1. Transfusion Therapy in Patients with Hemoglobinopathies
Isaac Odame
Division of Hematology/Oncology
Hospital for Sick Children
Department of Pediatrics, University of Toronto

2. Objectives Two case studies
Review principles and indications for transfusion therapy in hemoglobinopathy patients
Discuss the challenges of transfusion therapy in hemoglobinopathy patients
Review clinical trials examining alternatives to transfusion therapy

3. Case # 1 Male born in 1997 in Pakistan
Diagnosed thalassemia major aged 6 mo
Red cell transfusion- monthly with no iron chelation therapy
Emigrated to Canada in 2001
Splenomegaly
Anti- HCV Ab +ve Normal LFTs
Rx. RBC transfusion to maintain Hb  90 g/L
Deferoxamine SC 45 mg/kg/day X 7/7
Hep B vaccination

4. Case # 1 After 6 mo of deferoxamine Age 6 years Age 7 years
Liver iron content (biopsy) 21.1  11.4 mg Fe/g dry wt
HLA-typing: sibling match identified
Age 6 years
Plans for BMT
RBC transfusions 2-3 wkly ? Alloantibody
GI consult: HCV RNA +ve genotype 3A Normal LFT
Age 7 years
ALT 227 AST 110
Liver biopsy: mild focal siderosis + portal fibrosis
Liver enzymes settled

5. Case # 1 Age 10 years 3 months into anti-HCV therapy
Rx HCV infection: PEG-IFN & Ribavirin x 24 wks
Complications: hemolytic anemia, neutropenia
Blood bank: Autoantibody + alloantibody
RBC transfusions: every days
3 months into anti-HCV therapy
Severe IFN/Ribavirin –induced hemolysis Hb 49 g/L
IFN/Ribavirin discontinued
PEG-IFN monotherapy restarted

6. Case # 1 4 months anti-HCV therapy Age 11 years HCV PCR- Neg
IFN stopped
RBC transfusion requirements  weekly
Liver iron content (MRI) 15 mg Fe/g (ferritin 2220)
Deferoxamine switched to deferasirox (oral chelator)
Age 11 years
RBC transfusions 3 weekly
Liver iron content (MRI) 5.3 mg Fe/g Ferritin 1300
Liver biopsy: mild fibrosis (0 - 1+)

7. Case # 1 Age 11 years Sibling-donor BMT Bu/Cy/ATG conditioning
Complications: ALT 750, hemorrhagic cystitis
HCV PCR- neg
Engraftment 4 weeks
Blood bank:
DAT pos (anti-C3D and anti-IgG)
Ab screen- Jk(a)
DAT negative at discharge post- BMT

8. Transfusion Therapy in Thalassemia Major

9. Thalassemia in the early 1960s
Ehlers KH, et al. J Pediatr. 1991;118;540-5.

10. Goals of Transfusion Therapy in TM
Treat anemia and eliminate hypoxia
Normal growth pattern
Suppress endogenous erythropoieisis
Pre-transfusion Hb g/L
↓Extramedullary hematopoiesis
↓Bony deformities
Minimize alloantibody formation and transfusion reactions
D, C, E, c, e, and K matching
Leucodepletion
Manage iron overload
Quantification of iron load: hepatic and cardiac
Effective iron chelation therapy

11. Survival in β-thalassemia Major
1.00
1.00
0.75
0.75
Birth cohort
1985–1997
Females
1980–1984
Males
Survival probability
0.50
1975–1979
Survival probability
0.50
1970–1974
1965–1969
1960–1964
(p = )
0.25
0.25
(p < ) 5 10 15 20 25 30 5 10 15 20 25 30
Age (years)
Age (years)
Risk factors for mortality in β-thalassemia major include: serum ferritin levels > 2,500 μg/L (HR: 3.7); arrhythmia (HR: 2.4); male sex (HR: 1.9); heart failure (HR: 11.3)
HR = hazard ratio.
Borgna-Pignatti C, et al. Haematologica. 2004;89: 11

12. Modell B, 2008

13. The Challenge of Compliance Iron Overload Overview
Kaplan-Meier analysis of survival in 257 consecutive thalassemia patients
according to the mean compliance with subcutaneous DFO therapy
Age, years
Survival, % 10 20 30 40 50 60 70 80 90
100 2 4 6 8 12 14 16 18 22 24 26 28 32 34 36 38
0 - 75
Deferoxamine infusions/year
Gabutti V and Piga A. Acta Haematol. 1995;95:26-36

14. Anemia Iron overload Sideroblastic anemias Thalassemias
Sickle cell disease
Rare anemias
Anemia
Iron overload 14

15. 200 mg Fe 15

16. Anemia Iron overload Dyserythropoiesis hepcidin Sideroblastic anemias
Thalassemias
Sickle cell disease
Rare anemias
Anemia
Dyserythropoiesis
Iron overload
hepcidin 16

17. Case # 2 Male born in 2003 in Nigeria Age 2 years
Diagnosed SCD aged 7 mo
Recurrent painful VOC
No RBC transfusion
Age 2 years
Emigrated to Canada
Transcranial Doppler (TCD) velocities:
MCA 244/201
dICA 110/210
Brain MRI: T2 hyperintense area in Lt parietal, no restricted diffusion
Parents resisted prescribed chronic RBC transfusion therapy

18. Case # 2 Age 4 years Age 5 years TCD MCA 201/187
Sleep study: obstructive sleep apnea
Underwent tonsillectomy & adenoidectomy
Pre-operative RBC transfusion (first)
Blood Gp A POS Ab screen- NEG
Age 5 years
TCD MCA: 217/173 dICA: 118/247
RX options presented to parents
Chronic RBC transfusions to keep Hb S < 30% (preferred)
Hydroxyurea therapy

19. Case # 2 Transfusion history April 08 May 08 Aug 08 Dec 08
transfusion # 2 Ab screen: Anti-S DAT neg
May 08
DAT- pos anti- C3D pos anti-IgG neg
DAT- neg in June 08
Aug 08
Ab screen : anti-S, anti-Jk(b), unidentified Ab (?autoAb)
Dec 08
Anti-S, anti-Jk(b)

20. Case # 2 Clinical progress: 2009 2010 HLA typing: no sibling match
Hb S: 27-40% anti-S, anti-Jk(b)
TCD velocities conditional range: < 200 cm/s
Liver iron content (MRI): 6.7 mg Fe/g
RBC transfusion # 16
Commenced Deferasirox (oral Fe chelator)
2010
Hb S: 16-28%
Brain MRI/MRA: moderate narrowing of A1 segment of ACA
Blood bank: DAT weakly POS anti-IgG (probable autoAb)

21. Transfusion Therapy in Sickle Cell Disease

22. Major RCT in SCD Preoperative transfusion in SCD
Simple Tx to Hb 100 g/L is as effective as exchange Tx to reduce Hb S to 30%
Vichinsky et al. NEJM 1995;333:206-13
Prophylactic transfusion in pregnancy
Prophylactic Tx to Hb 100 g/L vs. Tx to Hb < 60 g/L or for emergent situations did not improve obstetric or perinatal outcome
Koshy et al. NEJM 1988;319:

23. Major RCT in SCD Stroke prevention in SCD (STOP I)
Children at risk of stroke based on abnormal TCD velocity benefit from prophylactic transfusions
Adams et al. MEJM 1998;
Optimizing primary stroke prevention in SCD (STOP II)
Prophylactic transfusions for patients with high-risk TCD cannot be stopped safely at 30 months
Adams et al. NEJM 2005;353:5-11

24. Stroke Incidence
Ohene-Frempong et al. Blood 1998;91:

25. TCD Screening

26. STOP I Trial Age: 2 to 16 years old Genotype: SS and S°-thal
Adams et al. NEJM 1998; 339: 5-11

27. STOP II Trial How long should transfusions be continued?
Transfusion-halted group:
2 strokes
14 abnormal TCD
Transfusion continued group:
No event
STOP II Trial Investigators. NEJM, 2005.

28. TCD and Incidence of Stroke
Fullerton et al. Blood. 2004; 104:

29. Approximate stroke rates in different
sickle cell anemia (SS) populations
(incidence per person-years)
Platt, O. S. Hematology 2006;2006:54-57
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

30. Indications for transfusion therapy in SCD
Acute/episodic
Long-term management
Anaemia
Splenic sequestration
Severe or long-lasting aplastic crises
Malaria-associated severe haemolytic anaemia
Stroke
Acute chest syndrome
Preoperative (selected cases)
Multiple-organ failure syndrome
Acute multiple-organ failure syndrome
Priapism
Prophylaxis against recurrent stroke
Prevention of first episode of stroke in high-risk paediatric patients
Heart failure
Chronic pulmonary hypertension
Chronic pain in hydroxyurea non- responders
Previous splenic sequestration in children aged ≤ 2–3 years
Short programme: pregnancy
Ohene-Frempong K. Semin Hematol. 2001;38:5-13. Stuart MJ, et al. Lancet. 2004;364:
Vichinsky E. Semin Hematol. 2001;38:2-4. 30

31. Relationship between blood viscosity and hematocrit2 4 6 8 10 12 14 20 40 60 80
100
Viscosity relative to H2O
Hematocrit (%)
O2 transport
Viscosity
O2 transport (viscosity x Hct) 1
Reproduced from Wayne AS, et al. Blood. 1993;81: © 1993 by The American Society of Hematology.
Hct = haematocrit. 31

32. Chronic transfusion methods
Simple transfusion
Manual exchange transfusion
Erythrocytapheresis
Easy to perform; one venous access
Time-consuming; manual
Expensive; requires 2 good venous accesses
Iron overload+++
Iron overload+
No iron overload; good clinical tolerance
Allo-immunization +++
infections
Standards for the clinical care of adults with sickle cell disease in the UK. Sickle Cell Society; Available from: Accessed March 2009. 32

33. Complications of Transfusion
Volume overload
– physiological changes with chronic anemia
– chronic renal or cardiac disease
Hyperviscosity
– consequences of elevated hematocrit in presence of Hb S-containing red cells
Alloimmunization
– % of multiply transfused SCD patients
Iron overload
– chelation therapy (deferasirox / deferoxamine)
– erythrocytapheresis

34. Delayed Hemolytic Transfusion Reaction
Typical presentation
– days after transfusion
– positive direct antiglobulin test
Atypical presentation in SCD
– severe painful episode
– post-transfusion Hb dropping below pre-transfusion level
– hemoglobinuria
– pulmonary infiltrates
– life-threatening or fatal anemia

35. Selection of Blood Components
Blood lacking hemoglobin S
Limited antigen matching: C, E, K
Extended antigen matching for patients with known allo-antibodies
Leukocyte depletion

36. Hydroxyurea in Sickle Cell Disease
Increased fetal hemoglobin levels
Increased hydration of erythrocytes
Decreased adhesion of erythrocytes to vascular endothelium
Decreased neutrophils
Enhancement of nitric oxide

37. Multicenter Study of Hydroxyurea in Sickle Cell Anemia
Methods: Randomized clinical trial of hydroxyurea therapy in symptomatic Hb SS disease
Study Population: 152 patients assigned to hydroxyurea treatment
147 patients given placebo
Mean follow-up: months
Charache et al., 1995;NEJM 332:1317

38. Results Annual rate of crisis 2.5/year 4.5/year p<0.0001
Hydroxyurea Placebo
Annual rate of crisis /year 4.5/year p<0.0001
Median time to first crisis months 1.5 months p=0.01
Median time to second crisis months 4.6 months p<0.001
Acute chest syndrome patients 51 patients p<0.001
Transfusion therapy patients 73 patients p=0.001

39. Indications for Hydroxyurea Therapy
Frequent moderate - severe painful episodes
3 or more VOC significant episodes in the previous 1 year
Very frequent non-hospitalized painful episodes
Recurrent or severe acute chest syndrome
Symptomatic anemia

40. New/Ongoing Clinical Trials: Transfusion vs. Hydroxyurea
Stroke With Transfusions Changing to Hydroxyurea (SWiTCH)- Phase III randomized study- ongoing
TCD With Transfusions Changing to Hydroxyurea (TWiTCH)- Phase III randomized study-commencing 2010

41. Ongoing Clinical Trials: Transfusion vs. No Transfusion
Silent Infarct Transfusion Trial (SIT)- Phase III randomized study- ongoing
Transfusion Alternatives Pre Operatively in Sickle Cell disease (TAPS)- randomized controlled trial-ongoing

42. Summary
Transfusion therapy is the bedrock of management of patients with thalassemia major Chronic transfusion therapy is increasingly being used as disease-modifying therapy for SCD Efforts should be made to recruit regular blood donors from the African Canadian population The advent of oral iron chelators has significantly reduced the burden of iron chelation therapy

43. Summary
Hydroxyurea therapy could be an alternative to blood transfusion in SCD patients
The indications for blood transfusion in hemoglobinopathies need evidence-based evaluation
The challenges of chronic blood transfusion should be an impetus for exploring alternative therapies e.g. Hb F-inducing agents