How I safely transfuse patients with sickle-cell disease and manage delayed hemolytic transfusion reactions

Abstract

Transfusions can be a life-saving treatment of patients with sickle-cell disease (SCD). However, availability of matched units can be limiting because of distinctive blood group polymorphisms in patients of African descent. Development of antibodies against the transfused red blood cells (RBCs), resulting in delayed hemolytic transfusion reactions (DHTRs), can be life-threatening and pose unique challenges for this population with regard to treatment strategies and transfusion management protocols. In cases where the transfused cells and the patient's own RBCs are destroyed, diagnosis of DHTR can be difficult because symptoms may mimic vaso-occlusive crisis, and frequently, antibodies are undetectable. Guidelines are needed for early diagnosis of DHTR because treatment may need to include temporarily withholding any new transfusions to avoid further hemolysis. Also needed are case-control studies to optimally tailor treatments based on the severity of DHTR and develop preventive transfusion strategies for patients at DHTR risk. Here, we will review gaps in knowledge and describe through case studies our recommended approach to prevent alloimmunization and to diagnose and treat symptomatic DHTRs for which complementary mechanistic studies to understand their pathogenesis are sorely needed.

Figure 1.

Recommended transfusion guidelines for patients with SCD. All transfused patients with SCD should receive serologically crossmatch-compatible leukodepleted RBCs and be monitored carefully by performing regular antibody screening tests including DAT and checking for pain, urine color, and signs of anemia. Total Hb and HbA% measurements (Figure 2) are recommended for patients at high risk of DHTR. Patients on a chronic transfusion protocol are considered low-risk DHTR. For patients receiving episodic transfusions, 3 criteria, assigned different point values based on statistical analysis, are considered DHTR risk factors: (1) History of RBC immunization. A point value of 6 is given if the patient has a history of at least 1 clinically significant antibody (other than anti-Rh or anti-K) classically known to be involved in transfusion reactions, such as anti-Jk^b, Fy^a, S, Hr^S. A point value of 5 is given if the patient has a history of only anti-Rh/-K and/or antibodies considered not clinically (clin) significant (eg, autoantibodies or nonspecific antibodies [Ab’s]). Thus, a patient who has an anti-Rh plus an anti-Jk^b is given a point value of 6 (and not 6 + 5). (2) Cumulative transfusions of 12 units or less. (3) A previous DHTR. By adding the point values, a DHTR risk score is calculated and transfusion is tailored accordingly. Patients with a score of <8 are considered low risk. Patients transfused episodically who have a low risk of DHTR are transfused with Rh (D, C, E, c, e) and K matched RBCs, which is extended to Fy, Jk, and Ss only if the patient has developed antibodies against any one of these antigens. *AUS, antibody with unknown specificity. **Patients who score between 8 and 14 have an intermediate risk. For such patients, the extent of matching should be based on their DHTR history and number of previous transfusions; those with no history of DHTR who have been transfused only a few times are considered at a lower risk similar to low-risk patients, but they should still be monitored closely. However, for patients with intermediate DHTR risk who have a history of DHTRs and few transfusions in the past (≤12), we generally consider them high risk, and they receive extended matched RBCs (Fy, Jk, Ss). Patients with a score of >14 are considered at high DHTR risk. Episodically transfused patients with a high risk of DHTR (based on the predictive score) always receive extended matched RBCs (Fy, Jk, Ss). Prophylactic rituximab use should be considered for patients with a history of alloantibodies and severe DHTR.

Figure 2.

Recommended guidelines for diagnosis of DHTR in adult patients with SCD. (A) Our assessment criteria to diagnose DHTR in adult SCD patients who are recently transfused is based on clinical and laboratory features (pain, anemia, urine color, elevated LDH) and immune-hematologic analysis, which may or may not reveal the presence of new antibodies. If DHTR is suspected, we recommend using immediate posttransfusion total Hb in g/dL and HbA% following the nomogram shown, to determine the likelihood that a patient is experiencing DHTR. The formula can be calculated directly by using the link provided in the figure. (B) Based on total Hb and HbA%, DHTR was suspected for cases 2 and 3, but not for case 1, as confirmed by the nomogram.

Figure 3.

Recommended treatment of patients with SCD experiencing posttransfusion hemolysis. In such cases, transfusions should be stopped unless (indicated by asterisk) the patient has profound anemia (total <3 g/dL with shock or hyperlactemia), in which case rituximab is also indicated for patients with antibodies requiring transfusions. Symptomatic patients experiencing DHTR can be immediately treated with intravenous immunoglobulin (IVIg), adding erythropoietin (EPO) if the DHTR is also associated with reticulocytopenia. Prophylactic anticoagulation is administered to lower the risk of thrombosis associated with EPO administration. Supportive care is always indicated. If the patient has severity criteria (acute chest syndrome or acute pulmonary hypertension, stroke or organ failures), additional treatment with eculizumab can be effective.