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Page 1: Coagulation Disorders in ICU



Page 2: Coagulation Disorders in ICU


Coagulopathic conditions frequently encountered in the intensive care unit (ICU)can be arbitrarily divided into three categories:

(i) Those associated with serious bleeding or a high probability of bleeding,

(ii) Thrombotic syndromes or conditions associated with a higher probability of

thrombosis, and (iii) Systemic disease associated with

acquired selective coagulation factor deficiencies.

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Overview of Coagulation Disorders Seen in the ICU


1. Disseminated intravascular coagulation (DIC)2. Liver disease/hepatic insufficiency3. Vitamin K deficiency/depletion4. Massive transfusion syndrome5. Anticoagulant overdose (heparin, warfarin)6. Thrombocytopenia (drug-induced, immunologic)7. Acquired platelet defects (drug-induced, uremia)

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1. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome

2. Deep venous thrombosis3. Pulmonary embolism4. Coronary thrombosis/acute myocardial


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1. Lupus anticoagulant2. Reactive hyperfibrinogenemia

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1. Hemophilia (A and B)2. Specific factor deficiencies associated with

specific diseases3. Amyloidosis, factor X; Gaucher, factor IX;

nephrotic syndrome, facto IX, antithrombin III4. Cyanotic congenital heart disease

(polycythemia, qualitative platelet defect)5. Depressed clotting factor levels (newborns)

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An Approach to the Patient With an Actual OrSuspected Coagulation Disorder

The medical history, both past and present, may lend some insight into the risk for significant bleeding .

A prior history of prolonged or excessive bleeding, or of recurrent thrombosis, is a significant finding and should be ruled out

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Specific questions regarding bleeding should investigate the occurrence of any of the following:

1. Spontaneous, easy, or disproportionately severe bruising2. Intramuscular hematoma formation (either spontaneous or

related to trauma)3. Spontaneous or trauma-induced hemarthrosis4. Spontaneous mucous membrane bleeding5. Prior problems with bleeding related to surgery (including

dental extractions,tonsillectomy, and circumcision)6. The need for transfusions in the past7. Menstrual history8. Current medications

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Physical examination of the patient with a bleeding disorder should answer several basic questions.

Is the process localized or diffuse Is it related to an anatomic or surgical lesion? Is there mucosal bleeding? And finally, when appropriate, are there signs of either

arterial or venous thrombosis? These answers may give clues to the cause of the

problem as being a primary versus secondary hemostatic dysfunction, or anatomic bleeding versus

generalized coagulopathy.

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The presence of an enlarged spleen coupled with thrombocytopenia suggests that splenic sequestration may be a contributor to the observed thrombocytopenia.

Furthermore, evidence of liver disease, such as portal hypertension and ascites, points to decreased factor synthesis as a possible cause of a prolonged PT or aPTT.

When lymphadenopathy, splenomegaly, or other findings suggestive of disseminated malignancy are detected, acute or chronic DIC should be suspected as the cause of prolonged coagulation times, hypofibrinogenemia, and/or thrombocytopenia.

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Purpura that are palpable suggest capillary leak from vasculitis, whereas purpura associated with thrombocytopenia or qualitative platelet defects are generally not elevated and cannot be distinguished by touch.

Finally, venous and arterial telangiectasia may be seen in von Willebrand disease and liver disease, respectively.

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Diagnostic Laboratory Evaluation

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In the ICU, it is common for laboratory samples to be drawn through an indwelling arterial or central venous cannula, often because peripheral access is no longer available.

Heparin-containing solution is, therefore, commonly present, either in the cannula flush medium to transduce a waveform or as a component of the intravenous infusion.

Depending on the concentration of heparin in the infusing fluid and the volume of blood withdrawn, several tests can be influenced.

Fibrin degradation products (FDPs) can be falsely elevated, and fibrinogen can be falsely low. Likewise, the prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) can be spuriously prolonged.

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Disseminated intravascular coagulation (DIC) is a clinicopathologic syndrome characterized by widespread intravascular fibrin formation in response to excessive blood protease activity that overcomes the natural anticoagulant mechanisms.

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DIC is one of the most serious hemostatic abnormalities seen in the ICU.

The clinical syndrome itself results from the activation of blood coagulation, which then leads to excessive thrombin generation.

The final result of this process is the widespread formation of fibrin thrombi in the microcirculation, with resultant consumption of certain clotting factors and platelets.

Ultimately, this consumption generally results in the development of significant bleeding due to the rate of consumption outpacing the rate at which the clotting factors and platelets are produced.

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Underlying Diseases Associated with Disseminated Intravascular Coagulation:

Sepsis Liver disease Shock Penetrating brain injury Retained placenta Hypertonic saline abortion Amniotic fluid embolus Retention of a dead fetus

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Necrotizing pneumonitis Tissue necrosis/crush injury Intravascular hemolysis Acute promyelocytic leukemia Thermal injury Freshwater drowning Fat embolism syndrome Eclampsia Localized endothelial injury (aortic aneurysm, giant

hemangiomata, angiography) Disseminated malignancy (prostate,pancreatic)

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Fibrinolysis invariably accompanies thrombin formation in DIC

DIC represents an imbalance between the activity of thrombin, which leads to microvascular thrombi with coagulation factor and platelet consumption, and plasmin, which degrades these fibrin-based clots as they form.

Therefore, thrombin-induced coagulation factor consumption, thrombocytopenia, and plasmin

generation all contribute to the presence of bleeding.

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Clinical Presentation and Diagnosis

Generalized oozing or bleeding, or unexplained abnormal laboratory parameters of hemostasis.

The most common findings are bleeding ranging from oozing from venipuncture sites, petechiae, and ecchymoses to severe hemorrhage from the gastrointestinal tract, lung, or into the CNS.

In chronic DIC, the bleeding symptoms are discrete and restricted to skin or mucosal surfaces. The hypercoagulability of DIC manifests as the occlusion of vessels in the microcirculation and resulting organ failure.

Thrombosis of large vessels and cerebral embolism can also occur.

Hemodynamic complications and shock are common among patients with acute

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Differential diagnosis:

Massive transfusion Primary fibrinolysis Thrombotic thrombocytopenic

purpura/hemolytic uremic syndrome Heparin therapy Dysfibrinogenemia

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Specific therapy for DIC should not be undertaken unless

(a) The patient has significant bleeding or

organ dysfunction secondary to DIC, (b)Significant thrombosis has occurred, or (c) if treatment of the underlying disorder

for example, acute promyelocytic leukemia is likely to increase the severity of DIC.

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Supportive therapy for DIC includes the use of several component blood products;

Fresh whole blood that is, less than 24 to 48 hours old also may be given to replete both volume and oxygen-carrying capacity, with the

additional potential benefit of providing coagulation proteins, including fibrinogen, and platelet.

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Cryoprecipitate contains a much higher concentration of fibrinogen than does whole blood or fresh frozen plasma (FFP), and therefore is more likely to provide the quantity of fibrinogen needed to replete fibrinogen consumed during DIC.

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If the serum fibrinogen level is less than 75 to 50mg/dL, repletion with cryoprecipitate to raise plasma levels to 100 mg/dL or higher

is the goal. A reasonable starting dose is one bag of

cryoprecipitate for every 10 kg body weight every 8 to 12 hours.

Platelet transfusions also may be used when thrombocytopenia is thought to contribute to ongoing bleeding.

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Pharmacologic therapy for DIC: 1) Recombinant-activated protein C.2) Recombinant-activated factor VII

(rhfVIIa).3) Other anticoagulant molecules such as

heparin and antithrombin III and thrombolytic agents continue to be studied as therapy for DIC and sepsis .

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Liver Disease and Hepatic Insufficiency

Liver disease is a common cause of abnormal hemostasis in ICU patients, with abnormal coagulation studies or overt bleeding occurring in approximately 15% of patients with either clinical or laboratory evidence of hepatic dysfunction.

It is a common cause of a prolonged PT or aPTT,

often without any clinical sequelae.

The hemostatic defect associated with liver disease is multifactorial, with multiple aspects of hemostasis affected.

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In liver disease, the synthesis of several plasma coagulation proteins is impaired.

These include factors II, V, VII, IX, and X.

In addition to these defects in plasma coagulation protein synthesis, many patient with liver disease, particularly cirrhosis, have increased fibrinolytic activity.

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Thrombocytopenia may be present to a variable degree in patients with hepatic dysfunction. This is usually ascribed to splenic sequestration.

Patients with hepatocellular disease may also exhibit decreased synthesis of the vitamin K dependent anticoagulant proteins, protein C and protein S, as well as antithrombin-III

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If the patient is not actively bleeding, no specific therapy is required

FFP provides the most immediate source of specific coagulation factors (i.e., factor VII),

and usually corrects an isolated mild PT prolongation. Cryoprecipitate is required only if fibrinogen levels are

less than 50 to 100 mg/dL, or if there is documentation

of a significant dysfibrinogenemia. Vitamin K deficiency also is relatively common in this

patient population, and replacement may be needed.

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Recombinant human-activated factor VII (rhfIIa) infusions have been shown to control the bleeding in severe liver disease, although this does not necessarily result in reduced mortality.

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Vitamin K Deficiency

The most common cause of a prolonged PT in the ICU is vitamin K deficiency.

Vitamin K is necessary for the gamma-carboxylation of factors II, VII, IX, and X, without which these factors cannot bind calcium and are not efficiently converted into their activated forms.

Factor VII has the shortest half-life of these coagulation proteins; accordingly, the PT is the most sensitive early indicator of vitamin K deficiency.

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Vitamin K deficiency is relatively common in critically ill patients for several reasons,

1. The use of broad-spectrum antibiotics,2. Poor nutrition preceding or subsequent

to ICU admission, and 3. The use of parenteral nutrition without

vitamin K supplementation

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Many of the second- and third-generation cephalosporins (e.g.,ceftriaxone, cefpodoxime, cefepime, ceftazidime) may directly interfere with vitamin K absorption from the gut lumen.

The metabolites of some of these antibiotics may even act as competitive inhibitors of vitamin K (i.e., cefamandole).

In addition, these and other antibiotics may kill or inhibit the growth of gut bacteria, and thus limit the amounts of vitamin K that they normally produce and excrete into the gut lumen.

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Although malnutrition also may contribute to the

development of vitamin K deficiency, this usually requires 1 to 2 weeks to develop in the complete absence of vitamin K intake.

However, the use of parenteral alimentation without vitamin K supplementation, coupled with antibiotic use, may result in rapid vitamin K depletion; prolongation of the PT can occur within only 2 to 3 days.

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The management of vitamin K deficiency consists primarily of its repletion, usually by intravenous or subcutaneous routes in critically ill patients.

The usual dose of vitamin K in adults is 10 to 15 mg intravenously or subcutaneously, 1 to 5 mg in young children, and up to 10 mg in larger children. In an otherwise healthy person, the PT should correct within 12 to 24 hours after this dose.

Serial dosing of critically ill patients is often used, however, and the PT may require up to 72 hours to normalize.

If the PT does not correct within 72 hours after three daily doses of vitamin K, intrinsic liver disease should be suspected.

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Massive Transfusion Syndrome Transfusion of large quantities of blood

can result in a multifactorial hemostatic defect.

The genesis of this problem is related to the washout of plasma coagulation proteins and platelets, and it may be exacerbated by the development of DIC with consequent factor consumption, hypothermia, acidosis, or rarely, by citrate toxicity or hypocalcemia

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A washout syndrome can result from the transfusion of large amounts of stored blood products devoid of clotting factors and platelets.

Factors V and VII have short shelf half-lives

and are often deficient in blood that has been banked longer than 48 hours.

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As a general rule, residual plasma clotting activity after one blood volume exchange falls to 18% to 37% of normal, whereas after a two blood volume exchange, residual activity is only 3% to 14%; and after a three blood volume exchange, less than 5% of normal clotting function remains.

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The patient who is bleeding as a consequence of massive transfusion or washout presents with diffuse oozing and bleeding from all surgical wounds and puncture sites.

Laboratory abnormalities include prolonged PT, aPTT, and TT.

Fibrinogen levels and platelet counts are typically decreased;

FDPs are not usually increased unless concurrent DIC is present

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The therapeutic approach to patients who develop a coagulopathy from massive transfusion is supportive. Platelets and FFP are given to replete the components of coagulation that are typically lacking .

Platelet administration may help stem bleeding from anatomic wounds.

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In most patients (e.g., weight greater than or equal to 30 to40 kg or body surface area [BSA] greater than or equal to 1.0 m2), four units of

platelets and one unit of FFP should be given for each five units of whole blood or packed cells transfused.

This should prevent washout and its attendant bleeding.

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Anticoagulant Overdose

Heparin: Heparin is metabolized in the liver by the heparinase enzyme in a dose dependent fashion, with excess heparin then being excreted through the kidneys.

As the rate of heparin administration is increased, the half-life of the drug is prolonged due to the increase in the percentage of the drug being excreted by the kidney.

when a 10-unit/kg bolus of heparin is infused intravenously, the average half-life of the drug is 1 hour.

If the bolus is increased to 400 or 800 units/kg, however, the half-life is prolonged to 2.5 and 5 hours, respectively

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Serious bleeding associated with heparin overdose can be rapidly reversed by protamine sulfate.

As a general rule, 1 mg of protamine neutralizes approximately 100 units of heparin.

The drug should be given by slow intravenous push over 8 to 10minutes.

A single dose should not exceed 1mg/kg, with a 50-mg maximum dose

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LMWH is not consistently neutralized by protamine, so invasive procedures should not be performed within 24 hours of administration.

Bleeding following LMWH therapy has been treated effectively with rhfVIIa.

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Warfarin; The mechanism of action of warfarin is

through competitive binding at the vitamin K receptor site, where postribosomal modification, through carboxylation of the vitamin K dependent coagulation proteins factors II, VII, IX, and X occurs.

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The PT, or more precisely the international normalized ratio (INR) calculated from the PT, is an accurate indicator of the effects of warfarin when its use has continued beyond 2 or 3 days.

In severe cases of warfarin overdose, the aPTT also becomes prolonged as a result of depletion of the active forms of factors II, IX,

and X.

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Drugs That Potentiate the Anticoagulant Effects of Warfarin

ANTIBIOTICS Broad-spectrum antibiotics (especially cephalosporins) Griseofulvin (oral) Metronidazole Sulfinpyrazone Trimethoprim-sulfamethoxazole

ANTI-INFLAMMATORY DRUGS Steroids (anabolic, in particular) Acetylated salicylates Phenylbutazone (oxyphenbutazone) Sulfonamides

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OTHER DRUGS Cimetidine Clofibrate Disulfiram Phenytoin Thyroxine (both D- and L-isomers) Tolbutamide

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Management; The treatment of choice is FFP Vitamin K also may be administered,

particularly in situations that are less acute

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Platelet Disorders

Platelets are necessary for efficient clot formation

Quantitative and qualitative platelet disorders are a common cause of clinical bleeding

in the ICU.

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Platelet Disorders Seen in the ICUINCREASED DESTRUCTION Immune Idiopathic thrombocytopenic purpura Systemic lupus erythematosus Acquired immunodeficiency syndrome Drugs (gold salts, heparin, sulfonamides, quinidine, quinine) Sepsis

Nonimmune Thrombotic thrombocytopenic purpura/hemolytic uremic

syndrome Mechanical destruction (e.g., cardiopulmonary

bypass,hyperthermia) Consumption (i.e., DIC)

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DECREASED PRODUCTIONMarrow suppression Chemotherapy Viral illness (e.g., cytomegalovirus, Epstein-Barr virus, herpes simplex, parvovirus) Drugs (thiazides, ethanol, cimetidine)Marrow replacement Tumor MyelofibrosisOther conditions Splenic sequestration Dilution

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DRUGSAnti-inflammatory agents Aspirin (irreversible) Nonsteroidal anti-inflammatory agents CorticosteroidsAntibiotics Penicillins (e.g., ampicillin, carbenicillin, ticarcillin, penicillin-

G) Cephalosporins (e.g., cephalothin) Nitrofurantoin Chloroquine, hydroxychloroquinePhosphodiesterase inhibitors Dipyridamole Methylxanthines (e.g., theophylline)

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Other drugs Antihistamines Alpha-blockers (e.g., phentolamine) Beta-blockers (e.g., propranolol) Dextran Ethanol Furosemide Heparin Local anesthetics

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METABOLIC CAUSES Uremia Stored whole blood Disseminated intravascular coagulation

(i.e., FDPmediated inhibition) Hypothyroidism

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Quantitative Platelet Disorders; Decrease in the number of circulating

platelets reflects the presence of increased peripheral destruction/sequestration, decreased marrow production, or a combination of these factors.

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Qualitative Platelet Disorders Many of the drugs frequently used in the ICU

have the potential to impair platelet function.

Glanzmann thrombasthenia (abnormal platelet GP IIb/IIIa), Bernard-Soulier syndrome (abnormal GP Ib/IX), Wiskott-Aldrich syndrome, platelet storage pool deficiency (abnormal platelet dense bodies), and the Gray platelet disorder (abnormal platelet-granules).

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unnecessary medications should always be discontinued promptly

platelet transfusions

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Heparin-induced Thrombocytopenia

Acute nonidiosyncratic heparin-induced thrombocytopenia is seen in approximately 10% to 15% of patients receiving heparin.

The degree of thrombocytopenia is generally mild and usually remits despite continued use of the drug (type I HIT, or heparin-associated thrombocytopenia).

The thrombocytopenia that develops has no clinical significance, and heparin need not be stopped in these patients.

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Idiosyncratic heparin-induced thrombocytopenia is of much greater clinical consequence.

Although it is a less frequent occurrence, typically being seen in fewer than 5% of patients receiving heparin, it has a much greater potential for

clinical morbidity. Arterial thrombosis is the most significant risk of

this form of heparin-induced thrombocytopenia (type II HIT) and may be life threatening,causing myocardial infarction, stroke, pulmonary embolism, or renal infarction

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Patients with type II HIT should receive continued anticoagulation with direct thrombin inhibitors (argatroban, lepirudin) or with the heparinoid,Danaparoid.

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Uremia: Uremia is commonly seen in the ICU and

is associated with an increased risk of bleeding .

Uremia has been shown to cause a reversible impairment of platelet function, although the toxin responsible for this defect is not well defined.

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Treatment : The primary therapy in this setting is


Cryoprecipitate, 1-deamino-8-D-arginine vasopressin (DDAVP), and conjugated estrogens (10 mg/day in adults) have been given to patients with severe uremia and an acquired defect in primary hemostasis with good results.

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Thrombotic Syndromes

1. Deep venous thrombosis (DVT) (specifically in association with a central venous catheter)

2. Heparin-induced thrombocytopenia 3. Pulmonary embolism syndrome 4. Thrombotic thrombocytopenic purpura/hemolytic

uremic syndrome 5. Thrombotic DIC 6. Stroke 7. Central nervous system (CNS) venous sinus

thrombosis (most commonly seen in infants and the elderly in association with marked dehydration)

8.Acute coronory syndrome

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Approximately 10% of ICU patients will develop DVT while in the ICU in spite of receiving a form of thromboprophylaxis, and up to 15% of these patients will experience a symptomatic pulmonary embolus

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Management: Anticoagulation with either UH or LMWH. The incidence of severe bleeding is less

with LMWH Most patients may be started on UH with

a bolus dose of 50 units/kg, followed by a continuous infusion of 10 units/kg/hour; these doses may be reduced for the elderly or frail patient.

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Civetta, Taylor, & Kirby's: Critical Care, 4th Edition.

Harrisons 18th edition

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Thank you…