Transfusion Support for Patients with Hemoglobinopathies

SEAABB

March 18, 2010

Jeanne Hendrickson, MD

Objectives

To understand the basis of current recommendations for transfusion thresholds in patients with sickle cell disease

To understand the current state of knowledge of proper dosing in these patients

Background

5000 children with sickle cell disease are born annually in the US 1 in 600 African American babies is born with

sickle cell disease

Children’s Healthcare of Atlanta cares for more than 2000 children with hemoglobinopathies

More than 10% of African Americans have sickle cell trait Greater than 2.5 million affected individuals in the

US

The majority of patients with sickle cell disease have Hb SS

Hb SS: 65%

Hb SC: 25%

Hb S β+ thalassemia: 8%

Hb S β° thalassemia: 2%

Hemoglobin S

Glutamine to Valine substitution in the 6th

codon of the Beta globin gene cluster on chromosome 11

Leads to polymerization (and sickling) when deoxygenated

Membrane changes lead to increased adherence to the vascular endothelium

Deoxygenated Hemoglobin (alpha chains are light

color, beta chains are dark color) From UpToDate

RBC Transfusion

Simple versus exchange

Acute versus chronic

To be discussed:

Acute chest syndrome

Splenic sequestration

Priapism

Pre-operative transfusion

CVA

Others

Acute Chest Syndrome

Defined as a new infiltrate in a patient with sickle cell disease

May be accompanied by chest pain, fever, tachypnea, wheezing, or cough

A leading cause of death

http://www.ispub.com/ispub/ijeicm/volume_9_number_2_3/acute_chest_syndrome_in_a_patient_with_sickle_cell_anemia_successfully_treated_with_erythrocytapheresis/chest-fig1.jpg

Vichinsky et al, NEJM 2000

Acute chest syndrome has many causes

Transfusion, a common treatment for ACS, improves oxygenation

670 episodes of ACS

68% of patients received simple transfusion

pAO2 improved from 63 mm Hg to 71 mm Hg with transfusion

O2 saturations increased from 91% to 94% with transfusion

Similar increases with simple versus exchange transfusion

Vichinsky et al, NEJM 2000

Vichinsky et al, NEJM 2000

Transfusion decreases length of hospitalization in patients with acute chest syndrome

Is simple or exchange transfusion best for ACS?

Not known

No adequately powered, randomized trials have examined this question

Historic data suggests dramatic response to exchange

32/35 patients with severe ACS “responded dramatically” to exchange transfusion

Many patients initially received simple transfusion without improvement

Nathan et al, Blood 1993

No difference in outcome with simple versus exchange transfusion seen in a recent retrospective study

Similar baseline characteristics between patient groups

Higher admission Hb levels in exchange group

Higher post-transfusion Hb in exchange group

4 times more blood exposure in exchange group

10.3 versus 2.4 units

Turner et al, Transfusion 2009

Turner et al, Transfusion 2009

Exchange transfusion decreases % S as well as platelet count, ANC, and sVCAM-1

Liem et al, AJH 2004

Liem et al, AJH 2004

Transfusion may prevent ACS predicted by elevated sPLA2

Secretory phospholipase A2 (sPLA2) is an inflammatory mediator that may precede the development of ACS

Simple RBC transfusion may prevent ACS in patients with VOC and sPLA2 > 100 ng/mL (with fever and a negative CXR)

5 of 8 patients randomized to standard care developed ACS, compared to none of 7 patients randomized to transfusion

PROACTIVE (Preventing ACS by Transfusion Feasibility) and ANTHERA studies (sPLA2 inhibitor)

Styles et al, BJH 2006

ACS, transfusion, and neurologic events in patients with sickle cell disease

Neurologic complications are associated with ACS

Including altered mental status, stroke, and seizures

22% of adults, 8% of children with neurologic complications in trial by Vichinsky et al (n=538)

5 consecutive children with ACS in study by Henderson et al developed neurologic complications ( 3 with posterior leukoencephalopathy syndrome)

All were intubated and received exchange transfusion after simple transfusion

Does simple or exchange transfusion contribute to neurologic complications?

Short term chronic transfusion therapy may decrease incidence of ACS in select patients

27 patients with recurrent or unusually severe ACS were treated with chronic transfusion therapy

Incidence of ACS decreased from 1.3 episodes/pt year to 0.1 episodes/pt year

No obvious difference in severity of ACS in patients on chronic transfusion therapy

Chronic lung damage may be minimized

Hankins et al, JPHO 2005

Chronic transfusion arm of STOP with less ACS

Miller et al, J Pediatr 2001

Splenic Sequestration

Collection of sickled RBCs in splenic sinusoids

Often quite acute; “minor” episodes also occur

Precipitating events unclear

Peak age 6 months-2 years

Occurs at an earlier age in children with low fetal Hb levels

Tends to recur

Historically a leading cause of death in infants with Hb SS disease

Rates of sequestration have increased with parental education

Splenic sequestration occurred in 43 of 694 patients in Cooperative Study infant cohort

Gill et al, Blood 1995

From Georgia Comprehensive Sickle Cell Center website

Age at initial splenic sequestration in 89 (of 308) affected children in Jamaica

Serjeant et al, J Peds 1984

132 total attacks, 13 were fatal. 49% had a recurrence with diminishing intervals between events.

Buchanan et al, J Peds 1989

Intensive hypertransfusion may improve splenic function

Splenic sequestration treatment

Transfusion of small aliquots (5 cc/kg) of RBCs slowly is advocated for acute splenic sequestration Beware of autotransfusion

Splenectomy is a potential treatment for patients with recurrent sequestration Often done after 2 years of age

Chronic transfusion therapy may bridge gap until splenectomy can be done Limited efficacy data

Priapism

Results from vaso-occlusion of venous penile drainage

Transfusion for priapism

Review of existing case reports (n=42) shows no decrease in “time to detumescence” with conventional therapy (8 days, n=16) versus transfusion therapy (10.8 days, n=26)

Merritt et al, CJEM 2006

ASPEN (association of sickle cell disease, priapism, exchange transfusion, and neurologic events)

Has been reported in a total of 9 patients

May present immediately or within a week following transfusion

Etiology unclear

Hyperviscosity?

Release of activated clotting factors, activated platelets, and cytokines from sludge like blood in corpora cavernosa?

Sickle patients have increased vWF and fibrinogen at baseline, with decreased protein S

Rackoff et al, J Peds 1992

ASPEN may be more likely in cases with high post-exchange Hb levels

Other priapism reports

Case series of 10 patients receiving whole blood exchange (and ending with Hb < 10 g/dL) had no neurologic complications

Case series of 7 patients receiving whole blood exchange had 1 neurologic complication

Ballas et al, J Clin Apheres 2006

McCarthy et al, Ther Apher 2000

Pre-operative transfusion

High rates of post-operative complications have been reported in patients with sickle cell disease

Including VOC, ACS, other

Does pre-op transfusion decrease this risk?

How low does the %S have to be?

Fu et al, Pediatr Blood Cancer 2005

Minor elective surgical procedures done without transfusion

Retrospective

28 children with Hb SS

15% with post-op complications (fever, pain). No ACS.

Pre-operative transfusion

Preoperative Transfusion in Sickle Cell Disease Study:

551 patients with HbSS

Randomized to aggressive (Hb of 10 g/dL and Hb S <30%) or conservative (Hb of 10 g/dL regardless of percent S) arms

Vichinsky et al, NEJM 1995

Similar non-transfusion complication rates in each arm

Vichinsky et al, NEJM 1995

50% fewer transfusion related complications in conservative arm

Haberkern et al, Blood 1997

“high risk” surgeries

Abdominal procedures

Orthopedic procedures

Cardiac surgery

Retinal surgery

NIH Guidelines

Recommend preoperative simple transfusions to maintain (and not exceed) a Hb of 10 g/dL

CVA

At least 10% of patients with HbSS disease will have a clinical stroke by 20 yo

A higher percentage will have a silent stroke

Ohene-Frempong, Blood 1998

Patients from Cooperative Study, n=4082

Ohene-Frempong et al, Blood 1998

Treatment of acute ischemic events

Case reports of exchange transfusion reversing TIAs

Russell et al, JAMA 1979

Prevention of stroke

Stroke Prevention Trial in Sickle Cell Anemia (STOP):

Randomized “at risk” children with MCA velocity >200 cm/sec by TCD to standard therapy or chronic transfusion therapy (keeping %S <30)

Adams et al, NEJM 1998

Chronic transfusion therapy decreased risk of CVA by 92%

Adams et al, NEJM 1998

STOP 2: Randomized patients from STOP 1 and others with a

history of CVA or abnormal TCD who had been on transfusion therapy for 30 months to discontinue chronic transfusion therapy

Adams et al, NEJM 2005

Adams et al, NEJM 2005

“Events” included abnormal TCDs or CVAs

Chronic Transfusion Therapy

How low should we go?

Does percent S have to be <30% to be beneficial?

Rheology of sickle RBCs

Hct is inversely proportional to RBC flow at any Hb S > 20%

Nathan et al, Blood 1993

Cerebral blood flow decreases with increasing Hb (left) and increases with high %HbS (right)

Hurlet-Jensen et al, Stroke 1994

CBF was determined by Xe133

inhalation; %S determined to be more closely related to CBF than Hb

Nathan et al, Blood 1993

Can %S be liberalized?

After 4 years of maintaining %S < 30%, 15 patients were kept at %S of <50%

No cerebral infarcts in this group (1023 patient months)

Cohen et al, Blood 1992

J Peds, 1992

n=13; changed from routine chronic transfusion therapy (%S < 30) to less intensive therapy (%S < 60). No increased risk of CVA.

Miller et al, J Peds 1992

Cohen et al, Blood 1992

SWiTCH Trial

“Stroke with transfusion changing to hydroxyurea”

TWiTCH Trial

“TCD with transfusions changing to hydroxyurea”

SIT Trial

“Silent cerebral infarct multicenter transfusion trial”

Pulmonary HTN

Vichinsky et al, NEJM 2004

NEJM, 2004

Gladwin et al, NEJM 2004

Transfusion to reverse pulmonary HTN?

Trials are ongoing

Other potential (some controversial) indications for RBC transfusion

Aplastic crises

Pregnancy

Hepatic sequestration

Pain crises

Leg ulcers

Growth failure

Adverse Effects of RBC Transfusion

RBC Alloimmunization

Autoimmunization

Iron overload

HLA alloimmunization

Other serious hazards of transfusion

Transfusion reactions

Infectious disease transmission

Thank you