January 4, 2001
Elliot Vichinsky M.D.
Oakland Children's Hospital
Transfusion Therapy in Sickle Cell Disease
Used correctly, transfusion
can be life-saving and prevent progressive organ damage. Used unwisely,
transfusion therapy results in unnecessary and serious complications. Physicians
caring for sickle cell patients must become knowledgeable of specific indications,
types of red cell preparations, complications of transfusion therapy, and
methods to minimize adverse events.
Transfusions are indicated
for either episodic events triggered by an acute complication or a necessary
medical intervention (e.g., neurosurgery). In contrast to these episodic
indications, some clinical problems require long-term suppression of circulating
sickle cells. Chronic transfusion therapy usually achieves this goal.
Several methods of
transfusion are available, including simple transfusion, partial exchange
transfusion, or erythrocytapheresis. The method used depends on the specific
indications. Except for episodes of severe anemia, pheresis offers many
benefits and should be available to sickle cell patients.
After the decision
to transfuse, several goals should be set, including final post-transfusion
hematocrit, percent hemoglobin S desired, and type of red cells to be used.
Hyperviscosity from simple transfusion is a dangerous problem in sickle
cell patients, and must be avoided. The post-transfusion hematocrit should
not exceed 36 percent. In general, limited phenotypically-matched, sickle-negative,
leuko-depleted packed cells are the blood product of choice. Finally, there
should be a comprehensive transfusion protocol, that includes accurate
records, the patient's red cell phenotype, alloimmunization history, number
of units received, serial hemoglobin S percentages, and results of infectious
and iron overload monitoring results.
INDICATIONS FOR TRANSFUSIONS
The two primary goals
of transfusion are to correct the low oxygen-carrying capacity caused by
severe anemia, and to improve microvascular perfusion by decreasing the
proportion of sickle red cells in the circulation. In the clinical setting,
transfusions are often used to address both indications.
Management of severe anemia
In severely anemic patients,
simple transfusions should be used without taking any blood from the patient.
Acute splenic sequestration and transient red cell aplasia episodes (aplastic
crisis) are the most common causes of acute anemia. A third form of acute
anemia, called hyperhemolysis, is associated with infection, acute chest
syndrome, and particularly malaria. In general, patients should be transfused
if there is evidence of physiologic derangement, such as heart failure,
dyspnea, hypotension, or marked fatigue. No universally accepted laboratory
parameters exist for transfusion of patients with sickle cell disease.
Hemoglobin values of less than 5 gm/dl or a 20 percent fall below the base
line during an acute illness are common transfusion triggers, however.
Patients with an acute event associated with a falling hemoglobin can die
suddenly of cardiovascular collapse. Close monitoring of their hemoglobin
and clinical course is imperative.
Severe acute splenic
sequestration produces hypovolemia and cardiovascular decompensation. Patients
require immediate transfusion to prevent cardiovascular collapse. However,
sequestration crisis often is less severe. In general, transfusions are
indicated when the hemoglobin drops by more than 2 gm/dl from the steady
state. The rise in hemoglobin following transfusion is usually greater
than expected reflecting release of sequestered red cells. Consequently,
excessive initial transfusion should be avoided.
red cell aplasia
Parvovirus B19 is
the primary cause of transient red cell aplasia. Severe anemia develops
over a few days secondary to shortened red cell survival withoutcompensatory
production of new red cells. While many patients recover spontaneously,
red cell transfusions are indicated for those who become symptomatic or
whose hemoglobin value falls 2 gm/dl below baseline.
Management of sudden severe illness
Acute chest syndrome,
stroke, sepsis, and acute multi-organ failure are leading causes of death
in sickle cell disease. A falling hemoglobin value often accompanies these
events. Transfusions to improve tissue oxygenation and perfusion are indicated
in these seriously ill patients. Controlled clinical trials have not evaluated
transfusions in all life-threatening events, but they have become standard
medical practice for the events described below:
When acute chest syndrome
is associated with hypoxia and a falling hemoglobin, transfusions are indicated.
Studies suggest that early transfusion may prevent the progression of acute
pulmonary disease. Since the hemoglobin is low, many patients can be treated
with a simple red cell transfusion. In severe cases, exchange transfusion/red
cell pheresis is recommended.
therapy reduces the rate of recurrent vaso-occlusive stroke and is indicated
for all victims of this complication of sickle cell disease. The efficacy
of transfusion in the management of acute stroke has not been well-studied,
however, anecdotal reports suggest that early exchange transfusions may
improve perfusion and oxygenation to brain tissue, thus limiting damage.
Occasional cases of post-exchange transfusion reversal of cerebral vaso-occlusion
have been noted.
Management of multi-organ
failure is a devastating complication of sickle cell disease, classically
associated with falling hemoglobin and platelet count, as well as progressive
multi-organ failure. Limited studies indicate that aggressive transfusion
may improve survival and recovery of organ function.
PREPARATION FOR GENERAL ANESTHESIA
A multi-institution study
recently compared perioperative complications among patients with sickle
cell disease undergoing major surgery (e.g. cholecystectomy). Patients
were randomized to an aggressive transfusion arm (decrease hemoglobin S
to below 30 percent) or to a conservative transfusion arm (hemoglobin S
approximately 60 percent; hemoglobin corrected to 10 gm/dl). The control
patients did not receive perioperative transfusions. Complications occurred
in all groups, but were substantially more frequent in the non-transfused
patients. There was no difference between the conservatively or aggressively
transfused patients with respect to perioperative complications. However,
alloimmunization occurred more frequently in the aggressively transfused
group. The recommendation from this study is that
all sickle cell disease patients undergoing major surgery be prepared in
advance with transfusion to correct their anemia to a hemoglobin of approximately
10 gm/dl and hemoglobin S percent to approximately 60 percent. No
standard practice guidelines have been developed for patients undergoing
minor procedures or for patients with hemoglobin SC disease. The generally
accepted practice is to not use preoperative transfusion therapy in healthy
hemoglobin SC patients, nor for limited minor surgery in stable hemoglobin
CHRONIC TRANSFUSION THERAPY
Chronic transfusion therapy
programs are indicated for several conditions in which the potential medical
complications outweigh the risks of alloimmunization, infection and iron
overload. The goal of these programs is to maintain the hemoglobin S at
30-50 percent, depending on the specific disorder. Transfusions are usually
repeated every 3-4 weeks. Although simple transfusions can be used, some
investigators recommend red cell pheresis-exchange transfusions to decrease
the rate of iron acclimation. Anecodal reports exist of declining ferritin
values without chelation therapy.
Primary stroke prevention
The STOP trial demonstrated
that chronic transfusion therapy reduces the occurrence of first stroke
in children with a rate of high blood flow through the circle of Willis
cerebral arteries, as measured by Doppler ultrasonography. This was the
first application of chronic transfusion therapy to prevent potential complications
of sickle cell disease.
Prevention of recurrence of stroke
Chronic transfusion therapy
for children who suffer vaso-occlusive stroke decreases the recurrent stroke
rate from 90 percent to less than 10 percent. Initially, the hemoglobin
S level is maintained at 30 percent or less for approximately 5 years.
Well-controlled studies have not determined the duration or percent level
of hemoglobin S required for long-term treatment of these patients. Pilot
studies allowing the hemoglobin S to rise to 50 percent in patients with
stable neurologic disease are on-going.
Pulmonary hypertension and chronic lung
Chronic transfusion therapy
has been used to decrease the recurrence of pulmonary events in patients
experiencing severe acute chest syndrome. While pilot data suggests this
therapy is efficacious, rigorous clinical trials have not been completed.
The duration of such treatment programs is also unknown. Patients with
proven pulmonary hypertension and chronic lung disease should receive long-term
chronic transfusion therapy.
Vital organ failure
Chronic heart failure
is a late complication of sickle cell disease. Transfusion therapy for
these patients, along with interventions to improve cardiac function, enhances
quality of life. Severe anemia, secondary to chronic renal failure, often
becomes debilitating. Erythropoietin therapy is often ineffective, leaving
chronic transfusion therapy as the sole option.
CHRONIC DEBILITATING PAIN
A small percentage of
patients suffer from unusually protracted and severe pain episodes. These
patients have a very poor quality of life and are unable to engage in ordinary
daily activities. Chronic transfusions for debilitating pain may be used.
However, it must be part of the multidisciplinary pain program and requires
on-going assessment. Much of the pain likely derives from fixed organ injury
that improves little, if any, with chronic transfusions. Children generally
respond better to chronic transfusions than do adults. The likely cause
of the difference is a greater degree of fixed organ damage in adults.
Transfusions are sometimes
suggested for a number of conditions in which efficacy is unproven, but
may be considered under severe circumstances.
Management of acute priapism
Red cell transfusions,
in particular exchange transfusions, have been advocated for acute management
of priapism. However, the clinical response has been variable and associated
with neurologic events. No controlled trial has been performed. If early
intervention with conservative therapy fails, transfusions should be considered.
Recurrent priapism often produces impotence. Some physicians use chronic
transfusion therapy in an effort to prevent this complication. In these
cases, patients are transfused as if they were on a stroke protocol (maintenance
of hemoglobin S below 30 percent). These programs should be of limited
duration (6-12 months) with frequent assessment.
Preparation for infusion of contrast
In the past, sickle cell
patients were at high risk of complications due to red cell sickling in
hypertonic contrast media. Transfusions prior to these procedures were
used to lower the risk of complications. New technology, including gadolinium,
and non-ionic contrast media, substantially lowers the risk associated
with these studies.
At one time, transfusion
therapy was recommended for sickle cell patients because of poor pregnancy
outcome. With improved prenatal care, the benefit of transfusion therapy
is questionable. A prospective randomized trial of prophylactic transfusion
versus routine care found no major difference in outcome. This study did
not evaluate aggressive transfusion. The current recommendation nonetheless
is to confine transfusion therapy to women who experience frequent complications
Management of "silent" cerebral infarct
and/or neurocognitive damage
Subclinical infarcts detected
by magnetic resonance technology are often associated with neurocognitive
defects. These patients appear to be at higher risk of future stroke. These
patients have not been studied to evaluate the efficacy of primary preventive
transfusion. In the absence of rigorous controlled trials, routine chronic
transfusion therapy for these patients cannot be recommended.
Skin on the lower leg,
particularly the area of the medial malleous, is poorly supplied with blood
and is very prone to skin ulcers. The ulcers appear to correlate with a
degree of anemia, suggesting that transfusions may be beneficial. Unfortunately,
no rigorous clinical study exists. Transfusion should be considered in
recalcitrant or recurrent skin ulcers, if conservative therapy fails.
Non-indications and contra-indications
The following are considered
to be inappropriate indications for transfusion and are not recommended
in a clinical setting:
Chronic steady-state anemia.
Most patients with sickle cell disease are relatively asymptomatic from
their anemia and do not require transfusions to improve oxygen-carrying
Uncomplicated acute painful
Minor surgery not requiring
prolonged general anesthesia (e.g., myringotomy)
Aseptic necrosis of the
hip or shoulder (except when surgery is required)
TYPES OF BLOOD PRODUCTS TO BE USED
Standard bank blood is
appropriate for the patient with sickle cell disease. The "age" of the
blood (time since collection) is usually not important as long as it is
within limits set by the transfusion service. Exchange transfusion with
blood less than 5 days old (less than 3 days old in the small infant) helps
in acute situations requiring immediate correction of the oxygen-carrying
capacity. All blood should be screened for the presence
of sickle hemoglobin and confirmed to be negative. A solubility test is
adequate for screening in this situation. This procedure eliminates
blood with sickle cell trait, which will confuse later measurements of
the proportion of sickle cells or hemoglobin S.
The antigenic phenotype
of the red cells (at least ABO, Rh, Kell, Duffy, Kidd, Lewis, Lutheran,
P, and MNS groups) should be determined in all patients older than 6 months
of age. A permanent record should be maintained in the Blood Bank, and
a copy of the record should be given to the patient or family. All patients
with a history of prior transfusion should be screened for the presence
of alloantibodies. The efficacy of a chronic transfusion regimen should
be assessed periodically by determining the proportion of hemoglobin S
by quantitative hemoglobin electrophoresis as well as the hemoglobin concentration
The high prevalence
of alloimmunization in patients with sickle cell disease likely has several
causes. Lack of phenotypic compatibility between the donor and recipient
doubtless is a major factor. All patients should
receive limited phenotypic matching for antigens E, C and Kell. Extensive
phenotypic matching is recommended for patients who have formed alloantibodies.
of red cells is standard practice to reduce febrile reactions, platelet
refractoriness, infections, and cytokine-induced complications. Washed
red cells should be reserved for patients with a history of allergic reactions
Irradiated blood products
should be considered in possible bone marrow transplantation candidates.
Relatives should not be used as blood donors for children who could be
candidates for bone marrow transplantation.
Autologous blood transfusions
for patients with sickle cell disease should be avoided. Red cell substitutes
are experimental and generally not indicated.
Simple transfusions can
be used for acute anemia or hypovolemia. Packed red cells are preferred,
except when marked volume expansion is needed.
Chronic simple transfusion
Once a sufficient level
of transfused normal cells (60-70 hemoglobin A) is achieved, simple transfusions
at intervals every 2-4 weeks can be used to maintain this proportion of
normal cells for years. The level of hemoglobin A must be monitored regularly
by quantitative hemoglobin electrophoresis. Significant variation in transfusion
requirements between patients is common. In general, a pre-transfusion
hematocrit of between 25-30 percent is adequate. Due to the risk of hyperviscosity,
the post-transfusion hematocrit should be 36 percent or less, especially
early in the treatment program.
Exchange transfusion is
used to alter the hemoglobin level rapidly and to replace sickle cells
with normal cells. This type of transfusion reduces the concentration of
sickle cells without increasing the hematocrit or whole blood viscosity.
Several methods are available. Red cell exchange transfusion possibly reduces
iron accumulation since a volume of packed cells is removed equal to the
hemoglobin A containing cells that are infused. Chronic automated erythrocytapheresis
usually can be done rapidly and safely. The major concerns include increased
red cell utilization, venous access, and increased cost. Despite these
limitations, erythrocytapheresis is increasingly used due to its success
in decreasing iron burden.
Rapid partial exchange
In some patients, whole
blood can be removed from one arm at the same time that donor cells are
transfused into the other arm. In adults, this procedure can be performed
in 500 mL units. In children, the individual exchange aliquots are adjusted
to a safe and practical level.
The total volume of
blood to be used is proportional to the patientís body weight and hematocrit;
thus, different formulas are needed for different initial hematocrit ranges.
Exchange transfusions performed with whole blood (or, more commonly, packed
cells reconstituted to the volume and hematocrit of whole blood using saline
or other diluents) are more efficient than those using packed cells. They
may reduce the number of units needed but take slightly more time to administer.
In children, a practical estimate of the volume required for exchange (whole
blood or packed cells reconstituted to a hematocrit of 30-40 percent) is
50-60 mL/kg. In adults, blood can be removed from the patient in 500 mL
aliquots, followed by infusion of 500 mL of reconstituted blood; this may
be repeated for 6-8 units of transfusion. Alternatively, the following
technique can be used:
Bleed one unit (500 mL) of blood from
the patient, infuse 500 mL of saline.
Bleed a second unit from the patient,
infuse two units of blood.
Repeat steps 1 and 2; if the patient
has a large red blood cell mass, repeat once more.
Usually 6-8 units
of blood are needed to exchange and adult. Formulae are available to calculate
the exact amount needed depending on body size, pretreatment hematocrit,
desired hematocrit, and desired percentage of hemoglobin A. Such devices
can be used for pediatric patients if the size of the receptacle is sufficiently
small so as not to remove too much blood at one time.
Care must be taken
in all cases where exchange transfusion is used to insure that the final
hemoglobin level does not exceed 10-12 gm/dL to avoid the problems of hyperviscosity.
Careful monitoring of the level of hemoglobin and of the percentage of
hemoglobin A is necessary to be certain that the goals of the transfusion
have been met.
for sickle cell patients may be higher than in the general population.
Cases of transfusions precipitating painful events, stroke, and acute pulmonary
compromise have been reported. Hyperviscosity and relative hypertension
that can occur with transfusions are risk factors for these events.
Volume overload occurs
when too much volume is transfused too quickly. Congestive heart failure
and pulmonary edema are most likely to occur in patients who have cardiac
dysfunction or minimal cardiac reserve. Intravenous furosemide and partial
removal of red cell -preserving fluid before transfusion and a slow transfusion
rate can help avoid this serious problem.
Alloimmunization and delayed hemolytic
The incidence of alloimmunization
to red blood cell antigens in transfused patients with sickle cell anemia
is approximately 20-25 percent, which is greater than that of the general
population. Alloimmunization complicates obtaining compatible blood and
results in a high incidence of delayed hemolytic transfusion reactions.
delayed transfusion reaction occurs 5-20 days after transfusion due to
antibodies not detectable at the time of compatibility testing. Thirty
percent or more of antibodies to red blood cell antigens may disappear
with time. The recipient remains capable of mounting an anamnestic
response to further stimulation by transfusion however. Delayed hemolytic
transfusion reactions can cause severe anemia, precipitate painful crisis,
or even lead to death.
Acute hemolytic transfusion reactions
Acute hemolytic transfusion
reactions in sickle cell patients do not differ from from those in other
patients. Major hemolytic reactions occur primarily with major blood group
(ABO) mismatches and must be treated aggressively to maintain blood pressure
and glomerular filtration. Most cases can be prevented by avoiding clerical
and patient or sample identification errors that occur with cross-matching
or transfer of units from donor site to the patient. Minor hemolytic reactions
occur when the amount of antibody in the serum is limiting. These reactions
are characterized by the disappearance of the transfused blood during a
period of several days (with a consequent decrease in the hematocrit) and
the appearance of hyperbilirubinemia; no further treatment is necessary
except monitoring the hematocrit level to ensure that it does not fall
to a dangerously low level.
Any of these reactions,
particularly the delayed variety can trigger a pain crisis. In all cases,
the patientís blood should be examined very carefully by immunohematologists
in the transfusion service to document the antibody or antibodies responsible
for the reaction. The patient must be informed of the complication and
given a card describing the antibodies found.
hemolytic transfusion reactions resulting from it can be reduced by the
Acquiring and maintaining
adequate records of previous transfusions and transfusion complications.
Avoiding unwarranted transfusions.
Screening for newly acquired
antibodies 1-2 months after each transfusion to detect transient antibodies
capable of causing a subsequent delayed hemolytic reaction.
due to donor/patient antigen mismatch.
Patients who are alloimmunized
to one red blood cell antigen are more likely to develop antibodies against
others. Transfusion of carefully selected units of blood should be given
only for clearcut indications. These patients should be counseled to advise
any new physician of their history of alloimmunization. Carrying a card
or an identification bracelet listing the red blood cell phenotype and
any identified antibodies is strongly recommended. This procedure can prevent
delayed hemolytic reactions if previously identified antibodies subsequently
Typing the patient before
the transfusion for antigens of the Rh and Kell blood groups and avoiding
transfusion of antigen positive blood (particularly E, C, and Kell) if
the patient lacks the antigen.
More complete antigen
matching in alloimmunized patients.
Increasing the use
of African-American blood donors because of the similarity of red blood
cell antigenic phenotypes. Family members and community groups can assist
in donor recruitment.
AUTOIMMUNE ANEMIA FOLLOWING ALLOSENSITIZATION
In some highly alloimmunized
patients, a syndrome of autoimmune hemolytic anemia can follow allosensitization
or a hemolytic transfusion reaction. The patient can become more anemic
than before transfusion. The direct antiglobulin (Coombsí) test remains
positive even after the incompatible transfused cells have been destroyed.
This syndrome occurs because the body produces antibodies against self-antigens.
The condition may persist from several weeks to 2-3 months before disappearing.
Further transfusion is complicated by the autoimmune antibody and requires
sophisticated blood-banking techniques to find the "least incompatible"
blood for transfusion.
ALLOANTIBODIES TO WHITE CELLS, PLATELETS,
AND SERUM PROTEINS
Transfused patients can become alloimmunized
to antigens specific to leukocytes or platelets. These antibodies can cause
febrile reactions. Removal of the leukocytes by filtration or washing dramatically
reduces the frequency of febrile reactions. Plasma washing to antigenic
plasma proteins and administration of antihistamines also mitigate against
Hepatitis and other transfusion-transmitted
viral diseases occur with the same frequency in sickle cell patients as
with other patients receiving transfusions. The consequences of viral disorders
can be more severe in sickle cell patients because of pre-existing organ
damage. Patients who are negative for antibody against hepatitis B should
be immunized. Patients receiving multiple transfusions should be serially
monitored for hepatitis C and other viral infections. Therapy is evolving
for hepatitis C, and many patients are being successfully treated with
Interferon in combination with other antiviral agents.
Acquired immune deficiency
syndrome (AIDS) from transfusion has decreased dramatically in recent years.
However, HIV infection has been reported as late as eight years after transfusion
from a donor not known to be infected. Sickle cell patients transfused
before blood products were tested for HIV infection, as well as those transfused
with todayís "safe" blood, should be periodically screened and counseled.
infections occur in one in every 40,000 units and have been associated
with acute anemic events and multiple sickle cell complications. When available,
the parvovirus vaccine is recommended for all at-risk patients.
bacterial infections are uncommon. Repeatedly transfused hemoglobinopathy
patients are particularly vulnerable to Yersinia entercolitica and bacteremia
secondary to ineffective skin cleansing at the time of phlebotomy. All
patients developing fever after transfusion must be immediately assessed
for potential bacterial infection.
overload in sickle cell patients is often undetected and/or not treated.
In contrast to thalassemia patients who require routine transfusion, most
patients with sickle cell disease are iron overloaded because of intermittent
transfusions throughout their life. No evidence suggests that sickle cell
disease patients should be spared the fatal consequences of iron overload.
Therefore, a comprehensive program designed to monitor and treat iron overload
No simple test exists
to determine iron overload. Serial serum ferritin levels are a helpful
index of stores, but can be unreliable. Ferritin is an acute phase reactant
and levels are markedly altered by liver disease, inflammation, and vitamin
C stores. Liver biopsy is the most accurate test for iron overload and
is safe if performed by an experienced gastroenterologist. The sample must
be of adequate size and sent to a reference lab familiar with liver iron
quantification. Currently, the super conducting quantum interference device
(SQUID) provides the only reliable non-invasive method of quantifying liver
iron. Results with MRI and CT scan are improving, but their clinical use
is unproven. Some programs recommend liver biopsies at the initiation of
chelation, and every two years thereafter. Chelation therapy should begin
when the liver iron is 7 mg/gm per dry weight. Alternatively, cumulative
transfusions of 120 cc of packed red cells per kilogram per body weight
is occasionally used. Ferritin levels above 1,000 ng/mL in the steady state
are helpful, but risks of under and over treatment exist. All iron overloaded
patients must be followed at specialty centers that can monitor organ toxicity
and provide on-going patient education and support.
use has been associated with ototoxicity, opthalmologic toxicity, allergic
reactions, growth failure, unusual infections, and pulmonary hypersensitivity,
these complications are rare. The medication is generally quite safe. The
initial dose is approximately 25 mg/kg per day, over a period of 8-10 hours,
given subcutaneously. New methods of delivery, including twice-daily subcutaneous
injections or intravenous home parenteral access, are being studied. Desferal
therapy should always be discontinued during an acute infection.
Other chelators, including
oral iron chelator (L-1), HBED, and PIH are undergoing safety and efficacy
studies, and are not currently available for general clinical use.
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