revised January 4, 2001

Elliot Vichinsky M.D.
Director, Hematology/Oncology
Oakland Children's Hospital
Oakland, California

Transfusion Therapy in Sickle Cell Disease

TRANSFUSION THERAPY

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.

EPISODIC TRANSFUSIONS

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.

Acute splenic sequestration

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.

Transient 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:

Acute chest syndrome

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.

Stroke

Chronic transfusion 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

Acute 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 SS patients.

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 disease

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.

CONTROVERSIAL/EQUIVOCAL INDICATIONS

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 media

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.

Pregnancy

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 during pregnancy.

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.

Leg ulcers

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 capacity.

Uncomplicated acute painful crises.

Infections

Minor surgery not requiring prolonged general anesthesia (e.g., myringotomy)

Aseptic necrosis of the hip or shoulder (except when surgery is required)

Uncomplicated pregnancy

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 or hematocrit.

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.

Pre-storage leuko-depletion 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 following transfusion.

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.

TRANSFUSION METHODS

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

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.

TRANSFUSION COMPLICATIONS

Transfusion complications 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

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 transfusion reactions

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. The 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.

Alloimmunization and hemolytic transfusion reactions resulting from it can be reduced by the following:

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.

Reducing alloimmunization due to donor/patient antigen mismatch.

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.

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 become undetectable.

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 febrile reactions.

INFECTION

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.

Parvovirus 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.

Transfusion-induced 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.

IRON OVERLOAD

Iron 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 is necessary.

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.

Although desferrioxamine 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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