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) When this file is opened, Acrobat Reader will, by default, display the slides including the Acrobat reader controls. To return to full screen mode, hit Ctrl-L on your computer keyboard or use your mouse to click View>Full Screen on the menu bar of the Acrobat Reader program. To take the slides out of full screen mode and display the Acrobat Reader controls, simply hit the Esc key on your computer keyboard. To advance slides during the program, use the Enter, Page Down, down arrow or right arrow on your computer keyboard. To back up slides during the program, use the Page Up, up arrow of left arrow on your computer keyboard. Please remember to logon to the Live Learning Center using your email address and session number to complete an evaluation of the program and speakers. At this time, advance to the next slide and wait for the audioconference to begin. 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 6 th 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
in spite of the documented clinical data supporting transfusion therapy, the physiologic and rheologic aspects of this treatment approach are not fully understood Alexy et al, Transfusion 2006
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
Acute Chest Syndrome Has Many Causes Vichinsky et al, NEJM 2000
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
ASPEN May Occur in Cases with High Post Exchange Hb Levels Rackoff et al, J Peds 1992
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)
Similar Non transfusion Complication Rates in Each Arm Vichinsky et al, NEJM 1995
50% Fewer Transfusion Related Complications in Conservative Arm Vichinsky et al, NEJM 1995
Randomized Trial in Cholecystectomy Patients Haberkern et al, Blood 1997
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
Most CVAs <20 yo and >30 yo are Ischemic Ohene-Frempong et al, Blood 1998
Silent Cerebral Infarcts Have a High Prevalence (yet are not obviously associated with abnormal TCDs) DeBaun MR et al, Blood 2012
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
Events included abnormal TCDs or CVAs Adams et al, NEJM 2005
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
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 Ware et al, Blood 2012
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
Multiple Studies Show RBC Alloimmunization Rates Are Between 20 40% in Sickle Cell Patients Receiving Non Phenotypically Matched RBCs LaSalle-Williams M et al, Transfusion 2011
Average Frequencies of the Most Common Antibodies Made by Patients with Sickle Cell Disease Antibody Average Frequency (%) E 21 K 18 C 14 Le a 8 Fy a 7 Jk b 7 D 7 Le b 7 S 6 Fy b 5 M 4 e 2 c 2 Hillyer et al, Blood Banking and Transfusion Medicine
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 LaSalle-Williams M et al, Transfusion 2011
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 Fy a, anti Jk b, 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
New Alloantibodies May Not be Found Following DTHRs de Montalembert et al, Haematologica 2011
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, Kp b, Js b, Lu b 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 of 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