Sickle Cell Disease Overview/Transfusion Support Wednesday, August 29, :00 p.m. 3:30 p.m. (ET) / 6:00p.m.-7:30 p.m. (GMT)

Transcription

1 Sickle Cell Disease Overview/Transfusion Support Wednesday, August 29, :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 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

2 Sickle Cell Disease: Overview and Transfusion Support AABB Audioconference August 29, 2012 Jeanne Hendrickson, MD

3 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)

4 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)

5 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%

6 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

7 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

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10 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

11 Sickle Cell Disease: Manifestations Head/ENT Chest Abdomen GU Skeletal Other

12 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)

13 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

14 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

15 Transfusion Options One time vs chronic Simple vs exchange

16 Potential Transfusion Indications To Be Further Discussed: Acute chest syndrome Splenic sequestration Priapism Pre operative transfusion CVA Others

17 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

18 Acute Chest Syndrome Has Many Causes Vichinsky et al, NEJM 2000

19 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

20 Is Simple or Exchange Transfusion Best for ACS? Not known No adequately powered, randomized trials have examined this question

21 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

22 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

23 Turner et al, Transfusion 2009

24 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

25 Chronic Transfusion Arm of STOP with Less ACS Miller et al, J Pediatr 2001

26 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

27 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

28 Reverse Sequestration in a patient with sickle cell disease Lee et al, Postgrad Med J 1996

29 Priapism Results from vaso occlusion of venous penile drainage

30 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

31 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

32 ASPEN May Occur in Cases with High Post Exchange Hb Levels Rackoff et al, J Peds 1992

33 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?

34 Pre Operative Transfusion: NIH Guidelines Recommend preoperative simple transfusions to maintain (and not to exceed) a Hgb of 10 g/dl

35 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)

36 Similar Non transfusion Complication Rates in Each Arm Vichinsky et al, NEJM 1995

37 50% Fewer Transfusion Related Complications in Conservative Arm Vichinsky et al, NEJM 1995

38 Randomized Trial in Cholecystectomy Patients Haberkern et al, Blood 1997

39 May Consider RBC Exchange Prior to High Risk Surgeries: Abdominal procedures Orthopedic procedures Cardiac surgery Retinal surgery

40 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

41 Most CVAs <20 yo and >30 yo are Ischemic Ohene-Frempong et al, Blood 1998

42 Silent Cerebral Infarcts Have a High Prevalence (yet are not obviously associated with abnormal TCDs) DeBaun MR et al, Blood 2012

43 Wechsler FSIQ Scores are Significantly Lower in Patients with Infarcts (Silent or Overt) DeBaun et al, Blood 2012

44 Treatment of Acute Ischemic Events Case reports of exchange transfusion reversing TIAs Russell et al, JAMA 1979

45 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

46 Chronic Transfusion Therapy Decreased Risk of CVA by 92% Adams et al, NEJM 1998

47 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

48 Events included abnormal TCDs or CVAs Adams et al, NEJM 2005

49 Chronic Transfusion Therapy How low should we go? Does percent S have to be <30% to be beneficial?

50 SWiTCH Trial Stroke with transfusion changing to hydroxyurea TWiTCH Trial TCD with transfusions changing to hydroxyurea SIT Trial Silent cerebral infarct multicenter transfusion trial

51 SWiTCH: Hydroxyurea Arm (solid line) with 7 CVAs (6 ischemic, 1 hemorrhagic); Transfusion arm (dashed line) with 0 CVAs Ware et al, Blood 2012

52 SWiTCH: Hydroxyurea Arm (solid line) with 9 TIAs; Transfusion Arm (dashed line) with 6 TIAs Ware et al, Blood 2012

53 Progressive Cerebral Infarcts Continue to Occur in a Majority of Patients (18/40) Despite Chronic Transfusion Therapy Hulbert et al, Blood 2011

54 NEJM, 2004

55 Gladwin et al, NEJM 2004

56 Transfusion to Reverse Pulmonary HTN? Trials are ongoing

57 Other Potential (some controversial) Indications for RBC Transfusion Aplastic crises Pregnancy Hepatic sequestration Pain crises Leg ulcers Growth failure

58 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)

59 Adverse Effects of RBC Transfusion Hyperviscosity RBC Alloimmunization Autoimmunization Iron overload HLA alloimmunization Other serious hazards of transfusion Transfusion reactions Infectious disease transmission

60 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 ) 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

61 RBC Alloimmunization Vichinsky et al: NEJM, 1990; 332: % 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

62 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

63 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

64 C/E/K Phenotypic Matching Decreases But Does Not Eliminate RBC Alloimmunization Risk LaSalle-Williams M et al, Transfusion 2011

65 C/E/K Phenotypic Matching Decreases But Does Not Eliminate RBC Alloimmunization Risk LaSalle-Williams M et al, Transfusion 2011

66 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

67 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

68 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

69 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

70 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

71 Anamnestic Response

72 New Alloantibodies May Not be Found Following DTHRs de Montalembert et al, Haematologica 2011

73 Win et al, Transfusion 2008

74 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

75 Scheunemann et al, Am J of Medical Sciences, 2010

76 Scenario 2 years later, patient transfused with 1 unit of crossmatch compatible, leukoreduced, phenotypically similar RBCs during another episode of acute chest syndrome

77 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

78 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

79 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

80 HEA Beadchip Results

81 HEA Beadchip Results

82 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

83 MMA Positive (33%,9%)

84 Garratty et al, Transfusion 2004

85 Additional Specialized Testing Revealed anti Tca Many thanks to Connie Westoff and the NYBC Immunohematology Reference Laboratory

86 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

87 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

88 Thank you