1. Efficacy, Time Utilization and Clinical Outcome of Partial Manual Red Cell Exchange in Patients with Sickle Cell Disease
Kevin Kuo
Canadian Adult Comprehensive Hemoglobinopathy (CAtCH) Fellowship
University of Toronto
Canadian Blood Service
January 26, 2012

2. Outline
Indications, rationale and evidence for transfusion in Sickle Cell Disease
Compare and contrast different transfusion techniques: top-up/simple, exchange (automated, partial manual)
Results of the retrospective cohort study on PMXC
Laboratory and clinical efficacy
Iron balance
Time utilization
Adherence
Adverse events
Discussions and Future Directions

3. Case 18 year-old female with Sickle Cell Disease (Hb SS)
Frequent painful vaso-occlusive crises, renal tubular acidosis, osteoporosis with fracture, growth hormone deficiency with developmental delay
Started on simple transfusion at age 12 for elevated transcranial Doppler velocity
Developed severe transfusional iron overload
New narrowing of left ICA found on MRA in 2010
New progressive neurological symptoms in the past few months (memory loss, focal headaches) 3

5. Sickle Cell Disease
Encompasses SS, SC, S/b0thal, S/b+thal, S/D, S/CHarlem, S/OArab, C/SAntilles, S/Quebec-CHORI, A/SOman
Mutation in the 6th codon of the HBB gene
From Glutamic acid to Valine
Ethnic distribution coincide with the malaria belt
Heterozygote advantage vis-à-vis malaria
1/20 blacks are carriers
1/400 blacks are homozygotes or compound heterozygotes
The first human monogenic disorder described

6. Spectrum of SCD Complications
These mechanisms are not mutually exclusive

7. Rationale for Transfusion in SCD
Corrects anemia
Increases O2 carrying capacity
Decreases the proportion of Hb S carrying erythrocytes
Reduces blood viscosity by RBC exchange
Suppresses erythropoiesis (HbS synthesis)
Reduces hemolysis
Marouf R. Blood transfusion in sickle cell disease. Hemoglobin. 2011;35(5-6):
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet Dec 11;376(9757): 7

8. Evidence for Transfusion in SCD
Indication
Study
Methodology
Stroke 1° prevention
2° prevention
STOP, STOP2 (high TCD)
SIT (SCI patients)
SWiTCH 1
CSSCD
Pegelow, et al., 1995
RCT
RCT (ongoing)
Prospective cohort
Retrospective cohort
Surgery (pre-operative)
Vichinsky, et al. 1995
Al-Jaouni, et al
TAPS
Acute chest syndrome:
Preventive
Treatment
Styles et al., 2007
STOP 3
NACSSG 4
Emre, et al., 2005
Turner, et al., 2009
Mallouh, et al., 1998
Secondary analysis of RCT
Pregnancy (on-demand)
Koshy, et al., 1988
Renal concentrating defect
Statius van Eps, et al. 1967
Clinical trial?
Symptomatic anemia
1. Transfusion versus hydroxyurea for secondary stroke prophylaxis. Study was terminated prematurely because of significantly higher event rates in patients randomized to hydroxyurea (33% vs 3%)
2. The Al-Jaouni study compared transfusion vs. no transfusion in 369 patients and found higher rates of SCD-related complications (painful VOC, neurological events, respiratory complications) in the transfusion group
3. Retrospective review of patients enrolled in the STOP study revealed reduced incidence of ACS and painful VOC in patients on chronic transfusion therapy
4. National ACS Study Group; transfusion was associated with improved oxygenation but lengthened hospitalization (likely due to patients with worse clinical status were more likely to be prescribed transfusion) 8

9. Other Indications for Transfusion
Chronic ischaemic hepatic sequestration
Chronic renal failure related to sickle cell disease (biopsy proven)
Recurrent retinal infarction
Chronic leg ulcers not amenable to standard therapy
Recurrent painful VOC not controlled by hydroxyurea and conservative strategies
Recurrent priapism not responding to therapy
Complicated, twin, IUGR pregnancies
Transfusion is the treatment of last resort in many of these complications. The incidence of many are too few to allow adequately powered RCTs or observational studies in order to establish any high grade evidence beyond case reports and case series 9

10. Methods of Transfusion
Simple “top-up” transfusion
Exchange transfusion:
Automated exchange
Partial Manual RBC Exchange Transfusion (PMXC) 10

11. Why Exchange Transfusion?

12. Sickle Cell, Transfusion, Viscosity
Viscosity is a function of cell concentration (hematocrit), deformability and aggregation of the cells (sickle and normal RBCs) and viscosity of the suspending medium (plasma)
Early observation that reduction of Hb S to < 25 to 50% can prevent SCD complications
Transfusion to Hct > 0.35 worsened existing strokes or created new ones
Schmalzer EA, Lee JO, Brown AK, Usami S, Chien S. Viscosity of mixtures of sickle and normal red cells at varying hematocrit levels. Implications for transfusion. Transfusion. 1987;27:228–233

13. Sickle Cell, Viscosity, O2 Delivery Schmalzer, et al. 1987

14. Sickle Cell, Viscosity and Transfusion
Hct = 0.350
HbS = 14%
Hct = 0.200
HbS = 100%
Sickle Hct
Exchange transfusion
Simple transfusion
Hct = 0.350
HbS = 57%
O2 delivery
Shear rate and pO2 comparable to the microcirculation

15. Goals of RBC Exchange Transfusion
Reduce hemoglobin S level
Reduce blood viscosity
Improve oxygen carrying capacity
Maintain iron balance 15

16. Automated versus Partial Manual RBCX
Very effective at rapidly reducing Hb S < 30%
Maintains Hb S < 30%
More blood
Resource demanding
Apheresis nurse and equipment
Central venous access
Anticoagulation for CVC
Partial Manual
Less blood exposure (2 – 3 U pRBC)
Can be achieved with peripheral veins
Risk of hypotension and symptomatic anemia during phlebotomy
Both methods can maintain iron balance

17. Efficacy, Time Utilization and Clinical Outcome of PMXC in SCD Patients

18. Rationale for the study
Scant data on cost, outcomes and adverse events
How effective is PMXC at achieving pre-specified HbS and Hct targets?
What are the clinically-relevant outcomes?
How frequent are the adverse events? What are they?
Can PMXC maintain iron balance?
How compliant are patients on PMXC? 18

19. PMXC Method Exchange frequency: 4 to 6 weeks
Each PMXC session: 2 x 500cc phlebotomy with 500cc NS infusion in between, then 2U pRBCs
Procedure was repeated until pre-RBCX hemoglobin A (HbA) level >50% was reached
Phlebotomy was reduced or omitted during episodes of symptomatic anemia at the discretion of the treating hematologist
Patients with poor venous access had indwelling line with chronic, therapeutic anticoagulation against line-related thrombosis 19

20. Relaxation of Pre-transfusion HbS Target to < 50%
(recall that for stroke prophylaxis pre-transfusion HbS target is < 30%)
Cohen, et al. (1992) retrospective cohort study
15 patients with history of stroke but no recurrence for at least 4 years
Pre-transfusion Hb S maintained at < 50%
Median duration of follow-up: 84 months (14 to 130 months)
No recurrent stroke during follow-up 20

21. Methods Single-center retrospective cohort
April 1, 2010 to April 30, 2011 (13 mo)
Iron balance: ferritin level
Non-adherence to treatment: missing at least one session unrelated to medical events (e.g. hospital admission)
Statistical analysis: descriptive statistics, t-test for continuous variables, Fishers exact test for categorical variables 21

22. Results – Patient Characteristics
19 patients
176 RBC exchange sessions
Phenotype: 16 HbSS, 2 HbSC, 1 HbSD
Median age: 27 years-old
6 male, 13 female
None of the patients had an overt stroke in the past 4 years 22

23. Indications for PMXC
Pulmonary hypertension (confirmed by cardiac catheterization) 1
Painful VOC refractory to or intolerant of hydroxyurea 3
Prevention of intrahepatic cholestasis in liver allograft
Neurological Elevated TCD (n = 3) Silent cerebral infarct (n = 2) Transient Ischemic Attack (n = 1) Stroke (n = 10) Moyamoya (n = 3) Seizure (n = 2) Amaurosis Fugax (n = 1)
13*
5 patients have multiple neurological indications 23

24. Ability of PMXC to Achieve Pre-specified Hematologic Endpoints
Proportion of PMXC sessions with:
HbSS
HbSC or SD
Post-RBCX Hct <0.300
77% (97/126)
0% (0/30)
Pre-RBCX HbA >0.500
67% (73/109)
4% (1/26) 24

25. Variability in Attaining Target Hct and HbA25

26. Reasons for Not Achieving Target HbA Level
Sessions
HbSC or HbSD phenotype 3 25
Non-adherence to treatment 6 15
Exchange interval >4.0 weeks 11
Reduced or no phlebotomy in previous session 5
Not on transfusion prior to starting PMXC 1
No identifiable cause 26

27. Adherence and Efficacy of PMXC
Recurrent complications
Adherent
Not Adherent
Yes 3 No 13
Painful VOC (n = 2)
Moyamoya-like changes (n = 1) 27

28. PMXC and Iron Balance # Not adherent to RBCX * Not on iron chelation28

29. Adverse Events 2 transfusion-related events
fever, pruritis
2 phlebotomy-related events
pre-syncope, nausea
25 partial/cancelled phlebotomy sessions:
11 Symptomatic anemia prior to phlebotomy
1 Inadequate time to complete procedure
5 Poor/lost venous access
1 Active GI bleed
7 No reason documented 29

30. Time Utilization with PMXC
55 ± 30
53 ± 37
88 ± 20
88 ± 23 30

31. Comparison with the Literature
Cabibbo S, et al. 2005
20 SCD patients, manual (n= 7) and automatic (n = 13) exchanges
394 exchanges over 6 years
Single-donor units to minimize alloimmunization
Prophylactically matched for Rh(C,c,E,e) and Kell
Did not specify the PMXC protocol
Patients were put on PMXC “because of poor compliance with the cell separator or difficult venous access”
Cabibbo S, Fidone C, Garozzo G, et al. Chronic red blood cell exchange to prevent clinical complications in sickle cell disease. (2005) Transfusion and Apheresis Science 32:315-21

32. Comparison with the Literature
Target: pre-XC HbS <60%, post-XC HbS <30%, Hct > 0.300
Mean RBC consumption:
6.1 units for automatic XC
1.8 units for PMXC (comparable to our data)
0% alloimmunization rate, 1 episode of hemolytic transfusion reaction
Cabibbo S, Fidone C, Garozzo G, et al. Chronic red blood cell exchange to prevent clinical complications in sickle cell disease. (2005) Transfusion and Apheresis Science 32:315-21

33. Summary Patients who are adherent on PMXC:
can maintain a pre-RBCX HbS <50% with good clinical outcomes,
low rates of adverse events,
reduced blood consumption compared to automated RBCX,
obviate the need for ongoing iron chelation in those without pre-existing iron overload
In patients with iron overload, PMXC with iron chelation therapy can maintain iron balance 33

34. Summary
In patients with good peripheral venous access, indwelling lines do not confer an advantage to the speed of phlebotomy or transfusion
Patient with pre-RBCX HbS level >50% may benefit from a single session of automated RBCX to “reset” their HbS level before commencing PMXC 34

35. Limitations Single-centered study Retrospective in nature
Small sample size
precludes multivariable and subgroup analysis
Volume of phlebotomy should be recorded rather than in “units”
Ideally, changes in iron burden should be measured in liver iron concentration as assessed by Ferriscan
Iron chelation acted as moderator in assessment of iron balance 35

36. Future Directions
Prospectively determine the rate of new or progressive silent infarcts, vasculopathy and reduction of iron burden via partial manual RBCX
Retrospectively and prospectively compare the outcomes of patients on automatic and partial manual exchange transfusions
Examine the kinetics of HbS and Hct recovery in these 2 groups to determine the “optimal” interval of exchange
Develop guidelines to optimize the exchange parameters in these patients 36

37. References
Hirst C, Williamson L. Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev Jan 18;1:CD
Mahomed K. Prophylactic versus selective blood transfusion for sickle cell anaemia during pregnancy. Cochrane Database Syst Rev. 2000;(2):CD
Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions. J Pediatr Jun;126(6):896-9
Styles LA, Abboud M, Larkin S, Lo M, Kuypers FA. Transfusion prevents acute chest syndrome predicted by elevated secretory phospholipase A2. Br J Haematol Jan;136(2): Epub 2006 Nov 30.
Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med Jun 22;342(25):
Turner JM, Kaplan JB, Cohen HW, Billett HH. Exchange versus simple transfusion for acute chest syndrome in sickle cell anemia adults. Transfusion May;49(5): Epub 2009 May 1.
Emre U, Miller ST, Gutierez M, Steiner P, Rao SP, Rao M. Effect of transfusion in acute chest syndrome of sickle cell disease. J Pediatr Dec;127(6):901-4.
Mallouh AA, Asha M. Beneficial effect of blood transfusion in children with sickle cell chest syndrome. Am J Dis Child Feb;142(2):
Miller ST, Wang WC, Iyer R, Rana S, Lane P, Ware RE, Li D, Rees RC; BABY-HUG Investigators. Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG). Pediatr Blood Cancer Feb;54(2):265-8.
Koshy M, Burd L, Wallace D, Moawad A, Baron J. Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. A randomized cooperative study. N Engl J Med Dec 1;319(22):
Cho G, Hambleton IR. Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. Cochrane Database Syst Rev Sep 7;9:CD 37

38. Supplementary Materials

39. Acute Indications for RBC Exchange
Acute ischaemic/haemorrhagic stroke
Acute retinal infarction
Severe acute chest syndrome 1
Sickle cell hepatopathy
Priapism 2
Multiorgan failure
Pre-operative cardiovascular, intrathoracic, retinal, neuro-spinal surgery 3
Hb SD = a2bE6V/E121Q

40. Acute Indications for RBC Exchange
1, 2: RBC exchange generally indicated for clinical deterioration despite standard therapy (hydration, simple transfusion, oxygenation, pain control, antibiotics)
3: In the Preoperative Transfusion Sickle Cell Study:
Pre-op patients were randomized to:
simple transfusion (target Hb 90 – 110) versus
aggressive transfusion (target Hb 90 – 110 AND HbS < 30%, 73% of the participants achieved the target by RBC exchange) (Vichinsky 1995)
frequency of serious complications was similar between the two groups
Nonetheless, many clinicians still perform RBC exchange for “risky” surgeries such as cardiovascular, intrathoracic, or joint replacement surgeries, especially in older patients and those with significant comorbidities (Swerdlow 2006)
Hb SD = a2bE6V/E121Q
Swerdlow PS. Red Cell Exchange in Sickle Cell Disease. Hematology 2006 p.48-53
Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med Jul 27;333(4):206-13
Vichinsky EP, Neumayr LD, Haberkern C, et al. The perioperative complication rate of orthopedic surgery in sickle cell disease: report of the National Sickle Cell Surgery Study Group. Am J Hematol Nov;62(3):129-38

41. STOP and STOP2 Study STOP Study
Chronic transfusion with a pre-transfusion Hb S < 30% is effective in preventing stroke in SCD patients with high TCD (>200 cm/s) compared no transfusion
STOP2 Study
Discontinuation of transfusion for SCD patients with elevated transcranial Doppler velocity results in a reversion to high rate of stroke
Transfusion is currently the only effective primary and secondary prophylactic agent against stroke
RR = 0.097
ARR = 0.015
RRR = 0.903
NNT = 67

42. Pre-Operative Transfusion Reduces Serious Adverse Events in Patients with Sickle Cell Disease (SCD): Results From the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) Randomised Controlled Multicentre Clinical Trial
Jo Howard, Moira Malfroy, Llewelyn Charlotte, Louise Choo, David Rees, Isabeau Walker, Tony Johnson, Louise Tillyer, Karin Fijnvandraat, Melanie Kirby-Allen, Renate Hodge, Shilpi Purohit, Sally C. Davies, and Lorna M Williamson
Introduction: The rate of complications after surgery is increased in patients with Sickle Cell Disease (SCD) and pre-operative blood transfusion has historically been used to decrease this risk. Observational studies and one limited Randomised Controlled Trial (RCT) have suggested that in some patients, transfusion can safely be omitted. Since transfusion is associated with complications including alloimmunisation and increased post-operative infections, we performed a RCT to address whether overall peri-operative complications in SCD are reduced by pre-operative transfusion.
Methods: TAPS was a Phase III multicentre, pragmatic, randomised controlled trial with a parallel group sequential superiority design, carried out between November 2007 and March 2011 at 22 sites in the UK, Netherlands and Canada. Eligible patients had HbSS or HbSβ°thal, were aged one year or more and were having low risk (eg adenoidectomy, dental surgery) or medium risk (eg joint replacement, cholecystectomy, tonsillectomy) elective surgery. Patients were excluded if they had a haemoglobin (Hb) <6.5g/dl, had received a blood transfusion within the last 3 months or had severe SCD. Patients were randomly assigned to Arm A, which received no pre-operative transfusion, or Arm B, which received a top-up transfusion if Hb<9g/dl or a partial exchange if Hb9g/dl. Sites followed their own standards for all other aspects of peri-operative care, although guidance was provided. The primary outcome was all significant complications between randomisation and 30 days post surgery as defined in the protocol. These were sent blinded to the End-Point Review Panel for final classification. Complications which were life-threatening, or resulted in death or persistent or significant incapacity/disability and other important medical events were also recorded as Serious Adverse Events (SAEs) and were reviewed by an Independent Data Monitoring Committee (IDMC). Due to a major imbalance in the number of SAEs between treatment groups, the trial was terminated early following an IDMC recommendation.
Results: 333 patients were screened for the trial and 70 patients were randomised at the time the trial was terminated. Thirty three completed 30 day follow up in Arm A and 34 in Arm B. Both groups were comparable with respect to age, gender, severity of SCD, type of surgery and baseline Hb. Only 13 patients had low risk surgery. The pre-operative (post-transfusion) Hb was higher in Arm B (9.7g/dl vs 7.7g/dl) and 5 patients in Arm B received partial exchange transfusion with a mean pre-operative HbS% of 47.2%. There were no differences in peri-operative management, including fluid support and oxygen therapy, between the two groups.
There were 11 SAEs (33%) in patients who did not receive a pre-operative transfusion, compared to only 1 SAE (3%) in patients who did receive a top-up transfusion or partial exchange. Eleven of the SAEs were Acute Chest Syndrome (ACS). Patients in the no pre-operative transfusion group also had more significant complications (13/33, 39%), which included SAEs, as compared to patients in the top-up/exchange group (5/34, 15%).
Type of surgery: 58% of patients underwent abdominal or ENT surgery. Four out of 13 patients (31%) who had Abdominal surgery in Arm A had ACS events compared to none out of 10 patients in Arm B. Out of the 9 patients who had Tonsillectomy in Arm A, 3 patients had ACS events (33%) compared to none in 7 patients in Arm B.
Discussion: This RCT has shown a large increase in SAEs in un-transfused patients with HbSS and HbSβ°thal having low and moderate risk surgery. In particular there was a striking increase in ACS, a potentially life-threatening complication. We therefore recommend that pre-operative transfusion should be strongly considered for patients with HbSS and HbSβ°thal undergoing moderate risk surgery, in particular abdominal surgery and tonsillectomy. There was no evidence of increased benefit of exchange transfusion over top-up, although numbers were small, and exchange transfusions should be reserved for patients with a Hb>9g/dl. There is insufficient evidence to reach a conclusion on the role of pre-operative transfusion in other types of surgery or in patients with other sickle genotypes. Pre-operative transfusion in these patients should be decided on a case by case basis.

43. PMXC Method - Swerdlow, 2006
A. Calculate exchange volume as 1.5 red cell volumes.
B. Red cell volume = hematocrit × total blood volume.
a. Assume total blood volume is 70 cc/kg if over 20 kg, 85 cc/kg if under 20 kg.
b. Each standard unit has a red cell volume of ~200 cc
(Hct ~40 × 500 cc)
C. Perform adult manual exchange as follows:
1. Bleed 500 cc and then infuse 500 cc saline
2. Bleed 500 cc and then infuse 2 units packed red cells
3. Repeat steps 1 and 2 until volume of packed cells administered is equal to planned exchange volume (up to three or even four repeats for large adults)
For pediatric patients, use smaller comparable volumes (such as 5-10 cc/kg for bleeds and saline and calculate red cell volume based on 1- to 1.25-fold the amount of blood removed in bleeds).