patients may have adverse effects that can also lead to anaemia. For example, drugs such as piperacillin are associated with haemolytic anaemia that is caused by increased destruction of erythrocytes by mac-rophages in the spleen and liver [69]. Furthermore, drugs blocking angiotensin receptors or angiotensin-converting enzymes may interfere with Epo production, thereby inhibiting erythropoiesis [68].

Haemostatic abnormalities such as thrombocytopenia, von Willebrand syn-drome, factor XIII deficiency or hyper-fibrinolysis are common in critically ill patients. Identification of the underlying cause of these coagulation abnormalities is essential, since each coagulation disorder necessitates different therapeutic manage-ment strategies. About 14% to 28% patients admitted to ICU shows prolongation of clotting times [57]. The incidence of low platelet count <150 × 109/l is 35–44% and 30–50% for <100 × 109/l, respectively [59, 70]. Typically, the platelet count decreases during patient’s first 4 days in the ICU [71]. It is noteworthy that in some diseases with thrombocytopenia, the risk for vascular occlusion is higher than haemorrhage.

Most guidelines approve platelet transfusion in patients with platelet count of <30–50 × 109/l accompanied by bleeding or at high risk for bleeding, and in patients with a platelet count <10 × 109/l, regardless of the presence or absence of bleeding [72]. Patients with fever, disseminated intravascular coagulation or splenomegaly may display reduced response. Furthermore, non-effective transfusion may indi-cate allo-immunization of the patient after repeated transfusion. Disorders of enhanced platelet destruction (e.g. immune thrombocytopenia) require alternative therapies.

The goal of platelet transfusion is to stop or prevent bleeding in thrombocytope-nic patients or those with platelet dysfunction. In a similar fashion to RBC transfu-sion, platelet transfusion has been considered as essentially benign. Therefore,


417

platelet transfusion has often been used in clinical routine to prevent rather than treat bleeding. Two types of platelet products are used for transfusion: (1) whole blood platelet derived from four to five whole blood donations that were pooled, leuko-reduced, bacterially tested and irradiated and (2) apheresis platelets derived from donors who spent a couple of hours on a cell separator. Risk of haemolytic reactions in case of ABO mismatch [73–75] and risk of acute lung injury (transfu-sion-related acute lung injury) or infections are few side effects associated with platelet transfusion [76, 77]. Furthermore, the incidence of multiorgan failure [76], acute lung injury [78] and bacterial sepsis [79, 80] and even recurrence of leukae-mia [81] has been reported after platelet transfusion. The clinician should also con-sider that platelet transfusion is likely prothrombotic and pro-inflammatory; and transfused platelet is highly activated [81]. A recent study conducted by Aubron and colleagues investigated whether platelet transfusion is associated with hospital- acquired infection in ICU patients. Of 18,965 included patients, 11.9% received platelet transfusion. After adjusting for confounders, platelet transfusions were independently associated with infection (odd ratio 2.56; 95% CI 2.3–4.74; p < 0.001) [82]. A recent trial conducted by Leahy and colleagues demonstrated that after implementation of PBM, consumption of platelet could be reduced by 27% (RR 0.73; 95% CI 0.70–0.76; p < 0.001) [83].

Patient Blood Management in Practice

Several studies published in the last years have validated and most notably confirmed the efficacy of PBM. Patient safety could be enormously improved by reducing anae-mia-associated risk factors. Three recent landmark studies involving a large number of patients compared a control pre-PBM cohort with a multimodal post-PBM cohort. Meybohm and colleagues conducted a prospective, multicentre observational study including 129,719 surgical patients between 2012 and 2015 in Germany. The analy-sis revealed that implementation of PBM was non-inferior and safe compared to standard care and was associated with a significant reduction in number of trans-fused RBC units and related resource consumption [84]. Gani and colleagues per-formed a pre-post, cross-sectional study involving 17,144 patients undergoing gastrointestinal surgery between 2010 and 2013. Implementation of PBM enabled adherence to a restrictive transfusion practice and reduced thereby the number of over-transfused patients [85]. Leahy and colleagues analysed retrospectively 605,046 patients admitted to 4 Australien hospitals between 2008 and 2014. Upon implemen-tation, savings of AU$ 18,507,092 could be achieved by reducing transfusion of RBCs, fresh frozen plasma and platelets by 41%. Furthermore, transfusion of single RBC units increased from 33.3 to 63.7%, and hospital mortality, length of stay, hos-pital-acquired infections and acute myocardial infarction were reduced [83].

Given the use of proven change management principles, an international expert PBM group recently proposed simple, cost-effective measures enabling any hospital to reduce both anaemia and RBC transfusions in surgical and medical patients pro-


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viding comprehensive bundles of PBM components [1]. It may act as a working template to develop institutions’ individual PBM practices for hospitals beginning a program or trying to improve an already existing program. A stepwise selection of the most feasible measures might facilitate the implementation of PBM. In this manner, PBM represents a new quality and safety standard that has significant implications for the critically ill patient.

Outlook

Critical illness is a life-threatening condition that needs individualized treatment. PBM is a concept that supports patient’s recovery at any time during ICU stay and hospitalization. Future studies will prove the effects of anaemia and RBC transfu-sion on disease progression and whether and when treatment with, for example, iron or Epo is indicated for ICU patients. In the interim, the main focus should be given to adequate early anaemia management, minimizing iatrogenic blood loss and the rational use of all haemotherapy with a focus on patient safety and outcome.

Conflict of Interest PM and KZ received grants by B. Braun Melsungen, CSL Behring, Fresenius Kabi and Vifor Pharma for the implementation of Frankfurt’s Patient Blood Management Program; honoraria for scientific lectures from B. Braun Melsungen, Vifor Pharma, Ferring, CSL Behring and Pharmacosmos. All other authors have no conflicts.

Funding Sources This work did not receive any specific grant from funding agen-cies in the public, commercial or not-for-profit sectors.

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425© Springer International Publishing AG, part of Springer Nature 2018 A. Shander, H. L. Corwin (eds.), Hematologic Challenges in the Critically Ill, https://doi.org/10.1007/978-3-319-93572-0

AABC PICU study, 310, 311Abciximab, anemia, 146ABL FLEX, 67ABLE study, 313ABLflex 800, 69ABO blood group system, 294ABO-incompatible blood transfusions, 281Acquired FVIII inhibitors, 230–231Acquired hemophilia A (AHA), 230Acquired von Willebrand syndrome

(AvWS), 226ACS TQIP Massive Transfusion in Trauma

Guidelines, 110Activated clotting time (ACT), 77, 243, 244Activated partial thromboplastin time (aPTT),

76, 77, 230, 244, 344Activated prothrombin complex concentrates

(aPCC), 330Acute chest syndrome, 353Acute coronary syndrome (ACS), 146, 147,

150–152Acute graft versus host disease (aGvHD), 356,

357Acute hemorrhagic anemia, 260Acute kidney injury (AKI), mannitol-induced

acute kidney injury, 96Acute respiratory distress syndrome

(ARDS), 238Acute stroke, 353Acute Venous Thrombosis: Thrombus Removal

With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial, 221

ADIVA 2120 method, 69ADVIA system, 66Allergic transfusion reactions, 285, 286

Allogeneic blood transfusion, 391Allogeneic RBC transfusion, 408American Association for the Study of Liver

Diseases (AASLD), 169American Association of Blood Banks

(AABB) guidelines, 170impact, 409, 410

Anemia, 394, 409ACS, 147, 150, 152blood loss-induced anemia, 2, 3cardiac surgery, 153, 154causes, 1of chronic disease, 5, 6, 415–416comprehensive anaemia management,

411–413in CVD, 145–147definition, 1diagnosis

hemoglobin concentration/hematocrit determination, 7

with overt/occult bleeding, 8without overt/occult bleeding, 8–10

direct antiglobulin test, 44fatal role, 409ferroportin levels, 43folate and B12 levels, 45haptoglobin levels, 44hemoglobin concentration in men and

women, 1and hemoglobinopathies, 6, 7haemoglobin progression with and

without, 413hepcidin levels, 43, 44homocysteine testing, 45in ICU patients, 2IDA, 42

Index

https://doi.org/10.1007/978-3-319-93572-0

426

Anemia (cont.)impact, 409, 410of inflammation, 415in pregnancy, 201iron and/or erythropoietin therapy, 10, 11ischemic stroke, 189, 190kidney transplant, 268laboratory tests, 45macrocytic anemia, 45mean reticulocyte volume, 43microcytic anemia, 42National Institutes of Health Stroke Scale, 190nonroutine laboratory tests, 42normocytic anemia, 42, 43nutritional deficiency anemia, 4, 5protracted and low-volume bleeding, 4RBC transfusion, 11, 12red blood cell breakdown, 6reticulocyte hemoglobin, 42, 43solid organ transplant

clinical diagnosis, 260etiologies, 260management, 261postoperative period, 260

transferrin saturation, 43traumatic brain injury, 185

Aneurysmal SubArachnoid Hemorrhage-Red Blood Cell Transfusion and Outcome (SAHaRA) trial, 189

Annexin II, 229Antibiotics, 274Anticoagulation/anticoagulants, 323–324

antiplatelet agents, 243direct factor Xa inhibitor

activated charcoal, 339andexanet alfa, 338apixaban, 337betrixaban, 338edoxaban, 337LMWH monitoring, 338rivaroxaban, 336, 337

direct thrombin inhibitors, 242factor Xa inhibitors, 243fibrinolytic agents, 331, 332fondaparinux, 324, 330heparin, 242low-molecular-weight heparins, 322, 324management, 247novel oral anticoagulants, 333, 334oral direct thrombin inhibitors, 334–335parenteral direct thrombin inhibitors

argatroban, 330, 331bivalirudin, 330desirudin, 331

unfractionated heparin, 321, 322warfarin, 332

Anticomplement therapy, 223Anti-factor Xa level assay, 244Antifibrinolytic agents, 395Antifibrinolytic therapy, 230, 248Antineoplastic therapy, 215Antiphospholipid antibody, 222Antiphospholipid syndrome (APS), 351Antiplatelet agents, 243, 264Antithrombin, 21, 245Antivirals, 273–274Anti-Xa assay, 231Anti-Xa monitoring, 220Apixaban, 337Argatroban, 330, 331Arterial thromboembolism, 221–222Arterial thrombotic events, 217Artificial blood, 364Artificial oxygen carriers, 397–398Aspirin therapy, 268Asymptomatic hypercoagulable state, 216Atypical hemolytic-uremic syndrome (aHUS),

26, 349Autoimmune hemolytic anemia, 350Automatic cytometers, 226

BBacterial infection transmission, 282Bethesda assay (BA), 230Betrixaban, 338Biopure, 376Bivalirudin, 330Bland-Altman difference plot, 71Bleeding, ECMO, complication, 245Blood clot micro-elastometry device, 85Blood components, 282Blood donor’s microbiome, 294Blood loss-induced anemia, 2, 3Blood processing method, 314Blood transfusion

ABO blood group system, 294allergic reactions, 285, 286blood components, 280causes, 280due to human error, 281–282fatal transfusion reaction, 279febrile reactions, 285hemovigilance network, 280immune system, 280leukoreduction, 280MOF and mortality, 290, 291necrotizing enterocolitis, 287

Index

427

nosocomial infection, 288–289outcomes, 294–295pathogen inactivation technologies

FRALE method, 284INTERCEPT® blood system, 283, 284Mirasol® system, 284Octaplas LG, 285plasma units, 283THERAFLEX® MB-Plasma

system, 284THERAFLEX® UV-C, 284

risks, 279serologic techniques, 279spontaneous intracranial bleeding, 293TACO, 286TBI, 292thrombosis, 287TRALI, 286transfusion-transmitted infectious

diseases, 282TRIM, 293–294

Board certification in critical care pharmacy (BCCCP), 392

Board certification in pharmacotherapy (BCPS), 392

Bone marrow necrosis, 354

CCalcineurin inhibitors (CNIs), 271Cancer

indirect systemic effects, 215procoagulant pathways, 215thrombotic risk, 216

Cancer-mediated hypercoagulability, 215Cardiovascular disease (CVD)

anemia, 145–147mortality rates, 145 (see also Myocardial

infarction)red blood cell transfusion, 150, 151

Catastrophic antiphospholipid syndrome (CAPS), 351–352

Cell-based immunomodulatory therapy, 356Cell-free DNA (cfDNA), 313Cellular depletion

definition, 341indications

erythrocytosis/absolute polycythemia, 356

hyperleukocytosis, 355leukocytapheresis, 355polycythemia vera, 356

Centers for Medicare and Medicaid Services (CMS), 139

Coagulation, activation of, 240, 241Coagulation abnormalities

acquired FVIII inhibitors, 230–231antineoplastic therapy, 232–233DIC, 229, 230factor X deficiency, 231thrombocytosis, 232

Coagulation factors, 338Coagulation profile, 262Coagulation testing and monitoring

ACT, 77aggregometry, 83anti-factor Xa chromogenic assay, 78aPTT, 76, 77cone and plate(let) analyzer, 84DOACs, 75DRVVT, 83dTT, 77ecarin chromogenic assay, 78ecarin clotting time, 78factor X assay, 78hepcon/HMS, 79HPOCH, 79LHR, 84LSR, 85platelet function analyzer 100, 84PT/INR, 75, 76resonant acoustic spectroscopy, 85TGA, 82, 83TT, 77viscoelastic hemostatic point-of-care

assays, 80–82VKAs, 75

Coagulopathy, 413–414activated partial thromboplastin time, 47anti-Xa assay, 49, 50chromogenic factor X assay, 49factor VIII inhibitors, 49fibrinolysis tests, 58hypercoagulability tests, 54, 55lupus anticoagulant testing, 48, 49organ transplant

clotting physiology, 261coagulation profile, 262conventional testing, 262functional recovery, 262management, 263point-of-care whole blood testing, 262

platelet function tests, 55–57prothrombin time, 47routine coagulation assays, 47, 48TBI, 187viscoelastic testing, 50–53von Willebrand disease, 53, 54

Index

428

Cold autoimmune hemolytic anemia (CAIHA), 350

Colloids, 363Complex coagulopathy, 215Cone and plate(let) analyzer (CPA), 84Co-oximeters, 66Corticosteroids, 272Crystalloid fluids, 363Crystalloid minimization, 205Cytokines, 229Cytomegalovirus (CMV), 269

DDabigatran

bleeding patient, management of, 335Ecarin clotting time assay, 334Hemoclot Thrombin Inhibitor assay, 334secondary prevention, 334treatment, 334

Damage control resuscitation (DCR)ACS TQIP Massive Transfusion in Trauma

Guidelines, 110in civilian trauma care, 106–108in combat casualty care, 106Eastern Association for the Surgery of

Trauma Damage Control Resuscitation Guidelines, 109

Joint Trauma System Clinical Practice Guidelines, 109

massive transfusion protocols, 117, 118national and international guidelines,

109, 110NICE guideline on Major Trauma, 110

Damage-associated molecular patterns (DAMPS), 313

1-Deamino-8-D-arginine vasopressin (DDAVP), 166

Deep vein thrombosis (DVT), 217, 252Delayed cerebral ischemia (DCI), 188Desirudin, 331Desmopressin (DDAVP), 192, 247, 396Dilute Russell Viper venom time (DRVVT), 83Dilute thrombin time (dTT), 77Direct-acting oral anticoagulants (DOAC), 401Direct antiglobulin test (DAT), 44Direct factor Xa inhibitor

activated charcoal, 339andexanet alfa, 338apixaban, 337betrixaban, 338edoxaban, 337LMWH monitoring, 338rivaroxaban, 336, 337

Direct oral anticoagulants (DOACs), 75, 78, 219Direct thrombin inhibitors (DTIs), 242Disseminated intravascular coagulation (DIC),

18, 130, 216, 229, 230ECMO, 252

Drug RSR-13, 365Drug-induced RBC disorders, 398

EEarly goal-directed therapy (EGDT), 138Eastern Association for the Surgery of Trauma

Damage Control Resuscitation Guidelines, 109

Ecarin chromogenic assay (ECA), 78Ecarin clotting time (ECT) assay, 78, 334Edoxaban, 337Eexchange transfusion, see Red cell exchangeEndogenous antithrombin, 242Endothelin-1, 374Enzyme-linked ABO-sorbent assay (ELISA),

230ε-aminocaproic acid (EACA), 395Erythrocyte sedimentation rate (ESR), 191Erythrocytosis/absolute polycythemia, 356Erythropoietin therapy, 10, 11Erythropoietin-stimulating agents (ESAs),

227, 393, 394Essential thrombocythemia (ET), 232European System for Cardiac Operative Risk

Evaluation (EuroSCORE) II, 409Extracellular vesicles (EVs), 313Extracorporeal Life Support Organization

(ELSO), 245Extracorporeal membrane oxygenation

(ECMO)advantages, 237anticoagulation

antiplatelet agents, 243direct thrombin inhibitors, 242factor Xa inhibitors, 243heparin, 242

coagulation, 240, 241disseminated intravascular coagulation,

252hemolysis, 252, 253hemorrhage

anticoagulation management, 247antifibrinolytic therapy, 248bleeding complication (see

Hemorrhage)prothrombin complex concentrate, 248recombinant activated factor 7a, 248transfusion thresholds, 246

Index

429

heparin-induced thrombocytopenia, 249–250heparin resistance, 245monitoring

activated clotting time, 243, 244activated partial thromboplastin time, 244anti-factor Xa level assay, 244viscoelastic testing, 244

principlesgas exchange, 238, 239mechanical circulatory support, 238single-site, dual-lumen venovenous

ECMO configuration, 239, 241two-site venovenous ECMO

configuration, 239, 240venoarterial ECMO, 238

surgical procedures, 253thrombocytopenia, 249thrombotic complications

embolic CVAs, 251oxygenator thrombosis, 250, 251pump head thrombosis, 251

Von Willebrand factor deficiency, 250Extracorporeal photopheresis (ECP), 356

acute graft versus host disease, 356, 357cell-based immunomodulatory therapy, 356definition, 342

FFactor X deficiency, 231Factor Xa inhibitors, 243Febrile transfusion reactions, 285Fibrinolysis, 114–116, 163Fibrinolytic agents, 331, 332Fibroblast growth factor-4 (FGF-4), 226Fondaparinux, 324, 330, 4004T scoring system, 225FRALE method, 284

GGastrointestinal hemorrhage, 159

mortality, 169multimodal approach, 169prophylactic platelet transfusions, 169–171

Graft-versus-host disease (GVHD), 275

HHaemostatic abnormalities, 416Hematinic agents, 393–395Hematopoietic stem cell transplantation

(HSCT), 216Hematopoietic stem cells, 226Heme moieties, 365

Hemoclot Thrombin Inhibitor assay, 334HemoCue, 67Hemoglobin, 366Hemoglobin-based oxygen carriers (HBOCs)

“alkaline” fluids, 372biconcave disc, 378Biopure, 376blood transfusion, 379–380DCLHB, 374determination, 375endothelin-1, 374free heme, 372glutaraldehyde, 373harvest, 373hemoglobin-saline solutions, 372HemoLink study, 376inflammation, upregulation of, 372infused stroma-free hemoglobin, 371kidney block, 372low P50 pegylated Hgb (Hemospan), 377lysed erythrocytes, 371Lysineα199 residues, 373man-made oxygen carriers, 370methemoglobin, 372microencapsulated O2 systems, 379microparticle production

techniques, 379modified Hgb molecules, 378nitric oxide (NO), 372nonmammalian hemoglobins, 378Northfield Poly Heme trials, 376Optro, 375outcome variable, 376OxyVita, 378Polyheme study, 377reticuloendothelial system, 372shock severity index, 375toroidal, 379

Hemoglobin testing and monitoringcolorimeters, 66hemoglobin-cyanide method, 66hemoglobinometry, 65noninvasive and continuous Hb

monitoringBland-Altman difference plot, 71multiwavelength pulse co-oximetry

sensor, 70occlusion spectroscopy, 70SpHb monitoring, 70–74transcutaneous reflection spectroscopy,

70oxygen reserve index, 74photometric determination, 66point-of-care testing, 66–69time colorimeter technologies, 66

Index

430

Hemoglobin-based oxygen carriers (HBOCs), 364, 397, 398

Hemoglobin-based oxygen compounds (HBOCs), 364

Hemoglobin-cyanide method, 66Hemoglobinometry, 65Hemoglobinopathies, 6, 7HemoLink study, 376Hemolysis, 252, 253Hemolytic-uremic syndrome (HUS), 223Hemophagocytic lymphohistiocytosis

(HLH), 130Hemopure (HBOC-201), 397Hemorrhage

anticoagulation management, 247antifibrinolytic therapy, 248bleeding complicaions, 245, 246prothrombin complex concentrate, 248recombinant activated factor 7a, 248transfusion thresholds, 246

Hemorrhagic complications, 215Hemorrhagic disorders

allogeneic HSCT, 228autologous HSCT, 228platelet transfusion threshold, 227–229thrombocytopathies, 226–227thrombocytopenia, 225uremic platelet dysfunction, 227

Hemostatic abnormalitiescoagulation factors and platelets

DIC, 18liver dysfunction, 18pharmacologic inhibition, 21, 22platelet-derived mediators, 21thrombocytopenia, (see

Thrombocytopenia)vascular/tissue injury, 19, 21vitamin K deficiency, 18

coagulopathy, 32hemostatic management principles, 31laboratory evaluation, 30, 31massive hemorrhage, 33pathophysiology, 17, 18single coagulation factor

acquired inhibitor, 29, 30hereditary deficiencies, 28, 29

thrombotic microangiopathies, see Thrombotic microangiopathies (TMAs)

Hemothorax, 246Hemovigilance network, 280Heparin(s), 21, 231, 242

adverse effects, 322Heparin resistance, 245

Heparin-induced thrombocytopenia (HIT), 27, 28, 217, 224, 225, 249–250, 322, 344

abnormal physiology, 266diagnosis of, 266immune-mediated, 266platelet transfusions, 267

Heparin-platelet factor 4 antibodies (H-PF4 ab), 225

Hepatic vascular thrombosis, 263Hepcon, 79Heptest POC-Hi (HPOCH), 79Hokusai VTE Cancer trial, 219Human albumin solution (HAS), 91Human immunodeficiency virus (HIV)

infectivity, 364Hyperchloremia, 93Hyperfibrinolysis, 266Hyperleukocytosis, 355Hyperviscosity syndrome, 350Hypocalcemia, 345Hypofibrinogenemia, 32Hypomagnesemia, 345Hypoproliferative thrombocytopenia, 45–46

IIatrogenic blood loss

coagulopathy, 413–414point-of-care testing, 414prevention, 414–415

Idarucizumab (Praxbind), 335Immune thrombocytopenic purpura (ITP), 224Immunosuppression, 270Impaired renal function, 219Inferior vena cava (IVC) filters, 220INFORM study, 311INFORM trial data, 311Informing Fresh versus Old Red cell

Management (INFORM) trial, 291INTERCEPT® blood system, 283, 284International Committee for the

Standardization in Hematology (ICSH), 65

International Sensitivity Index (ISI), 163International Society for Thrombosis and

Haemostasis (ISTH) guidelines, 48Intracranial bleeding, 293Intracranial hemorrhage (ICH), 246

anticoagulation, 192desmopressin, 192PATCH trial, 191primary, 191warfarin-associated ICH, 192

Index

431

Intrahepatic cholestasis, 354Intravenous (IV) formulations, 394Intravenous fluids

acid-base effects, 91–94blood rheology, 95coagulation derangements, 90composition, 90crystalloids/colloids

dextrans, 90dilutional coagulopathy, 94glycoprotein IIb/IIIa type effect, 95human albumin solution, 91hypercoagulability, 94non-resuscitation crystalloids, 90resuscitation crystalloids, 89synthetic hydroxyethyl starches, 90

glycocalyx, 96, 97intravascular volume management, 97–99mannitol administration, 96neurology, 95vascular biology, 90

Intravenous oxygen therapeuticsblood substitute, 364hemoglobin-based oxygen carriers

“alkaline” fluids, 372biconcave disc, 378Biopure, 376blood transfusion, 379–380DCLHB, 374determination, 375free heme, 372glutaraldehyde, 373harvest, 373hemoglobin-saline solutions, 372HemoLink study, 376inflammation, upregulation of, 372infused stroma-free hemoglobin, 371kidney block, 372low P50 pegylated Hgb (Hemospan), 377lysed erythrocytes, 371Lysineα199 residues, 373man-made oxygen carriers, 370methemoglobin, 372microencapsulated O2 systems, 379microparticle production techniques, 379modified Hgb molecules, 378nitric oxide, 372nonmammalian hemoglobins, 378Northfield Polyheme trials, 376Optro, 375outcome variable, 376OxyVita, 378Polyheme study, 377reticuloendothelial system, 372

shock severity index, 375toroidal, 379

oxygen delivery to tissues, 364–367PFC, 379–385unmet need, 364–370

Iron deficiency anemia, 394Iron hormone hepcidin, 261Iron therapy, 10, 11Iron-deficiency anemia (IDA), 42Ischemic stroke, 189–191

KKidney transplant (KTx)

anemiadiagnosis, 268management, 268prognostic indicator, 268work-up, 268

antivirals, 273–274graft-versus-host disease, 275infectious agents

cytomegalovirus, 269parvovirus B19, 269sepsis, 269

medicationsantibiotics, 274azathioprine, 271calcineurin inhibitors, 271immunosuppression, 270MMF, 271mTOR inhibitors, 272rabbit-derived antithymocyte globulin,

272steroids, 272

PTLD, 274

LLaser speckle rheology (LHR), 84Leukocytapheresis, 343, 355Leukoreduction, 228Leukostasis, 355Liver disease

coagulation disturbance, 160–162fibrinogen testing, 164fibrinolysis, 163international normalized ratio, 163, 164low molecular weight heparins, 175partial thromboplastin time, 164PCCs, 173, 174pharmacologic therapies

antifibrinolytic agents, 167DDAVP, 166

Index

432

Liver disease (cont.)recombinant factor VIIa, 166thrombopoietin (TPO) receptor

agonists, 168vitamin K, 165, 166

plasma transfusion, 171–173platelet count, 164platelet dysfunction, 162platelet transfusions, 171prevalence of, 159prevention and management, 176, 177red blood cell transfusion, 174–175ROTEM, 164TEG, 165TGT, 164thrombocytopenia, 162thromboprophylaxis, 175vascular disturbance, 160vitamin K antagonists, 175

Low-molecular-weight heparins (LWMH), 217, 219, 220, 242, 322, 324, 400

Lupus anticoagulant (LA), 231

MMacrocytic anemia, 45Macrophage activation syndrome, 130Mammalian target of rapamycin (mTOR),

270, 272Massive bleeding, 2, 3Massive transfusion (MT), 104, 105, 118, 261Massive transfusion protocols (MTPs), 205Mechanical circulatory support, 238Medication experts, 398Membrane integrity, 307Metalloproteins, 365Microangiopathic process, 226Microangiopathy, 229Microcytic anemia (MCV), 42Microencapsulated O2 systems, 379Microparticle production techniques, 379Mirasol® system, 284Model for end-stage liver disease (MELD), 260Modern blood banking, 305Modern healthcare reform, 391Modified Rankin Scale (mRS) score, 190Multi-organ failure (MOF), 290, 291, 354Multiple organ dysfunction syndrome

(MODS), 310Myelodysplastic syndrome, 226Myeloproliferative neoplasms (MPN), 232Myocardial infarction (MI)

acute myocardial injury, 148chronic myocardial injury, 148

definition, 147diagnosis, 148–149therapeutic intervention, 148treatment, 149, 150types, 148

NNational and international damage control

resuscitation (DCR) guidelines, 109, 110

National Institute for Health and Care Excellence (NICE) guideline on Major Trauma, 110

National Institutes of Health Stroke Scale (NIHSS), 190

Natural fibrinolytic processes, 242Necrotizing enterocolitis (NEC), 287Neurological diseases

antiplatelets and anticoagulants, 191, 192ischemic stroke, 189–191subarachnoid hemorrhage, 188, 189traumatic brain injury, 185–187

Neutropenia, 267Neutrophilia, 135New or progressive multiple organ dysfunction

syndrome (NPMODS), 310Nijmegen-Bethesda assay (NBA), 230Non-transferrin-bound iron (NTBI), 306Normocytic anemia, 42, 43Northfield Polyheme trials, 376Nosocomial infection, 288–289Novel oral anticoagulants (NOACs), 333, 334Nutritional deficiency anemia, 4, 5Nuvox product, 384

OO2-carrying intravenous fluids, 363Obstetrics

antepartum hemorrhage, 201, 202bleeding conditions, 199causes of trauma, 200coagulation changes, 199emergency drills, 206fetal well-being, 200goal-directed patient blood management, 200hypertensive disease, 209massive hemorrhage management, 208patient blood management, 205placental abruption, 200point-of-care viscoelastic tests, 200postpartum hemorrhage

anticipation of, 203

Index

433

definition, 202early recognition and diagnosis, 203fetal heart rate monitor, 203laboratory testing, 204low case fatality rates, 208maternal vital signs, 203, 204noninvasive hemodynamic monitors, 203pharmacology, 206, 207risk factors, 201–203surgical interventions, 206, 208transthoracic echocardiography, 204treatment, 204visual estimation, 203

renal failure, 209sickle-cell disease, 200, 201stabilization and management of mother, 200thrombotic risk, 200venous thromboembolism, 201

Octaplas LG, 285Optro, 375Orthotopic liver transplantation (OLT)

anemiaclinical diagnosis, 260etiologies, 260management, 261postoperative period, 260

coagulopathyclotting physiology, 261coagulation profile, 262conventional testing, 262functional recovery, 262management, 263point-of-care whole blood testing, 262

hyperfibrinolysis, 266MELD scoring system, 260neutropenia, 267physiologic derangement, 260thrombocytopenia, 266thrombosis

diagnosis, 264incidence, 264management, 264–265

Oxygen (O2)-carrying capacity, 363Oxygen reserve index (ORI), 74Oxygenator membrane, 238, 239Oxygenator thrombosis, 250, 251OxyVita, 378

PParenteral direct thrombin inhibitors

argatroban, 330, 331bivalirudin, 330desirudin, 331

Parvovirus B19 infection, 269Pathogen inactivation (PI) technologies

FRALE method, 284INTERCEPT® blood system, 283, 284Mirasol® system, 284Octaplas LG, 285plasma units, 283THERAFLEX® MB-Plasma system, 284THERAFLEX® UV-C, 284

Patient blood management (PBM)advantage, 407anemia, 409

comprehensive anemia management, 411–413

fatal role, 409haemoglobin progression with and

without, 413impact, 409, 410

clinical practice, 407, 417–418evidence-based practice, 392history, 408iatrogenic blood loss

coagulopathy, 413–414point-of-care testing, 414prevention, 414–415

ongoing ICU-related anemia and coagulopathy, 415–417

pharmacy and therapeutics (P&T) committees, 392

strategies, 392technology and decision support

systems, 392transfusion, 409–411

PCCs, see Prothrombin complex concentratesPediatric Index of Mortality (PIM2), 290Pediatric Logistic Organ Dysfunction

(PELOD) scores, 290Pediatric Risk of Mortality (PRISM) III, 290Perfluorocarbon emulsions (PFC), 381–385,

397Pharmacologic alternatives, 393Pharmacological anticoagulant reversal agents

DOAC, 401fondaparinux, 400low-molecular-weight heparins (LWMH),

400vitamin K antagonists, 399

Pharmacomechanical catheter-directed thrombolysis, 221

Pharmacy practice advancement initiative (PAI), 391

Platelet consumption, 226Platelet destruction and sequestration, 226Platelet function analyzer 100, 84

Index

434

Platelet transfusions, 224, 267, 287, 416Point-of-care (POC) whole blood testing, 262Point-of-care Hb monitoring, 66–69Point-of-care testing (POCT), 414Polycythemia vera (PV), 356Polyheme study, 377Post-transplant lymphoproliferative disease

(PTLD), 274Procoagulant pathways, 215Programmed cell death ligand 1 (PD-L1), 233Programmed cell death receptor 1 (PD-1), 233Pro-inflammatory bioactive lipids, 307Prothrombin complex concentrates (PCCs),

173, 174, 248, 396, 400Prothrombin time/International normalized

ratio (PT/INR), 75, 76, 344Protracted and low-volume bleeding, 4Pulmonary embolism (PE), 217

RRabbit-derived antithymocyte globulin

(rATG), 272Randomized Evaluation of Normal Versus

Augmented Level (RENAL) replacement therapy, 290

RBC transfusion, 103, 104Recombinant activated factor 7a (rFVIIa),

248, 396Recombinant factor VIIa (rFVIIa), 324, 338Red blood cell filtration method, 305–306, 314Red blood cell storage

ABC PICU study, 310, 311clinical impacts, 314continental divide, 308donor characteristics, 314efficacy studies, 309, 310factors, 306long-term blood storage, 311MAP, 306meta-analysis, 310modern blood banking, 305multiple hypotheses, 309observational studies, 308PAGGSM, 306primary outcome, 310RECESS trial, 310red blood cell filtration method, 306, 314secondary outcome measures, 310sensitivity analysis, 310short-term blood storage

ABLE study, 313CfDNA, 313DAMPs, 313

EVs, 313INFORM study, 311mortality, 311, 312TRANSFUSE study, 313

storage lesion, 306, 307time line, 309washed cells, 308whole blood filtration method, 305, 314world’s blood suppliers, 306, 307

Red cell exchange (RCE)definition, 341indications

acute chest syndrome, 353acute multi-organ failure, 354acute stroke, 353bone marrow necrosis, 354intrahepatic cholestasis, 354splenic/hepatic sequestration, 353

Reduction of immunosuppression (RIS), 269Resonant acoustic spectroscopy, 85Resuscitation crystalloids, 89Reticuloendothelial system, 372Rivaroxaban, 76, 336, 337Rotational thromboelastometry (ROTEM),

113, 114, 164, 262

SSaline infusion therapy, 91Sepsis, 269

CMS SEP-1 measures, 139early goal-directed therapy, 138hypoperfusion, 137, 138mixed venous oxygen saturation

(SvO2), 139protocolized quantitative resuscitation, 139protocolized resuscitation, 139RBC rheology, 136, 137RBC transfusion, 140sepsis-induced tissue hypoperfusion, 139surviving sepsis guidelines (SSC), 138,

139 (see also Thrombocytopenia)white blood cell alterations, 135, 136

Sequential/intermittent flow, 342Serious hazards of transfusion (SHOT)

report, 281Shiga toxin-associated hemolytic-uremic

syndrome, 26Shiga toxin-induced hemolytic uremic

syndrome (ST-HUS), 349Shiga toxin-producing Escherichia coli

(STEC), 26Shock severity index, 375Sickle cell disease, 190

Index

435

Sickle-cell hemoglobinopathies, 200, 201Single-site, dual-lumen venovenous ECMO

configuration, 239, 241Society for the Advancement of Blood

Management (SABM), 392Solid organ transplants (SOT)

orthotopic liver transplantation, (see Kidney transplant (KTx); Orthotopic liver transplantation (OLT))

Splanchnic vein thrombosis, 217Splenic sequestration, 353Spot and also continuous noninvasive Hb

(SpHb) monitoring, 70–74Stewart’s physicochemical approach, 91, 92Storage lesion, 291Stroke Prevention Trial in Sickle Cell Anemia

(STOP), 190Stromal-derived factor-1α (SDF-1 α), 226Subarachnoid hemorrhage (SAH), 188–189Systemic inflammatory response syndrome

(SIRS), 189, 269

TTACO, see Transfusion associated circulatory

overload (TACO)Target-specific oral anticoagulants (TSOACs),

see Novel oral anticoagulants (NOACs)

TEG 6 s instrument, 81THERAFLEX® MB-Plasma system, 284THERAFLEX® UV-C system, 284Therapeutic apheresis (TA)

adverse events, 345–346anticoagulation, 344assessing effectiveness, 345cellular depletion

definition, 341erythrocytosis, or absolute

polycythemia, 356hyperleukocytosis, 355leukocytapheresis, 355polycythemia vera, 356

continuous flow procedures, 342ECP, 342, 356–357exchange volume, 343RCE (see Red cell exchange)replacement fluid, 343sequential/intermittent flow, 342TPE (see Therapeutic plasma exchange)vascular access, 342

Therapeutic plasma exchange (TPE)definition, 341

indicationsatypical HUS, 349autoimmune hemolytic anemia, 350catastrophic antiphospholipid

syndrome, 351–352hyperviscosity syndrome, 350secondary TMAs, 349ST-HUS, 349thrombotic microangiopathy, 347thrombotic thrombocytopenic

purpura, 347Thrombin generation assay (TGA), 82, 83Thrombin generation test (TGT), 164Thrombin time (TT), 77Thrombocytopathies, 226–227Thrombocytopenia, 220, 225, 249

adverse clinical outcomes, 128causes, 19cutoff values, 127differential diagnosis, 19, 20heparin-induced thrombocytopenia, 27, 28heparin-platelet factor 4 (PF4) antibodies, 46hypoproliferative thrombocytopenia, 46in sepsis, 19in septic patient, 128, 129

ADAMTS 13 levels, 130causes, 128, 130disseminated intravascular coagulation,

130evaluation, 131, 132hemophagocytic lymphohistiocytosis,

130macrophage activation syndrome, 130management, 132–135thrombopoietin levels, 130

incidence of, 19, 127liver disease, 162multivariate analysis, 128nonimmune causes, 46PLASMIC score components, 46prevalence, 19recovery rate, 128risk factors, 19, 127treatment, 31, 32

Thrombocytosis, 232Thromboelastography (TEG), 80, 85, 165, 262Thromboembolism, 251

clinical consequence, 251Thrombolytic therapy, 219Thrombosis

blood tranfusion, 287diagnosis, 263–264incidence, 264management, 264–265

Index

436

Thrombotic biomarkers, 216Thrombotic complications, 215, 217Thrombotic microangiopathies (TMAs), 222,

271, 347aHUS, 26diagnostic tests, 23DIC, 23, 24drug-Induced TMA, 26, 27etiologies, 23with malignant hypertension, 24of pregnancy, 25shiga toxin-associated hemolytic-uremic

syndrome, 26treatment, 23TTP, 25

Thrombotic thrombocytopenic purpura (TTP), 25, 222, 223, 347

Tissue plasminogen activator (tPA), 396Topical hemostatic agents, 395Toroidal, 379TRALI, 286Tranexamic acid (TXA), 395TRANSFUSE study, 313Transfusion associated circulatory overload

(TACO), 152Transfusion medicine, 391Transfusion Requirements in Critical Care

(TRICC) trial, 119, 186, 247Transfusion thresholds, 246Transfusion-associated circulatory overload

(TACO), 286, 348Transfusion-associated necrotizing

enterocolitis (TANEC), 287Transfusion-related immunomodulation

(TRIM), 261, 293–294Transfusion-transmitted infectious diseases, 282Transplant-associated thrombotic

microangiopathy (TA-TMA), 223Trauma resuscitation

blood transfusion, 103, 104bloody vicious cycle, 112DCR (see Damage control resuscitation)fibrinolysis, 114–116hemorrhage control, 119, 120hypotensive/delayed resuscitation, 111lethal triad of acidosis, hypothermia, and

coagulopathy, 112massive transfusion, 104, 105, 118PROMMTT study, 108PROPPR trial, 108–109ROTEM, 113, 114tranexamic acid (TXA) clinical trials,

115, 117trauma-induced coagulopathy, 112, 113

Trauma-induced coagulopathy (TIC), 112, 113Traumatic brain injury (TBI), 292

anemia, 185biomarkers, 187coagulopathy, 186, 187hematocrit, 186hemoglobin concentration, 186hypotension, 186hypothermia, 186incidence, 185leukocytosis, 187restrictive transfusion goal, 186TRICC trial, 186

Trousseau’s syndrome, 191Ttransfusion associated with graft-versus-host

disease (Ta-GVHD), 307Tumor-induced blood vessel compression, 222Two-site venovenous ECMO configuration,

239, 240

UUnfractionated heparin (UFH), 321, 322University of Michigan massive transfusion, 119Upper-body cannulation strategies, 240Uremic platelet dysfunction, 227

VValganciclovir therapy, 267Vaso-occlusive crisis (VOC), 200Venoarterial ECMO, 238Veno-occlusive disease (VOD), 225, 288Venous thromboembolism (VTE), 201

chemotherapeutic agents, 217DOACs, 219duration of therapy, 218DVT, 217incidence, 217initial treatment, 218IVC filters, 220LMWH, 217, 219, 220long-term treatment, 218with malignancy and thrombocytopenia,

220management, 217mortality, 220pulmonary embolism, 217recurrence, 220, 221recurrence and bleeding rates, 217risk of, 217splanchnic vein thrombosis, 217

VerifyNow instrument, 84VerifyNow system, 57

Index

437

Viscoelastic hemostatic point-of-care assays, 80–82

Viscoelastic testing, 244Vitamin K antagonists (VKAs), 75, 399Vitamin K deficiency, 18Von Willebrand disease, 28von Willebrand factor (vWF), 161Von Willebrand factor (VWF) deficiency, 250von Willebrand factor (vWF) multimers, 232, 240

VTE vs. arterial thromboembolism, 221Vvenoarterial ECMO, 238

WWarfarin, 332Warm autoimmune hemolytic anemia

(WAIHA), 350Whole blood filtration method, 305, 314

Index

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