Blood transfusion is the mainstay of care for individuals with thalassemia major and many with intermedia. The purpose of transfusion is twofold: to improve the anemia and to suppress the ineffective erythropoiesis. Chronic transfusions prevent most of the serious growth, skeletal, and neurological complications of thalassemia major. However, once started, the transfusion-related complications become a major source of morbidity. Standards must be developed and maintained to ensure a safe and rational approach to the use of blood transfusions in the management of these rare disorders.
Patients with ß+/ß+ thalassemia; hemoglobin E-ß thalassemia; hemoglobin H disease; and hemoglobin H–Constant Spring often have a thalassemia intermedia phenotype and do not necessarily require chronic transfusion. However, the DNA mutations do not reliably predict the clinical phenotype. ß0/ß+ and even ß0/ß0 may occasionally have a thalassemia intermedia clinical phenotype. The clinical phenotype of thalassemia intermedia patients may change as they age and may require transfusion therapy. Ongoing assessment of transfusion requirements are necessary for both thalassemia major and intermedia.
The decision to start transfusions is based on inability to compensate for the low hemoglobin (signs of increased cardiac effort, tachycardia, sweating, poor feeding, and poor growth), or less commonly, on increasing symptoms of ineffective erythropoiesis (bone changes, massive splenomegaly). The decision to institute chronic transfusion should not be based exclusively on the presence of anemia.
The decision to initiate chronic transfusion therapy requires significant input from the patient, family, and medical team. Anemia alone is not an indication of the need for chronic transfusion. Anemia should be linked with a significant impairment in quality of life or associated morbidities. Factors to consider include: poor growth; inability to maintain daily routines and activities such as going to school and work; evidence of organ dysfunction; evidence of cardiac disease; pulmonary hypertension; and dysmorphic bone changes.
It may be necessary to initiate a six-month trial of blood transfusions in patients of families whose decision to transfuse is uncertain. After six months, transfusions can be stopped and the patient observed for a brief period of time to give the family and medical team information as to the clinical benefits and psychological impact of the transfusions.
The decision to start regular transfusions is clear when the initial hemoglobin level is well below 6 g/dL. To assess a child’s need for routine transfusions due to thalassemia, anemia caused by sepsis or viral infection must be ruled out. Assessment may be accomplished by withholding transfusions and monitoring weekly hemoglobin level. If the hemoglobin drops under 7 g/dL on two occasions, two weeks apart, then regular transfusions should be commenced.
Patients with a hemoglobin level less than 7 g/dL may sometimes require regular transfusions in the presence of growth impairment, marked skeletal changes, or extramedullary hematopoiesis.
An extended red cell phenotype must be obtained to reduce the future probability of developing alloantibodies. If a child has already started transfusions, the red cell antigen genotype can be determined by DNA testing, and at the minimum, should include the C, E, and Kell alleles.
Although the hemoglobin level can define a patient’s disease type, seldom does it alone determine the need for transfusion. Antibodies to hepatitis B, hepatitis C, and HIV should also be determined. Patients should demonstrate immunity to hepatitis B. The bilirubin, transaminase, and serum ferritin levels should be checked.
The aim of transfusion therapy is to permit normal growth and activity level and to prevent skeletal changes associated with marrow hyperplasia. Adequate transfusion therapy will also reduce splenomegaly and hypersplenism and decrease absorption of dietary iron.
Transfusions should be administered in a designated outpatient clinical area by staff experienced with transfusion policies. Written transfusion policies—including maximum rate, volume of transfusion, and protocol for transfusion reactions—are required. The availability of access to outpatient transfusion services on weekdays, weekends, and evenings is important for school-aged children and working adults.
The product of choice is packed red blood cells depleted of leucocytes and matched with the patient’s red antigen phenotype for at least D, C, c, E, e, and Kell.
Whole blood or blood without leukodepletion is unsuitable for regular transfusions, since non-hemolytic transfusion reactions are common. When possible, large units less than two weeks of age are recommended.
Patients should be assessed for hemolytic reactions if any adverse event is noted during a transfusion. Febrile and allergic reactions may respond to acetaminophen and diphenhydramine before future transfusions.
Patients who develop allergic reactions should be given washed packed red blood cell units.
The development of alloantibodies can complicate transfusion therapy and may require the use of frozen packed red blood cell units of rare blood types. Some patients are transfused with irradiated red cells. This process is used to prevent graft-versus-host disease. It is largely unnecessary unless the patient is undergoing a bone marrow transplant or has an underlying immunodeficiency. Cytomegalovirus (CMV) infection is transmitted via transfusion. Leukocyte depletion of a red cell unit prevents its transmission. CMV negative units are usually unnecessary once the unit is leukocyte-depleted.
The goal of transfusion is to shut off erythropoiesis as much as possible. Transfusions should generally be given at an interval of three to four weeks. (With aging patients, a transfusion every two weeks may be necessary.) Transfusions should be scheduled in advance and maintained at a fixed schedule. This enables patients and families to establish routines and will improve quality of life.
The amount of blood received on transfusion day is determined by pre-transfusion hemoglobin levels. The target is to maintain the pre-transfusion hemoglobin level between 9 and 10 g/dL. Attempts to maintain pre-transfusion hemoglobin at above 10 g/dL increase transfusion requirements and the rate of iron loading. Transfusions should be given in an outpatient setting with an experienced transfusion team that uses proper safety precautions (patient/blood identification bracelets). Blood should be transfused at 5 mL/kg per hour, and the post-transfusion hemoglobin should not exceed 14 g/dL.
In patients with severe anemia (hemoglobin less than 5 g/dL) or cardiac compromise, the rate of transfusion should be reduced to 2 mL/kg per hour to avoid fluid overload. Diuretics such as furosemide (1 to 2 mg/kg) may be necessary for some patients.
If cardiac insufficiency is present, higher pre-transfusion hemoglobin levels (10 to 12 g/dL) should be maintained with smaller volume transfusions given every one to two weeks.
The patient’s weight and pre-transfusion hemoglobin and the volume of transfusion should be recorded at each visit. These values should be periodically reviewed to assess the volume of blood required to maintain the desired pre-transfusion hemoglobin level. Annual blood transfusion requirement in patients without hypersplenism is usually below 200 mL packed red blood cells/kg per year.
The very best practices for blood transfusion must be employed, since the need for lifelong transfusions leads to a cumulative increase in the risk of adverse reactions.
Alloimmunization is a frequent problem that can be prevented by transfusing blood matched for the patient’s extended red blood cell phenotype (not just the ABO and RhD antigens). An alloantibody screen should be performed prior to each transfusion. An alloantibody is an antibody made by the patient against an antigen present on the transfused red cell. Once alloimmunized, patients may be at risk for developing an antibody against their own red cells (an autoantibody). Up to 10 percent of patients who develop alloantibodies will develop an autoantibody. The presence of an autoantibody does not always result in decreased red cell survival, but it may. An autoantibody will delay the patient’s cross match and transfusion program. Autoantibodies can best be avoided by preventing alloantibodies.
If an autoantibody and/or alloantibody is detected, the specific antibodies causing the transfusion reaction should be determined by the blood bank or by a reference laboratory.
The management of patients who develop antibodies requires use of blood matched by extended red cell antigen phenotype.
The risk of transfusion-transmitted infections, while low, is still a concern for known and emerging pathogens, and annual monitoring for hepatitis B, hepatitis C, and HIV is necessary.
The risk of bacterial infection is small, but the transmission of parasitic infections (particularly malaria) is a significant threat in certain geographical areas.
The other complications of blood transfusion include the risk of mismatched transfusion, allergic reactions, and febrile, non-hemolytic reactions.
The use of splenectomy in thalassemia has declined in recent years. This is partly due to a decreased prevalence of hypersplenism in adequately transfused patients. There is also an increased appreciation of the adverse effects of splenectomy on blood coagulation. In general, splenectomy should be avoided unless absolutely indicated.
Splenectomy is indicated in the transfusion-dependent patient when hypersplenism increases blood transfusion requirement and prevents adequate control of body iron with chelation therapy. An enlarged spleen—without an associated increase in transfusion requirement—is not necessarily an indication for surgery. Patients with hypersplenism may have moderate to enormous splenomegaly, and some degree of neutropenia or thrombocytopenia may be present.
Annual transfusion volume exceeding 225 to 250 mL/kg per year with packed red blood cells (hematocrit 75 percent) may indicate the presence of hypersplenism. The volume calculation should be corrected if the average hematocrit is less than 75 percent. The possible development of alloantibody should also be ruled out. Splenectomy should be avoided unless there is an inability to maintain iron balance with optimal chelation, or if there are clinically significant complications such as pancytopenia and marked enlargement. Often, hypersplenism develops because of a low pre-transfusion hemoglobin. Increasing the pre-transfusion hemoglobin to between 9.5 and 10 may reverse hypersplenism.
If a decision to perform surgery is made, partial or full splenectomy is the option. Partial splenectomy is a complicated surgery utilized to preserve some splenic function. It should be reserved for infants requiring splenectomy. Full splenectomy can usually be performed by laparoscopic technique. However, open procedure is necessary in cases of marked splenomegaly. The indications for splenectomy in hemoglobin H–Constant Spring patients are different than in beta-thalassemia disorders. Transfusion-dependent infants with hemoglobin H–Constant Spring respond rapidly to splenectomy but require prophylactic anticoagulation because of a high incidence of serious thrombosis.
Patients must receive adequate immunization against Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitides prior to surgery. Splenectomy should be avoided in children younger than five years because of a greater risk of fulminant post-splenectomy sepsis.
After splenectomy, patients should receive oral penicillin prophylaxis (250 mg twice daily) and be instructed to seek urgent medical attention for a fever over 101º Fahrenheit.
Post-splenectomy thrombocytosis is common, and low-dose aspirin should be given during this time. Another complication following splenectomy is the development of a thrombophilic state. Venous thromboembolism, more common in thalassemia intermedia and hemoglobin H–Constant Spring, can develop following splenectomy.
Patients should have annual echocardiographic measurement of the pulmonary artery pressure to monitor for development of pulmonary hypertension.
People with thalassemia are at increased risk of thrombosis. Thrombotic events include pulmonary embolism, arterial occlusion, portal thrombosis, and deep vein thrombosis. Approximately 1 to 2 percent of thalassemia major patients and 5 percent of thalassemia intermedia patients experience a serious thrombosis. One of the most common and serious complications is stroke. Recent brain MRI studies suggest that thalassemia patients (particularly those with thalassemia intermedia) are at high risk for subclinical infarction or silent stroke. Splenectomy significantly increases the prevalence of thrombotic events. Inadequate transfusion may increase the risk of thrombosis secondary to increased release of procoagulant red cell particles. Many people recommend that all post-splenectomy patients should receive anti-platelet or anti-thrombosis therapy with aspirin or low dose warfarin.