Sickle Cell Disease: Overview and Transfusion Support AABB - - PowerPoint PPT Presentation

Sickle Cell Disease Overview/Transfusion Support

Wednesday, August 29, 2012

2:00 p.m. – 3:30 p.m. (ET) / 6:00p.m.-7:30 p.m. (GMT)

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A 2012 Audioconference presented to you by AABB

Sickle Cell Disease: Overview and Transfusion Support

AABB Audioconference August 29, 2012 Jeanne Hendrickson, MD

Objectives

• To define sickle cell disease and determine

what population is affected

• To assess the indications for transfusion of

sickle cell patients

• To review potential adverse outcomes of

transfusion in sickle cell patients (eg RBC alloimmunization and delayed hemolytic transfusion reactions)

Objectives

• To define sickle cell disease and determine

what population is affected

• To assess the indications for transfusion of

sickle cell patients

• To review potential adverse outcomes of

transfusion in sickle cell patients (eg RBC alloimmunization and delayed hemolytic transfusion reactions)

Sickle Cell Disease: 5000 Affected Babies Born Each Year in the U.S.

• Hb SS: 65%
• Hb SC: 25%
• Hb S β+ thalassemia: 8%
• Hb S β° thalassemia: 2%

Sickle Cell Trait

• 8‐10% of African Americans in the U.S. have

sickle cell trait (Hb AS)

 2.5 million people

• Sickle Dex or sickle prep is positive

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

Newborn Screen

**Hemoglobin presented in quantitative order**

• Hb FA = normal (80% F, 20% A)
• Hb FS = sickle cell disease

 Most likely to be Hb SS, but could be Hb S β°

thalassemia

• Hb FSA = sickle cell disease

 Hb S β+ thalassemia

• Hb FAS = sickle cell trait
• Hb FSC = SC disease
• Hb FA with Bart’s = alpha thalassemia variant
• Hb F = beta thalassemia major

Sickle Cell Disease: Manifestations

• Head/ENT
• Chest
• Abdomen
• GU
• Skeletal
• Other

Objectives

• To define sickle cell disease and determine

what population is affected

• To assess the indications for transfusion of

sickle cell patients

• To review potential adverse outcomes of

transfusion in sickle cell patients (eg RBC alloimmunization and delayed hemolytic transfusion reactions)

Risk/Benefit Ratio of RBC Transfusion in Sickle Cell Disease

• Benefit of increasing oxygen carrying

capacity must be balanced by the risk of serious hazards of transfusion

Alexy et al, Transfusion 2006

“in spite of the documented clinical data supporting transfusion therapy, the physiologic and rheologic aspects of this treatment approach are not fully understood”

Transfusion Options

• One time vs chronic
• Simple vs exchange

Potential Transfusion Indications To Be Further 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

Vichinsky et al, NEJM 2000

Acute Chest Syndrome Has Many Causes

Transfusion 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

 Length of hospital stay decreased with transfusion

Vichinsky et al, NEJM 2000

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 a 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 with a few exceptions:

 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

Short Term Chronic Transfusion Therapy May Decrease ACS Incidence

• 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

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

“Reverse Sequestration” in a patient with sickle cell disease

Lee et al, Postgrad Med J 1996

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 Occur in Cases with High Post‐Exchange Hb Levels

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?

Pre‐Operative Transfusion: NIH Guidelines

• Recommend preoperative simple

transfusions to maintain (and not to exceed) a Hgb of 10 g/dL

Pre‐Operative Transfusion

• Preoperative Transfusion in Sickle Cell

Disease Study:

 551 patients with Hgb SS disease  Randomized to 2 transfusion arms:

 Aggressive (Hb of 10 g/dL and Hb S <30%)  Conservative (Hb of 10 g/dL regardless of percent S)

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

Randomized Trial in Cholecystectomy Patients

May Consider RBC Exchange Prior to “High Risk” Surgeries:

• Abdominal procedures
• Orthopedic procedures
• Cardiac surgery
• Retinal surgery

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 et al, Blood 1998

Most CVAs <20 yo and >30 yo are Ischemic

DeBaun MR et al, Blood 2012

Silent Cerebral Infarcts Have a High Prevalence (yet are not obviously associated with abnormal TCDs)

Wechsler FSIQ Scores are Significantly Lower in Patients with Infarcts (Silent or Overt)

DeBaun et al, Blood 2012

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

• r CVAs

Chronic Transfusion Therapy

• How low should we go?

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

SWiTCH Trial

• “Stroke with transfusion changing to hydroxyurea”

TWiTCH Trial

• “TCD with transfusions changing to hydroxyurea”

SIT Trial

• “Silent cerebral infarct multicenter transfusion trial”

Ware et al, Blood 2012

SWiTCH: Hydroxyurea Arm (solid line) with 7 CVAs (6 ischemic, 1 hemorrhagic); Transfusion arm (dashed line) with 0 CVAs

Ware et al, Blood 2012

SWiTCH: Hydroxyurea Arm (solid line) with 9 TIAs; Transfusion Arm (dashed line) with 6 TIAs

Progressive Cerebral Infarcts Continue to Occur in a Majority of Patients (18/40) Despite Chronic Transfusion Therapy

Hulbert et al, Blood 2011

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

Objectives

• To define sickle cell disease and determine

what population is affected

• To assess the indications for transfusion of

sickle cell patients

• To review potential adverse outcomes of

transfusion in sickle cell patients (eg RBC alloimmunization and delayed hemolytic transfusion reactions)

Adverse Effects of RBC Transfusion

• Hyperviscosity
• RBC Alloimmunization
• Autoimmunization
• Iron overload
• HLA alloimmunization
• Other serious hazards of transfusion

 Transfusion reactions  Infectious disease transmission

RBC Alloimmunization:

• 1) Increases the risk of immediate as well as

delayed hemolytic transfusion reactions

 #2 cause of transfusion related death reported to

the FDA in 2011

• 2) May increase the risk of RBC autoantibody

formation

• 3) May lead to lengthy and costly blood

product delays

• 4) Increases the risk of hemolytic disease of

the newborn

RBC Alloimmunization

• Vichinsky et al: NEJM, 1990; 332: 1617‐1621

 30% alloimmunization rate in transfused patients with

sickle cell disease (5% rate in control, non‐sickle patients)

 17/32 made multiple alloantibodies  66% of alloantibodies were anti‐C, anti‐E, or anti‐K

LaSalle-Williams M et al, Transfusion 2011

Multiple Studies Show RBC Alloimmunization Rates Are Between 20‐40% in Sickle Cell Patients Receiving Non‐Phenotypically Matched RBCs

Average Frequency (%) 21 18 14 8 7 7 7 7 6 5 4 2 2 Average Frequency (%) 21 18 14 8 7 7 7 7 6 5 4 2 2 Antibody E K C Lea Fya Jkb D Leb S Fyb M e c Average Frequency (%) 21 18 14 8 7 7 7 7 6 5 4 2 2

Hillyer et al, Blood Banking and Transfusion Medicine

Average Frequencies of the Most Common Antibodies Made by Patients with Sickle Cell Disease

LaSalle-Williams M et al, Transfusion 2011

C/E/K Phenotypic Matching Decreases But Does Not Eliminate RBC Alloimmunization Risk

LaSalle-Williams M et al, Transfusion 2011

C/E/K Phenotypic Matching Decreases But Does Not Eliminate RBC Alloimmunization Risk

RBC Phenotypic Matching

• A 2005 CAP survey found that only 37% of

laboratories performed a RBC phenotype on non‐alloimmunized patients with sickle cell disease

 Only 75% of these laboratories provided C/E/K

phenotypically matched RBCs for such patients

Osby M et al, Arch Path Lab Med 2005, and Afenyi-Annan A et al, Immunohematology 2006

RBC Genotyping

• Increasingly being utilized at a number of

institutions that care for large numbers of patients with sickle cell disease

 Longitudinal studies are ongoing to determine

feasibility (from a donor and recipient perspective) and to determine the cost/benefit ratio compared to RBC phenotyping alone

Scenario

• 8 yo female with Hgb SS disease, transfused

with 2 units crossmatch compatible, leukoreduced, phenotypically similar RBCs during an episode of acute chest syndrome

Scenario

• Returned 12 days later with abdominal pain,

blood in urine, and severe anemia (Hgb 3.7)

• DAT positive
• Antibody screen remarkable for anti‐Fya,

anti‐Jkb, anti‐S

Delayed Hemolytic Transfusion Reaction

• 3‐10 days after transfusion of blood that

appears compatible

• Patients previously immunized
• Antibody not detected pre‐transfusion

 Anamnestic antibody response

• Intra and/ or extravascular hemolysis
• Can be severe (ARF, DIC)
• Rh and Kidd most common offenders

Anamnestic Response

de Montalembert et al, Haematologica 2011

New Alloantibodies May Not be Found Following DTHRs

Win et al, Transfusion 2008

DHTR in SCD

• High rate of alloimmunization (18‐36%)
• High rate of DHTR (4‐22%)
• Severe, life‐ threatening anemia
• Alloantibodies and autoantibodies
• Bystander hemolysis
• Hyperhemolysis
• Suppression of erythropoiesis

Scheunemann et al, Am J of Medical Sciences, 2010

Scenario

• 2 years later, patient transfused with 1 unit of

crossmatch compatible, leukoreduced, phenotypically similar RBCs during another episode of acute chest syndrome

Scenario

• Re‐admitted 13 days later with abdominal

pain and anemia (Hgb 4.9)

• DAT positive

 All panel cells reactive  Repeat crossmatch with seg of unit transfused

now grossly incompatible

Scenario

• Sample sent to local reference laboratory

 Antibody thought to be against “high incidence

antigen”

 Not anti‐k, Kpb, Jsb, Lub

 Recommended genotyping and performing MMA

Scenario

• The patient developed joint pains, rashes,

and a positive ANA months later

 Was initially diagnosed with “autoimmune

disorder, NOS”

 Was later diagnosed with SLE

 ANA positive 1:2560  Anti‐DS DNA positive

HEA Beadchip Results

HEA Beadchip Results

Additional (D) Genotyping Results

Rh(D) genotyping: R1 allele in trans to an African Black allele (RHCE*ce48C/ RHD*DAU0) This allele could produce a weak anti-Rh antibody, potentially of anti-e or anti-f specificity R1R1 cells would be expected to be compatible

MMA Positive (33%,9%)

Garratty et al, Transfusion 2004

Additional Specialized Testing Revealed anti‐Tca

Many thanks to Connie Westoff and the NYBC Immunohematology Reference Laboratory

How to prevent adverse transfusion related outcomes?

• Judicious use of RBCs
• Obtain accurate transfusion histories
• Centralize RBC alloimmunization data
• Provide leukoreduced RBCs
• Provide phenotypically similar RBCs

 NIH recommends obtaining a RBC phenotype at 6 months

• f age and providing antigen matched RBCs

 C,E,K  Fy, Jk, S

• Consider the role that RBC genotyping may play

Summary

• Transfusion therapy remains critically

important for patients with sickle cell disease

 More patients than ever before are on

chronic transfusion therapy, primarily for CNS indications

 Transfusion alone cannot prevent all complications

Thank you