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
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
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Laboratory and clinical efficacy
Iron balance
Time utilization
Adherence
Adverse events
• Discussions and Future Directions
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)
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
Spectrum of SCD Complications
These mechanisms are not mutually exclusive
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):495-502
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 11;376(9757):2018-31
Evidence for Transfusion in SCD
Indication
Stroke 1° prevention
2° prevention
Surgery (pre-operative)
Acute chest syndrome:
Preventive
Study
STOP, STOP2 (high TCD)
SIT (SCI patients)
SWiTCH 1
CSSCD
Pegelow, et al., 1995
Vichinsky, et al. 1995
Al-Jaouni, et al. 2006 2
TAPS
Styles et al., 2007
STOP 3
Treatment
NACSSG 4
Emre, et al., 2005
Turner, et al., 2009
Mallouh, et al., 1998
Pregnancy (on-demand)
Koshy, et al., 1988
Renal concentrating defect Statius van Eps, et al.
1967
Symptomatic anemia
Methodology
RCT
RCT (ongoing)
RCT
Prospective cohort
Retrospective cohort
RCT
RCT
RCT
RCT
Secondary analysis of RCT
Prospective cohort
Prospective cohort
Retrospective cohort
Retrospective cohort
RCT
Clinical trial?
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
Methods of Transfusion
• Simple “top-up” transfusion
• Exchange transfusion:
– Automated exchange
– Partial Manual RBC Exchange
Transfusion (PMXC)
Why Exchange Transfusion?
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
O2 delivery
Sickle Cell, Viscosity, O2 Delivery
Schmalzer, et al. 1987
Sickle Cell, Viscosity and Transfusion
Hct = 0.200
HbS = 100%
Hct = 0.350
HbS = 14%
Sickle Hct
O2 delivery
Exchange
transfusion
Simple
transfusion
Hct = 0.350
HbS = 57%
Shear rate and pO2 comparable
to the microcirculation
Goals of RBC Exchange Transfusion
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Reduce hemoglobin S level
Reduce blood viscosity
Improve oxygen carrying capacity
Maintain iron balance
Automated versus Partial Manual
RBCX
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Automated
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
Efficacy, Time Utilization
and Clinical Outcome of
PMXC in SCD Patients
Rationale for the study
• Scant data on cost, outcomes and adverse
events
• How effective is PMXC at achieving prespecified 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?
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
Relaxation of Pre-transfusion
HbS Target to < 50%
• (recall that for stroke prophylaxis pretransfusion 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
Methods
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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
Results – Patient Characteristics
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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
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
1
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*
Ability of PMXC to Achieve Prespecified 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)
Variability in Attaining
Target Hct and HbA
Reasons for Not Achieving
Target HbA Level
Reasons
N
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
No identifiable cause
1
1
5
Adherence and Efficacy of PMXC
Recurrent
complications
Adherent
Not Adherent
Yes
0
3
No
13
3
Painful VOC (n = 2)
Moyamoya-like changes (n = 1)
PMXC and Iron Balance
# Not adherent to RBCX
* Not on iron chelation
Adverse Events
• 2 transfusion-related events
– fever, pruritis
• 2 phlebotomy-related events
– pre-syncope, nausea
• 25 partial/cancelled phlebotomy sessions:
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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
Time Utilization with PMXC
P = 0.759
55 ± 30
P = 0.987
53 ± 37
88 ± 20
88 ± 23
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
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
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
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
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
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
References
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Hirst C, Williamson L. Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev.
2012 Jan 18;1:CD003149.
Mahomed K. Prophylactic versus selective blood transfusion for sickle cell anaemia during pregnancy.
Cochrane Database Syst Rev. 2000;(2):CD000040.
Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell disease treated
with erythrocyte transfusions. J Pediatr. 1995 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. 2007 Jan;136(2):343-4. 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. 2000 Jun 22;342(25):1855-65.
Turner JM, Kaplan JB, Cohen HW, Billett HH. Exchange versus simple transfusion for acute chest syndrome
in sickle cell anemia adults. Transfusion. 2009 May;49(5):863-8. 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. 1995 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. 1988 Feb;142(2):178-82.
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. 2010 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. 1988 Dec 1;319(22):1447-52.
Cho G, Hambleton IR. Regular long-term red blood cell transfusions for managing chronic chest
complications in sickle cell disease. Cochrane Database Syst Rev. 2011 Sep 7;9:CD008360.
Supplementary Materials
Acute Indications for RBC Exchange
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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
Acute Indications for RBC Exchange
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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)
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. 1995 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. 1999 Nov;62(3):129-38
STOP and STOP2 Study
STOP Study
• Chronic transfusion with a pretransfusion 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
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•
•
•
RR = 0.097
ARR = 0.015
RRR = 0.903
NNT = 67
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
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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 perioperative 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 (posttransfusion) 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).
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).