Transfusion Support for Patients with Hemoglobinopathies
SEAABB
March 18, 2010
Jeanne Hendrickson, MD
Objectives
To understand the basis of current recommendations for transfusion thresholds in patients with sickle cell disease
To understand the current state of knowledge of proper dosing in these patients
Background
5000 children with sickle cell disease are born annually in the US 1 in 600 African American babies is born with
sickle cell disease
Children’s Healthcare of Atlanta cares for more than 2000 children with hemoglobinopathies
More than 10% of African Americans have sickle cell trait Greater than 2.5 million affected individuals in the
US
The majority of patients with sickle cell disease have Hb SS
Hb SS: 65%
Hb SC: 25%
Hb S β+ thalassemia: 8%
Hb S β° thalassemia: 2%
Hemoglobin S
Glutamine to Valine substitution in the 6th
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
Deoxygenated Hemoglobin (alpha chains are light
color, beta chains are dark color) From UpToDate
RBC Transfusion
Simple versus exchange
Acute versus chronic
To be 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
Vichinsky et al, NEJM 2000
Acute chest syndrome has many causes
Transfusion, a common treatment for ACS, 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
Vichinsky et al, NEJM 2000
Vichinsky et al, NEJM 2000
Transfusion decreases length of hospitalization in patients with acute chest syndrome
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 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
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
Exchange transfusion decreases % S as well as platelet count, ANC, and sVCAM-1
Liem et al, AJH 2004
Liem et al, AJH 2004
Transfusion may prevent ACS predicted by elevated sPLA2
Secretory phospholipase A2 (sPLA2) is an inflammatory mediator that may precede the development of ACS
Simple RBC transfusion may prevent ACS in patients with VOC and sPLA2 > 100 ng/mL (with fever and a negative CXR)
5 of 8 patients randomized to standard care developed ACS, compared to none of 7 patients randomized to transfusion
PROACTIVE (Preventing ACS by Transfusion Feasibility) and ANTHERA studies (sPLA2 inhibitor)
Styles et al, BJH 2006
ACS, transfusion, and neurologic events in patients with sickle cell disease
Neurologic complications are associated with ACS
Including altered mental status, stroke, and seizures
22% of adults, 8% of children with neurologic complications in trial by Vichinsky et al (n=538)
5 consecutive children with ACS in study by Henderson et al developed neurologic complications ( 3 with posterior leukoencephalopathy syndrome)
All were intubated and received exchange transfusion after simple transfusion
Does simple or exchange transfusion contribute to neurologic complications?
Short term chronic transfusion therapy may decrease incidence of ACS in select patients
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
Rates of sequestration have increased with parental education
Splenic sequestration occurred in 43 of 694 patients in Cooperative Study infant cohort
Gill et al, Blood 1995
From Georgia Comprehensive Sickle Cell Center website
Age at initial splenic sequestration in 89 (of 308) affected children in Jamaica
Serjeant et al, J Peds 1984
132 total attacks, 13 were fatal. 49% had a recurrence with diminishing intervals between events.
Buchanan et al, J Peds 1989
Intensive hypertransfusion may improve splenic function
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
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
Rackoff et al, J Peds 1992
ASPEN may be more likely in cases with high post-exchange Hb levels
Other priapism reports
Case series of 10 patients receiving whole blood exchange (and ending with Hb < 10 g/dL) had no neurologic complications
Case series of 7 patients receiving whole blood exchange had 1 neurologic complication
Ballas et al, J Clin Apheres 2006
McCarthy et al, Ther Apher 2000
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?
Fu et al, Pediatr Blood Cancer 2005
Minor elective surgical procedures done without transfusion
Retrospective
28 children with Hb SS
15% with post-op complications (fever, pain). No ACS.
Pre-operative transfusion
Preoperative Transfusion in Sickle Cell Disease Study:
551 patients with HbSS
Randomized to aggressive (Hb of 10 g/dL and Hb S <30%) or conservative (Hb of 10 g/dL regardless of percent S) arms
Vichinsky et al, NEJM 1995
Similar non-transfusion complication rates in each arm
Vichinsky et al, NEJM 1995
50% fewer transfusion related complications in conservative arm
Haberkern et al, Blood 1997
“high risk” surgeries
Abdominal procedures
Orthopedic procedures
Cardiac surgery
Retinal surgery
NIH Guidelines
Recommend preoperative simple transfusions to maintain (and not exceed) a Hb of 10 g/dL
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
Ohene-Frempong, Blood 1998
Patients from Cooperative Study, n=4082
Ohene-Frempong et al, Blood 1998
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
Adams et al, NEJM 2005
“Events” included abnormal TCDs or CVAs
Chronic Transfusion Therapy
How low should we go?
Does percent S have to be <30% to be beneficial?
Rheology of sickle RBCs
Hct is inversely proportional to RBC flow at any Hb S > 20%
Nathan et al, Blood 1993
Cerebral blood flow decreases with increasing Hb (left) and increases with high %HbS (right)
Hurlet-Jensen et al, Stroke 1994
CBF was determined by Xe133
inhalation; %S determined to be more closely related to CBF than Hb
Nathan et al, Blood 1993
Can %S be liberalized?
After 4 years of maintaining %S < 30%, 15 patients were kept at %S of <50%
No cerebral infarcts in this group (1023 patient months)
Cohen et al, Blood 1992
J Peds, 1992
n=13; changed from routine chronic transfusion therapy (%S < 30) to less intensive therapy (%S < 60). No increased risk of CVA.
Miller et al, J Peds 1992
Cohen et al, Blood 1992
SWiTCH Trial
“Stroke with transfusion changing to hydroxyurea”
TWiTCH Trial
“TCD with transfusions changing to hydroxyurea”
SIT Trial
“Silent cerebral infarct multicenter transfusion trial”
Pulmonary HTN
Vichinsky et al, NEJM 2004
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
Adverse Effects of RBC Transfusion
RBC Alloimmunization
Autoimmunization
Iron overload
HLA alloimmunization
Other serious hazards of transfusion
Transfusion reactions
Infectious disease transmission
Thank you