MANAGEMENT AND THERAPY OF SICKLE CELL DISEASE

NIH Publication No. 95-2117, Revised December 1995 (Third Edition) National Institutes of Health, National Heart, Lung, and Blood Institute

Chapter 10-Transfusion

Transfusion should be used for specific indications in the treatment of patients with sickle cell disease and should be used as sparingly as possible. Transfusion is indicated for certain acute problems (not including acute painful episodes) or for the treatment or prevention of chronic complications and other health-related events. Several methods of transfusion are available (simple transfusion, partial exchange, and chronic exchange); the method used depends on the indication for the transfusion. The recommendations in this discussion are for patients with homozygous SS disease and S beta o thal.

The role of transfusion in the care of patients with Hb SC disease and Hb S beta + thalassemia is controversial. An important principle in the transfusion of sickle cell patients is the avoidance of excessive blood viscosity. Blood viscosity is a function of the intrinsic viscosity of the red blood cells and of the hematocrit. Because sickle cells are intrinsically less deformable than normal cells, raising the hematocrit without substantially reducing the proportion of sickle cells may raise the blood viscosity to dangerous levels. Therefore, simple transfusions should be used with caution in patients with high hematocrits, and the final posttransfusion hematocrit should be 36 percent or less. Patients with high baseline hemoglobin may be more safely transfused using an exchange technique.

INDICATIONS FOR TRANSFUSIONS

The following are generally considered to be indications for red blood cell transfusions in sickle cell disease:

In severely anemic patients, transfusions should be simple transfusions without exchange, hence, without removal of any blood from the patient. Simple transfusions of this sort should be considered in he following situations:

-- In patients who are so anemic that they have physiological derangement that is manifest by impending or overt high output cardiac failure, dyspnea, postural hypotension, angina, or cerebral dysfunction.

-- In patients who have had a sudden diminution in hemoglobin concentration, particularly patients having an acute splenic or hepatic sequestration crisis, manifest by rapid splenic or liver nlargement and rapidly falling hematocrit.

-- In patients who exhibit fatigue and dyspnea, usually at hemoglobin concentrations less than 5.0 g/dL and a hematocrit less than 15 percent, particularly in association with erythroid hypoplasia or aplasia.

* When there is a need to improve microvascular perfusion by decreasing the proportion of erythrocytes containing Hb S, an exchange transfusion is indicated unless the patient is severely anemic and has good cardiac function. Such onditions include both acute and chronic conditions:

-- Acute or suspected cerebrovascular accidents and TIA (see Chapter 9, Stroke). -- Multiorgan failure syndrome, including "fat embolization." -- Acute chest syndrome or other acute lung disease when arterial oxygen cannot be maintained at near- normal levels with oxygen therapy or when the process progresses, despite antibiotic and other indicated therapy.

-- Acute priapism unresponsive to therapy.

-- Surgery on the posterior segment of the eye, even when done under local anesthesia in a nonanemic patient (see Chapter 12, Eye). Transfusion is not needed for laser surgery.

-- Preparation for general anesthesia (see Chapter 21).

* Chronic transfusion programs, usually initiated by exchange transfusion, are indicated for several conditions. In these programs, an effort is made to maintain the percentage of Hb A above 50 to 70 percent, which usually requires repeated transfusions every 3 to 4 weeks. Indications for a chronic transfusion program include:

-- Children who have had a cerebral vascular accident for the prevention of further complications.

-- Chronic congestive heart failure in conjunction with other treatment.

EQUIVOCAL INDICATIONS

Transfusion is sometimes suggested for a number of conditions in which its efficacy is unproved. If transfusion is done in these conditions, it should be an exchange - transfusion. These conditions include the following:

* Intractable or frequent painful events.

* Situations in which the patient's condition is deteriorating rapidly, and all other treatments have been unsuccessful.

* Before injection of hypertonic contrast material

* Adults who have had a cerebrovascular accident. * Leg ulcers (see Chapter 16, Leg Ulcers).

* Complicated pregnancy. * Chronic organ failure.

* Extreme diminution in performance status due to recurrent complications of sickle cell disease. When chronic transfusion programs are stopped, many patients have an exacerbation of symptoms that may last for several weeks to months. If these symptoms become excessive or threatening to a patient's health, the transfusion program may need to be reinstituted and then stopped more gradually, although the physiologic justification may be unclear.

NONINDICATIONS AND CONTRAINDICATIONS

The following are not considered appropriate indications for transfusion, and transfusion is not recommended in these clinical settings:

* 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, simple biopsy).

* 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 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 this 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 program should be assessed periodically by determining the proportion of Hb S by quantitative hemoglobin electrophoresis as well as the hemoglobin concentration or hematocrit. Red blood cell preparations depleted of leukocytes by filtration are recommended because of the reduction in febrile reactions and decreased alloimmunization to leukocyte antigens. Washed red blood cells should be used in patients who have a history of severe allergic reactions (bronchospasm) following prior transfusions. The use of autologous blood transfusions in sickle cell disease should be avoided. Blood relatives should not be used as blood donors for children who may be candidates for bone marrow transplantation.

TRANSFUSION METHODS

Simple Transfusion Simple transfusions can be used for acute anemia or hypovolemia or in a chronic transfusion program. Packed red blood cells should not be used when only volume expansion is needed. Exchange Transfusion Exchange transfusion is used to alter the hemoglobin level rapidly and to replace sickle cells with normal erythrocytes. This type of transfusion reduces the concentration of sickle cells without substantially increasing the hematocrit or whole blood viscosity. Several methods are available that achieve this purpose. 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 patient's 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. In children, a practical estimate of the volume required for exchange (whole blood or packed cells reconstituted to a hematocrit of 30 to 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 six to eight units of transfusion. Alternatively, the following technique can be used:

Step 1. Bleed one unit (500 mL) of blood from the 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.

The devices used in plasmapheresis can be used to exchange transfuse patients efficiently; red blood cells are removed at the egress and normal blood is infused at the ingress. Usually six to eight units of blood are needed to exchange an adult; formulae are available to calculate the exact amount needed depending on body size, hematocrit, desired hematocrit, and desired percentage of Hb 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 be certain that the final hemoglobin level does not exceed 10-12 g/dL to avoid the problems of hyperviscosity. Careful monitoring of the level of hemoglobin and of the percentage of Hb A is necessary to be certain that the goals of the transfusion have been met.

Chronic Transfusion Programs

Once a sufficient level of transfused normal cells (greater than 50 to 70 percent Hb A) is achieved, it is often useful to maintain this for a period of weeks to years. This proportion of normal cells can be maintained by simple transfusions at intervals of 2 to 4 weeks. The level of Hb A must be monitored by quantitative hemoglobin - electrophoresis.

TRANSFUSION COMPLICATIONS

Transfusion complications for sickle cell patients are the same as those for any patient receiving acute or chronic - transfusion.

Volume Overload

This 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. Administration of intravenous furosemide and partial removal of red cell preserving-fluid before transfusion and a slow transfusion rate can help in preventing this serious problem.

Iron Overload

The serum ferritin levels should be measured periodically. If the level exceeds 2,000 ng/mL (usually after 1 to 3 years of chronic transfusion) and transfusions are still required, patients should be considered for chronic chelation therapy using Desferal. Complications of deferoxamine therapy may include ototoxicity, ophthalmic toxicity, allergic reactions, growth failure, unusual infections (Yersinia, fungi), and pulmonary hypersensitivity. Poor patient compliance, because of repeated subcutaneous infusions of medications, is a significant problem with chronic chelation therapy. Ongoing education and support, often provided by a specially trained nurse, is usually necessary to maintain the patients' cooperation. A subcutaneous infusion port or a Hickman catheter may be used for parenteral access. Desferal therapy should be discontinued during acute bacterial infections. A new oral iron chelator (L-1) is currently being evaluated for safety and efficacy.

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. This condition causes difficulty in obtaining compatible blood and results in a high incidence of delayed hemolytic transfusion reactions. The delayed transfusion reaction occurs 5 to 20 days after transfusion and is due to antibodies not detectable at the time of compatibility testing. It has been found that 30 percent or more of the antibodies to red blood cell antigens may disappear with time, although the recipient remains capable of mounting an anamnestic response to further stimulation by transfusion. The delayed hemolytic transfusion reaction that can result may cause severe anemia, onset of painful crisis, or even death.

ACUTE HEMOLYTIC TRANSFUSION REACTIONS

Acute hemolytic transfusion reactions in sickle cell patients are not different in cause 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 can be prevented by avoiding clerical and patient or sample identification errors in the cross- matching and transplantation of units from donor site to the patient. Minor hemolytic reactions occur when the amount of antibody in the serum is limiting, and they 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 greatly decrease. Any of these reactions, particularly the delayed variety, are able to initiate a painful episode in the patient with sickle cell disease. In all cases, the patient's 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 made aware of the complication and be 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 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 capable of causing a subsequent delayed reaction.

* Diminishing the opportunities for alloimmunization because of a mismatch in the antigens of donors and patients:

-- Typing the patient before the transfusion (if this has not already been done) for antigens of the Rh and Kell blood groups and avoiding the transfusion of cells bearing these antigens (particularly E, C, and Kell) if the patient lacks the antigen. More complete antigen matching has been suggested, but it is expensive and the utility of such matching is not clear.

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

The patient alloimmunized to one red blood cell antigen is more likely to become alloimmunized to others, and care should be taken in selecting transfusion units. Transfusions 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.

Autoimmune Anemia

Following Allosensitization In some highly alloimmunized patients, a syndrome of autoimmune hemolytic anemia may follow allosensitization or a hemolytic transfusion reaction. In this case, the patient may become more anemic than before transfusion, and the direct antiglobulin (Coombs') test remains positive even after the incompatible transfused cells have been destroyed. This syndrome occurs because the body produces antibodies against self-antigens, and it may persist from several weeks to 2 to 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 Patients who are transfused may become alloimmunized to antigens present on leukocytes and/or platelets but lacking on red blood cells. Such antibodies may cause a febrile reaction that can be prevented through the removal of the leukocytes by filtration or washing. These antibodies as well as those against serum proteins can cause allergic reactions that can be prevented by prophylaxis with an antihistamine (Benadryl (registered trademark)), removal of leukocytes or plasma by washing, or use of other measures previously noted.

Infection

Hepatitis and other transfusion-transmitted viral diseases in blood occur with the same frequency in sickle cell patients as in other patients receiving transfusions. The effects may be more severe in sickle cell patients because of the presence of the disease. Patients receiving multiple transfusions should be serially monitored for hepatitis C and other viral infections; alpha interferon may be useful in the treatment of patients with chronic hepatitis B and C. Posttransfusion human immunodeficiency virus (HIV) infection and AIDS are reported in sickle cell disease, occurring as late as 5 to 8 years after the transfusion with blood not known to be from an infected donor. Thus, patients with sickle cell disease who were transfused before blood products were tested for HIV antibodies (1975-85) as well as those transfused with today's "safe" blood should be considered for counseling on testing for HIV infection.

TRANSFUSION FOR SURGERY

A multi-institutional study recently prospectively compared perioperative complication rates of sickle cell anemia patients randomized to aggressive transfusion (decrease Hb S below 30 percent) and conservative transfusion (Hb S approximately 60 percent, Hb to 10 g/dL). Serious complications occurred in approximately one-third of both groups. The most common complication was acute chest syndrome, which occurred in 10 percent of patients. There were no significant differences between transfusion regimens and any complication except transfusion complications, which occurred in 14 percent of aggressively transfused patients and 7 percent of conservatively managed patients. In addition, preoperative hospitalization days attributed to transfusion preparation were 4 days in the aggressively transfused patients compared with approximately 2 days in conservatively managed patients. In conclusion, present data suggest that routine hemoglobin SS patients undergoing major elective surgery should be conservatively transfused as part of their routine management. Transfusion with limited phenotypic units would most likely eliminate the alloimmunization observed from E, K, C, and Fya. Definitive data to recommend no preoperative transfusion in sickle cell disease are not available. However, the present standard of practice suggests that no preoperative transfusion is a possible alternative in healthy hemoglobin SC patients and for limited surgery in stable hemoglobin SS patients. At present, patients having tonsillectomies and adenoidectomies should be transfused for surgery.

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