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Sickle Cell Disease

Sickle cells are prematurely removed from the circulation by the spleen, resulting in hemolytic anemia. The circulating half life of sickle cells is 16 to 20 days, which is much less than the normal half life of 120 days for normal RBCs.

RBC transfusion provides many benefits including increasing the patient’s hemoglobin, diluting the concentration of Hgb S with Hgb A and providing RBCs longer circulating half times that do not sickle nor polymerize. In addition, transfusion suppresses the patient’s own erythropoiesis, reducing production of sickle RBCs.

RBCs can be transfused as a simple transfusion or via exchange transfusion. A simple transfusion involves transfusing one or two units of RBCs through a peripheral IV. Exchange transfusion is usually performed using an automated apheresis machine that replaces one to two patient RBC volumes with donor RBCs.

Indications for transfusion in sickle cell disease include:

  • Aplastic Crisis
  • Stroke
  • Splenic Sequestration
  • Pregnancy with complications of sickle cell disease
  • Priapism if not responsive to hydration and analgesia
  • Presurgical
  • Acute Chest Syndrome

Simple transfusions are preferred for pediatric patients who suffer a stroke. Exchange transfusion can be used to rapidly reduce the amount of Hgb S. Once a patient has a stroke, they are at risk for additional strokes. Monthly transfusions, either simple or exchange, to maintain HbS concentration below 30% reduces the risk of recurrent stroke. Transfusion of about 10 mL/kg of red blood cells every 3 to 4 weeks is usually sufficient to maintain HbS near 30% and the pretransfusion hematocrit between 25 and 30%.

During transfusion of patients with splenic sequestration, the hemoglobin often increases beyond the expected level, so it is important to transfuse slowly to avoid over-transfusion.

Simple transfusion or exchange transfusion should be considered for patients with refractory priapism. Exchange transfusion has been associated with adverse neurologic sequelae, such as seizures and increased intracranial pressure, so this alternative should be reserved for the most refractory cases.

Patients with sickle cell disease are at high risk for complications during major surgery. Some practitioners recommend that patients be transfused to hemoglobin of 10 g/dL prior to surgery. Exchange transfusion is usually not necessary.

Patients with the acute chest syndrome benefit from transfusion early in the course of their disease. Acute chest syndrome is defined as the onset of pulmonary infiltrate, chest pain, fever, tachypnea, wheezing and cough. Acute chest syndrome is a risk factor for stroke. Simple transfusion is preferred for patients who are stable. Patients with hemoglobin below 7 g/dL should be transfused to increase their hemoglobin to between 9 and 10 g/dL. Higher levels are associated with vaso-occulsion. Exchange transfusion is recommended for patients who have a rapidly evolving course or do not respond to simple transfusion. The goal of exchange transfusion is to decrease HbS to less than 30% and final total hemoglobin between 9 and 10 g/dL. There does not appear to be any role for transfusion in the management of routine, uncomplicated painful crises.

Adverse Consequences of Transfusion of Patients with Sickle Cell Disease

Adverse consequences of transfusion of patients with sickle cell disease include alloimmunization, hyperhemolysis and iron overload. Patients with sickle cell disease are chronically transfused and have a high rate of alloimmunization (18-36%). Most patients with sickle cell disease in the United States are African American, and most donors are Caucasian from Western European descent. As a result of this ethnic difference, patients with sickle cell disease are exposed to RBC antigens that they lack, increasing the likelihood of alloantibody formation. Donors of primarily European descent have a higher prevalence of C, E, Fya, Jkb and S blood group antigens than patients of African origin. The most common antibodies formed in this population are C, E, K1 and Fya.

In order to prevent alloimmunization, some centers routinely perform RBC phenotypes on patients with sickle cell disease and only transfuse RBCs that are matched for Rh (D, C, E, c e) and K antigens. Extended matching for Fy, Jk and Ss blood group antigens can further reduce alloimmunization, but is not standard practice because only 5-10% of chronically transfused sickle cell patients form antibodies against these antigens, the availability of extended antigen matched units is more limited and the units are more expensive.

Individuals of African descent have a high degree of genetic variation in the RH locus and may have partial Rh antigens, which lack some immunogenic epitopes of the normal antigen. These patients may develop anti-Rh antibodies against these missing epitopes when transfused with RBCs carrying the normal antigen, even though the RBCs were phenotypically matched for Rh (D, C, E, c, e). Rh variants can be detected by RH genotyping, but is usually reserved for patients who are high antibody responders or form an Rh antibody despite conventional Rh antigen matching.

African Americans may also not express some high incidence blood group antigens that common in Caucasian donors. Sickle cell patients may be negative for Hrs (Rh partial e), HrB (Rh partial e), U (MNS blood group), Jsb (KEL blood group) and RN (Rh blood group). Once a sickle cell patient develops alloantibody to one of these antigens, future transfusion becomes very challenging due to the very limited supply of compatible antigen negative RBCs. More donors of African American descent need to be recruited to increase the rare blood type inventory.

The incidence of severe delayed hemolytic transfusion reactions (DHTR) in sickle cell patients is 11 to 16% in patients receiving only ABO and Rh D matched units and 4 to 7% in patients matched for Rh(D, C, E, c, e) and K. DHTR represent 4% of all causes of death in sickle cell disease. DHTR are frequently misdiagnosed as vaso-occlusive episodes. DHTR should be suspected when patients develop evidence of hemolysis up to 3 weeks after a transfusion. A decrease of total hemoglobin by more than 25% compared to the pretransfusion level should raise suspicion for DHTR. Hemoglobin electrophoresis can also be used to compare the extent of decrease in hemoglobin A concentration relative to the immediate posttransfusion value. A significant decrease indicates the destruction of transfused RBCs.

In some cases of suspected DHTR no alloantibodies are detected. Antibody screening should be repeated at regular intervals within 3 months from the diagnosis of DHTR to detect de novo alloantibodies.

A serious type of hemolytic transfusion reaction, called the hyperhemolytic syndrome can occur during transfusion of patients with sickle cell disease. In this syndrome, a patient’s hemoglobin falls, instead of rises, after transfusion. Both the patient’s own RBCs and the transfused RBCs are destroyed even though the transfused RBCs are crossmatch compatible and no new alloantibodies are detectable at the time of transfusion. Hyperhemolysis may be accompanied by reticulocytopenia, worsening the anemia. Hyperhemolysis can lead to multiorgan failure and death, presumably due to vascular damage by free hemoglobin and heme. Plasma exchange may be effective in detoxifying heme.

Further transfusion may compound the problem of hyperhemolysis. Therefore, it is important to recognize this syndrome early and, if possible, discontinue transfusion. If additional transfusions are required because of life-threatening anemia, they should be done cautiously, using concurrent IVIG and steroids. Eculizumab has been used to inhibit the complement cascade. All patients with reticulocytopenia should receive erythropoietin to stimulate RBC production. Hydroxyurea should be discontinued until cytopenia resolves.

Each unit of transfused RBCs contains about 200 to 250 mg of iron. With chronic transfusion, iron accumulates in the heart, liver, and endocrine glands. In order to prevent this complication, iron chelating medication is administered. Serum ferritin is serially measured to assess iron stores.

Transfusion Recommendations

Patients with sickle cell disease should not be transfused with RBCs containing Hgb S. Therefore, many laboratories test donor units with a simple solubility test and select units that lack Hgb S. Patients with sickle cell disease should also be transfused with leukocyte reduced blood products to decrease the risk of cytomegalovirus (CMV) transmission, febrile non-hemolytic transfusion reactions, immune suppression, HLA alloimmunization and RBC alloimmunization.

RBCs selected for transfusion of patients with sickle cell disease should be:

  • Sickle hemoglobin negative
  • Leukoreduced
  • Matched for Rh (D, C, E, c e) and K antigens
  • Negative for any other antigens to which the patient has already been sensitized
  • Collected from African American donors if a program exists

Quirolo, K. How do I transfuse patients with sickle cell disease? Transfusion 2010;50:1881-1886.

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