Delayed hemolytic transfusion reaction (DHTR) is one of the most feared complications of sickle‐cell disease (SCD). We retrospectively analyzed the clinical and biological features, treatments and outcomes of 99 DHTRs occurring in 69 referral center patients over 12 years. The first clinical signs appeared a median of 9.4 [IQR, 3–22] days after the triggering transfusion (TT). The most frequent DHTR‐related clinical manifestation was dark urine/hemoglobinuria (94%). Most patients (89%) had a painful vaso‐occlusive crisis and 50% developed a secondary acute chest syndrome (ACS). The median [IQR] hemoglobin‐concentration nadir was 5.5 [4.5–6.3] g/dL and LDH peak was 1335 [798–2086] IU/L. Overall mortality was 6%. None of the patients had been receiving chronic transfusions. Among these DHTRs, 61% were developed in previously immunized patients, 28% in patients with prior DHTR. Among Abs detected after the TT in 62% of the episodes, half are classically considered potentially harmful. No association could be established between clinical severity and immunohematological profile and/or the type and specificity of Abs detected after the TT. Management consisted of supportive care alone (53%) or with adjunctive measures (47%), including recombinant erythropoietin and sometimes rituximab and/or immunosuppressants. Additional transfusions were either ineffective or worsened hemolysis. In some cases, severe intravascular hemolysis can be likely responsible for the vascular reaction and high rates of ACS, pulmonary hypertension and (multi)organ failure. In conclusion, clinicians and patients must recognize early DHTR signs to avoid additional transfusions. For patients with a history of RBC immunization or DHTR, transfusion indications should be restricted. Am. J. Hematol. 91:989–994, 2016.

The complement system is an innate immune defense cascade that can cause tissue damage when inappropriately activated. Evidence for complement over activation has been reported in small cohorts of patients with sickle cell disease (SCD). However, the mechanism governing complement activation in SCD has not been elucidated. Here, we observe that the plasma concentration of sC5b‐9, a reliable marker for terminal complement activation, is increased at steady state in 61% of untreated SCD patients. We show that greater complement activation in vitro is promoted by SCD erythrocytes compared to normal ones, although no significant differences were observed in the regulatory proteins CD35, CD55, and CD59 in whole blood. Complement activation is positively correlated with the percentage of dense sickle cells (DRBCs). The expression levels of CD35, CD55, and CD59 are reduced in DRBCs, suggesting inefficient regulation when cell density increases. Moreover, the surface expression of the complement regulator CD46 on granulocytes was inversely correlated with the plasma sC5b‐9. We also show increased complement deposition in cultured human endothelial cells incubated with SCD serum, which is diminished by the addition of the heme scavenger hemopexin. Treatment of SCD patients with hydroxyurea produces substantial reductions in complement activation, measured by sC5b‐9 concentration and upregulation of CD46, as well as decreased complement activation on RBCs in vitro. In conclusion, complement over activation is a common pathogenic event in SCD that is associated with formation of DRBCs and hemolysis. And, it affects red cells, leukocytes and endothelial cells. This complement over activation is partly alleviated by hydroxyurea therapy.

Alloimmunization against red blood cell antigens and delayed hemolytic transfusion reaction (DHTR) are major barriers to transfusion in sickle cell disease (SCD). In SCD, DHTR is a potentially life-threatening. Blood group polymorphism in SCD patients, who are of African ancestry and frequently exposed to antigens they do not carry; an inflammatory clinical state; and occasional transfusion in acute situations are risk factors for alloimmunization and DHTR. In patients at risk, the transfusion indication must be balanced against the risk of developing DHTR. However, when transfusion is absolutely necessary, protocols combining the prevention of exposure to immunogenic antigens with immunosuppressive treatments must be implemented, and patients should be carefully monitored during posttransfusion follow-up. This close monitoring makes it possible to diagnose hyperhemolysis as soon as possible; to avoid retransfusion, which can exacerbate hemolysis; and to administer specific treatments, such as anticomplement therapy, in severe cases. Finally, in patients with severe disease, hematopoietic stem cell transplantation may be indicated. However, transfusion is also required in this context, and its management is complex because these risks must be taken into account.