NIH Publication No. 02-2117. Revised May28, 2002 (Forth Edition) National Institutes of Health, National Heart, Lung, and Blood Institute. Download the entire PDF file for Adobe

Chapter 25

TRANSFUSION, IRON OVERLOAD, AND CHELATION

Used correctly, transfusion can prevent organ damage and save the lives of sickle cell disease (SCD) patients. Used unwisely, transfusion therapy can result in serious complications.

The choice of several methods, such as simple transfusion, partial exchange transfusion, and erythrocytapheresis, depends on the specific requirements of the patient. Except in severe anemia, exchange transfusion offers many benefits and should be made available.

Once a decision is made to transfuse, the type of red cells to be given is specified and goals are set for the final posttransfusion hematocrit and percent sickle hemoglobin (Hb S) desired.

In general, phenotypically matched, sicklenegative, leukodepleted packed cells are the blood product of choice, and a posttransfusion hematocrit of 36 percent or less is recommended, since a higher value theoretically causes hyperviscosity, which is dangerous to sickle cell patients. A comprehensive transfusion protocol should include accurate records of the patient’s red cell phenotype, alloimmunization history, number of units received, serial Hb S percentages, and results of monitoring for infectious diseases and iron overload.

Transfusions are used to raise the oxygencarrying capacity of blood and decrease the proportion of sickle red cells. Clinically, they will improve microvascular perfusion of tissues.

Transfusions usually fall into two categories: episodic, acute transfusions to stabilize or reverse complications, and long-term, prophylactic transfusions to prevent future complications (1).

In severely anemic patients, simple transfusions should be used without removal of any blood from the patient. The most common causes of acute anemia are acute splenic sequestration (described in chapter 18, Splenic Sequestration) and transient red cell aplasia (see chapter 12, Transient Red Cell Aplasia). A third form of acute anemia, called hyperhemolysis, is associated with infection (see chapter 11, Infection), acute chest syndrome (see chapter 16, Acute Chest Syndrome and Other Pulmonary Complications), and particularly, malaria.

In patients hospitalized for pain episodes and other events, the Hb concentration may fall well below the admission value. If the patient is stable and the reticulocyte count high (>20 percent or >250,000/µL), transfusions can be deferred. In general, patients should be transfused if there is sufficient physiological derangement to result in heart failure, dyspnea, hypotension, or marked fatigue. Such symptoms tend to occur during an acute illness when hemoglobin falls under 5 g/dL. Patientswith an acute event associated with falling hemoglobin can die suddenly from cardiovascular collapse and should be monitored closely.

MANAGEMENT OF SUDDEN SEVERE ILLNESS

Leading causes of death in SCD, such as acute chest syndrome (see chapter 16, Acute Chest Syndrome and Other Pulmonary Complications), stroke (see chapter 13, Stroke and Central Nervous System Disease), sepsis, and acute multiorgan failure often are accompanied by a falling hemoglobin level.

Transfusions can improve tissue oxygenation and perfusion and are indicated in seriously ill patients to potentially limit areas of vaso-occlusion. Controlled clinical trials to evaluate transfusions in most life-threatening situations have not been performed, so medical practice is based mainly on clinical observations. However, limited studies indicate that aggressive transfusion regimens may improve recovery of organ function and survival in instances of acute multiorgan failure (2). In general, the goal is to maintain a Hb S level below 30 percent.

PREPARATION FOR GENERAL ANESTHESIA

A multi-institution study recently compared perioperative complications among sickle cell patients undergoing major surgery (e.g., cholecystectomy) (3). Patients were randomized to an aggressive transfusion arm (to decrease Hb S to below 30 percent) or a conservative transfusion arm (with Hb S at about 60 percent, total Hb corrected to 10 g/dL). The groups also were compared to patients who did not receive any perioperative transfusions.

Complications occurred in all groups but were substantially more frequent in nontransfused patients. There was no difference between the conservatively and aggressively transfused patients with respect to perioperative complications; however, the latter group had a higher alloimmunization rate.

Thus, there is good evidence to recommend that sickle cell patients be transfused before major surgery. Anemia should be corrected to a Hb concentration of about 10 g/dL and the Hb S level should be approximately 60 percent or lower. Although practice guidelines have not been established, it is generally acceptable to omit preoperative transfusions in healthy SCD-SC patients and stable SCDSS patients who undergo minor surgery (see chapter 24, Anesthesia and Surgery).

CHRONIC TRANSFUSION THERAPY

Chronic transfusion therapy is indicated when avoidance of potentially serious medical complications justifies the risks of alloimmunization, infection, and iron overload (4,5). The goal is to maintain the Hb S level between 30 and 50 percent, depending on the specific problem. Transfusions are usually repeated every 3 or 4 weeks. While simple transfusions may be used, red cell pheresis or exchange transfusions may help to decreasethe risk of iron overload (6).

Chronic transfusion therapy may be warranted for the primary prevention of stroke and prevention of stroke recurrence (see chapter 13, Stroke and Central Nervous System Disease). It may also be used to treat chronic debilitating pain (see chapter 10, Pain), pulmonary hypertension (see chapter 16, Acute Chest Syndrome and Other Pulmonary Complications), and anemia associated with chronic renal failure (see chapter 19, Renal Abnormalities in Sickle Cell Disease). In patients with chronic heart failure, transfusion therapy may assist cardiac treatments and improve quality of life (see chapter 15, Cardiovascular Manifestations).

Transfusions are sometimes suggested for conditions in which efficacy is unproven, but may be considered under extreme circumstances as described in chapter 20, Priapism; chapter 22, Leg Ulcers; and chapter 23, Contraception and Pregnancy.

PREPARATION FOR INFUSION OF CONTRAST MEDIA

In the past, sickle cell patients were at increased risk of sickling when given hypertonic contrast media for radiographic examinations. To eliminate this problem, transfusion was recommended beforehand, but new agents, such as gadolinium and nonionic contrast media, now lower the risk.

MANAGEMENT OF "SILENT" CEREBRAL INFARCT AND/OR NEUROCOGNITIVE DAMAGE

Subclinical infarcts detected by magnetic resonance technology often are associated with neurocognitive defects. Patients who have subclinical infarcts appear to have a higher incidence of strokes, but the efficacy of preventive transfusion has not been evaluated in these patients. Until rigorous controlled trials are conducted, routine chronic transfusion therapy cannot be recommended.

INAPPROPRIATE INDICATIONS AND CONTRAINDICATIONS

The following conditions alone do not justify transfusion:

• Chronic steady-state anemia. Most patients with SCD are relatively asymptomatic from their anemia and do not require transfusions to improve oxygen delivery.

• Uncomplicated acute pain episodes. ¦ Infections.

• Minor surgery that does not require prolonged general anesthesia (e.g., myringotomy).

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

• Uncomplicated pregnancies.

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TYPES OF BLOOD PRODUCTS TO BE USED

Standard bank blood is appropriate for patients with SCD. 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 for small infants) helps in acute situations requiring immediate correction of oxygen- carrying capacity. All blood should be screened for the absence of sickle hemoglobin; a solubility test is adequate. This eliminates blood with sickle cell trait, which can confuse later measurements of the proportion of sickle cells or Hb 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 of the phenotyping should be maintained in the blood bank to optimize matching, 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 program should be assessed periodically by determination of the proportion of Hb S by quantitative hemoglobin electrophoresis as well as the hemoglobin concentration or hematocrit. There are several causes of the high prevalenceof alloimmunization in SCD, and phenotypic incompatibility between the donor and recipient is a major factor (7). Limited matching for E, C, and Kell antigens is usually performed, unless patients have antibodies (8).

Prestorage leukodepletion of red cells is standard practice to reduce febrile reactions, platelet refractoriness, infections, and cytokineinduced complications (9). Washed red cells should be reserved for patients who had allergic reactions after prior transfusions. Irradiated blood should be considered in patients likely to be candidates for bone marrow transplantation, but relatives should not be used as blood donors for children who are such candidates. The use of autologous blood transfusions in SCD 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.

Once a sufficient level of transfused normal cells [60-70 percent normal hemoglobin (Hb A)] is achieved, simple transfusions every 2 to 4 weeks may maintain this proportion of normal cells for years. The level of Hb A must be monitored regularly by quantitative hemoglobin electrophoresis. Significant variation in transfusion requirements for each patient is common, but the pretransfusion hematocrit should be between 25 and 30 percent. The posttransfusion hematocrit should be 36 percent or less to prevent hyperviscosity, especially for initial transfusions.

Exchange transfusion is used to remove sickle cells and replace them with normal red cells without increasing whole blood viscosity or chronic iron burden (6,10). The volume of blood needed can be calculated from the patient’s weight, initial hematocrit, target hematocrit, and desired percentage of Hb A.

An adult exchange usually takes about 6 to 8 units, and children require about 50 to 60 mL/kg of blood. Whole blood or packed cells reconstituted to hematocrits of 30 to 40 percent are used to conserve units, but exchanges will take longer than with packed cells alone. Blood can be removed from the adult patient in 500 mL aliquots, followed by infusion of 500 mL of reconstituted blood, repeated for 6 to 8 cycles, or another schedule can be used.

The following is an example:

Step 1. Bleed one unit (500 mL) of blood from patient, infuse 500 mL of saline.

Step 2. Bleed a second unit from the patient, infuse two units of blood.

Step 3. Repeat steps 1 and 2; if the patient has a large red blood cell mass, repeat once more.

For children, smaller, more precise volumesshould be calculated and used in order not to remove or transfuse too much blood at one time. In some patients, whole blood can be taken from one arm at the same time that donor cells are transfused into the other.

For adults, this procedure can be performed in 500 mL units, whereas in children, smaller amounts are practical. Automated erythrocytapheresis is safe and is being used fairly often because it prevents iron overload, despite concerns about increased red cell utilization, venous access, and increased cost. When exchange transfusion is performed, the final hemoglobin value should not exceed 10 to 12 g/dL to avoid hyperviscosity, and the percentage of Hb A should meet the goals of therapy.

Transfusion complications, such as alloimmunization, hyperviscosity, and relative hypertension, may be higher for sickle cell patients than for members of the general population (1). Transfusions have precipitated pain episodes, strokes, and acute pulmonary insufficiency.

This condition occurs when a large volume of blood is transfused too quickly. Congestive heart failure and pulmonary edema tend tooccur in patients who have cardiac dysfunction or poor cardiac reserve. Administration of intravenous furosemide, partial removal of red cell supernatant fluid before transfusion, and a slow transfusion rate can help to prevent this 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 to 25 percent, which is greater than in the general population (7). This condition causes difficulty in obtaining compatible blood and results in a high incidence of delayed hemolytic transfusion reactions (12,13). Reactions occur 5 to 20 days after transfusion and are due to antibodies undetectable at the time of compatibility testing. More than 30 percent of antibodies disappear with time, but recipients can mount anamnestic responses to further stimulation by transfusion. Delayed hemolytic transfusion reactions may cause severe anemia, painful events, and even death.

ACUTE HEMOLYTIC TRANSFUSION REACTIONS

The causes of acute hemolytic transfusion reactions in sickle cell patients are not different from those in other patients. Major hemolytic reactions occur mainly with major blood group (ABO) mismatches and must be treated aggressively to maintain blood pressure and glomerular filtration. Most reactions can be prevented by avoiding clerical and sample identification errors in the cross-matching and transfer of units from the donor site to the patient. Minor hemolytic reactions occur when the amount of antibody in the patient’s serum is limiting and causes the transfused blood to disappear over several days, followed by hyperbilirubinemia. The hematocrit decreases, but no further treatment is needed unless the hematocrit falls greatly.

Any of these reactions, particularly the delayed variety, can initiate a pain episode in patients with SCD. In all cases, a patient’s blood should be examined very carefully byimmunohematologists to document the antibody or antibodies responsible for the reaction.

The patient must be told of the complication and be given a card describing the antibodies found.

Alloimmunization and hemolytic transfusion reactions can be reduced by:

• Acquiring and maintaining adequate records of previous transfusions and complications arising from them.

• Limiting the number of transfusions administered.

• Screening for newly acquired antibodies 1 to 2 months after each transfusion to detect transient antibodies that cause a subsequent delayed reaction.

• Diminishing the opportunities for alloimmunization because of a mismatch in the antigens of donors and patients (14).

This may be accomplished by:

– Typing the patient before transfusion (if this has not already been done) for Rh and Kell blood group antigens to avoid transfusion of cells with these antigens (particularly E, C, and Kell) if the patient lacks them.

– More extensive antigen matching in patients who are already alloimmunized.

– Increasing the numbers of African- American blood donors because of the similarity of their blood cell antigenic phenotypes. Family members and community groups can assist in accomplishing this objective.

Patients alloimmunized to one red cell antigen are more likely to become alloimmunized to others. Transfusions should be given only for clearcut indications, and care should be taken in the selection of units of blood. Patientsshould be counseled to advise any new physician of their history of alloimmunization and to carry a card or identification bracelet that lists their red blood cell phenotype and any identified antibodies.

AUTOIMMUNE ANEMIA FOLLOWING ALLOSENSITIZATION

In a highly alloimmunized patient, a syndrome of autoimmune hemolytic anemia may occur. In this case, the patient may become more anemic than before transfusion, and the directantiglobulin (Coombs’) test remains positive even after the incompatible transfused cells have been destroyed. Autoimmune anemia occurs because the recipient produces antibodies against self-antigens, which may persist up to 2 to 3 months before disappearing. Further transfusion is complicated by the autoimmune antibody and requires special blood bank tests to find the least incompatible units for transfusion.

Although transfusion may be necessary in some patients, an alternative course may be to avoid transfusion and to administer corticosteroids, large doses of erythropoietin, and possibly intravenous immune globulin.

ALLOANTIBODIES TO WHITE CELLS, PLATELETS, AND SERUM PROTEINS

Patients who are transfused may become alloimmunized to antigens present on leukocytes or platelets but absent from red blood cells. Such antibodies may cause febrile reactions that can be prevented by the removal of leukocytes by filtration or washing. These antibodies, and those for serum proteins, can cause allergic reactions that can be prevented by prophylaxis with an antihistamine (Benadryl®), leukodepletion, or removal of plasma.

Hepatitis and other transfusion-transmitted viral diseases in blood occur with the same frequency in sickle cell patients as in other patients who receive transfusions. The consequences may be more severe with concurrent SCD, however. Patients who have received multiple transfusions should be monitored serially for hepatitis C and other infections (15,16). Parvovirus occurs in 1 in every 40,000 units, and is associated with acute anemic events and multiple sickle cell complications.

Transfusion-induced bacterial infections are uncommon. Repeatedly transfused hemoglobinopathy patients are particularly vulnerable to Yersinia entercolitica and bacteremia from poor skin cleansing before phlebotomy. All patients who develop fever after transfusion need to be assessed immediately for potential bacterial infection.

IRON OVERLOAD AND CHELATION

Iron overload in sickle cell patients is often undetected or not treated. In contrast to thalassemia patients, most patients are iron overloaded because of intermittent transfusionsthroughout their lives. There is no evidence that SCD patients are spared the fatal consequences of iron overload. Therefore, a comprehensive program to monitor and treat iron overload is necessary.

There is no simple test to determine iron overload. Measurement of serial serum ferritins may help but can be unreliable because ferritin is an acute phase reactant and values are altered by liver disease, inflammation, and vitamin C stores. Liver biopsy is the most accurate test for iron overload and can be performed safely by an experienced physician. The sample should be of adequate size and sent to a reference lab familiar with liver iron quantitation. Some programs recommend liver biopsies at the start of chelation and every 2 years thereafter. As a noninvasive method, the superconducting quantum interference device (SQUID) is acceptable for quantitating liver iron (10). There is progress with MRI and CT, but their clinical use is unproven.

The best indication to begin chelation therapy is a rise in liver iron stores to 7 mg/g dry weight. Alternatively, cumulative transfusions of 120 cc of pure red cells per kilogram of body weight can be used (5). Serum ferritin levels above 1,000 ng/mL in the steady state are helpful, but the risk of under- and overtreatment occurs. All iron-overloaded patients should be followed at comprehensive sickle cell centers that can monitor organ toxicity and provide ongoing education and support.

Exchange transfusions and chelation therapy are the only two accepted methods to manage transfusion-related iron overload. Phlebotomy will remove iron in abnormal red cells, which are replaced by normal red cells. The initial dose of the chelator deferoxamine (Desferal™) is 25 mg/kg per day, over 8 hours subcutaneously (17); dose and duration of infusion can be increased, depending on patient age and iron load. Supplementation with vitamin C, 100 to 200 mg per day, may help to increase excretion, especially in those who are vitamin C deficient. New methods of delivery, including twice-daily subcutaneous injections and intravenous home parenteral access, are being studied. Deferoxamine is generally safe, but has been associated with ototoxicity, eye toxicity, allergic reactions, growth failure, unusual infections, and pulmonary hypersensitivity; therefore, patients should be monitored annually for growth and eye toxicity. Iron chelation always should be discontinued during an acute infection. Other chelators are experimental and are not recommended at this time.

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2. Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med 1994;96:155-62.

3. 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;333:206-13.

4. Styles LA, Vichinsky E. Effects of a long-term transfusion regimen on sickle cell-related illnesses. J Pediatr 1994;125:909-11.

5. Vichinsky E. Guest editor. Consensus document for transfusion-related iron overloads. Sem Hematol 2001;38(Suppl 1):2-4.

6. Singer ST, Quirolo K, Nishi K, et al. Erythrocytapheresis for chronically transfused children with sickle cell disease: An effective method for maintaining a low hemoglobin S level and reducing iron overload. J Clin Apheresis 1999;14:122-5.

7. Rosse WF, Gallagher D, Kinney TR, et al. Transfusion and alloimmunization in sickle cell disease. The Cooperative Study of Sickle Cell Disease. Blood 1990;76:1431-7.

8. Sosler SD, Jilly BJ, Saporito C, et al. A simple, practical model for reducing alloimmunization in patients with sickle cell disease. Am J Hematol 1993;43:103-6

9. Brand A. Passenger leukocytes, cytokines, and transfusion reactions. N Engl J Med 1994;331:670-1.

10. Brittenham GW, Cohen AR, McLaren CE, et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 1993;42:81-5.

11. Pegelow CH, Colangelo L, Steinberg M, et al. Natural history of blood pressure in sickle cell disease: Risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 1997;102:171-7.

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13. Petz LD, Calhoun L, Shulman IA, et al. The sickle cell hemolytic transfusion reaction syndrome. Transfusion 1997;37:382-92.

14. Tahhan HR, Holbrook CT, Braddy LR, et al. Antigen-matched donor blood in the transfusion management of patients with sickle cell disease. Transfusion 1994;34:562-9.

15. Hasan MF, Marsh F, Posner G, et al. Chronic hepatitis C in patients with sickle cell disease. Am J Gastroenterol 1996;91:1204-6.

16. Schreiber GB, Busch MP, Kleinman SH, et al. The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med 1996;334:1685-90.

17. Silliman CC, Peterson VM, Mellman DL, et al. Iron chelation by desferrioxamine in sickle cell patients with severe transfusion-induced hemosiderosis: A randomized, double-blind study of the dose-response relationship. J Lab Clin Med 1993;122:48-54.