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Red cell transfusion and alloimmunization in SCD
C/c, E/e, K, Jka/Jkb, Fya/Fyb, and S/s is recommended.2 Many patients improve with hydration, oxygen support, and pain management alone, but others develop severe complica- tions such as ACS and multiorgan failure.76 Erythropoietin with or without intravenous iron is an additional support- ive measure. High-dose steroids and intravenous immunoglobulins are suggested first-line therapy for patients with severe DHTR or ongoing hemolysis, although caution must be maintained, as high-dose steroids have been associated with rebound symptoms and worsening vaso-occlusive episodes.2,82,83 Prophylactic treatment with steroids and intravenous immunoglobulins prior to transfu- sion should be considered for patients with a history of multiple or life-threatening DHTR or for those for whom compatible blood is not available. Rituximab, an anti-CD20 monoclonal antibody, can be used to reduce the risk of fur- ther alloimmunization when future transfusion is likely and may be employed as a prophylactic therapy prior to trans- fusion for patients with a history of multiple or severe DHTR.83
There is growing evidence that the complement pathway plays a pivotal role in the pathogenesis of DHTR. Alloantibody-antigen complexes activate the classical com- plement pathway. Free heme and hemoglobin trigger the alternative complement pathway, leading to endothelial damage and organ injury.84,85 Eculizumab, a monoclonal anti-C5 antibody targeting terminal complement activation, has been used as salvage therapy in cases of severe DHTR and hyperhemolysis.85-92 Case reports have also described treatment of hyperhemolysis with tocilizumab, a mono- clonal antibody against the interleukin-6 receptor.93-95 These cases showed marked improvement after targeted anti- interleukin-6 receptor therapy, suggesting that blockade of macrophage activation may be an effective treatment strat- egy. Table 2 summarizes published reports describing use of eculizumab and tocilizumab in patients with SCD.
DHTR are associated with high mortality, underscoring the importance of early recognition and treatment, but pre- vention is key.80 Red cell exposure should be minimized by transfusing only for evidence-based indications.2 All patients should be prophylactically matched for Rh (C, E or C/c, E/e) and K antigens. Patients at high risk of DHTR should be identified and transfusions avoided or delivered with immunomodulatory agents as possible.2,80 Incomplete transfusion and alloantibody histories contribute to the incidence of DHTR. Most countries lack national transfu- sion databases, so patients should be encouraged to make new providers aware of their transfusion history and limit transfusions to one institution, if possible.
Iron overload
Each milliliter of transfused red cells contains 0.8-1 mg of iron. Transfusion of 3-5 units of packed red cells delivers 1 g of iron, a significant burden considering the total body iron of an average adult is 4-5 g. The human body has no mechanisms for excreting excess iron. While small amounts of iron are lost through the gastrointestinal tract and skin, iron homeostasis is primarily regulated by hepcidin, a pro- tein synthesized by the liver in response to iron overload and inflammation.96 Hepcidin inhibits dietary iron absorp- tion and blocks iron recycling through the reticuloendothe- lial system. Transfusional iron is delivered outside of these normal regulatory mechanisms, and there are no means of eliminating large amounts of iron from transfusion.
In SCD, iron accumulation is most prominent in the liver. Compared to thalassemia patients with equivalent transfu- sion volumes, patients with SCD are less vulnerable to iron overload-induced endocrinopathies and heart failure; how- ever, iron cardiomyopathy is detectable in 2.5% of SCD patients receiving chronic transfusion therapy.97,98 Iron toxi- city is estimated to contribute to 7-11% of deaths in patients with SCD.99,100
Table 2. Reports of studies investigating eculizumab and tocilizumab for the treatment of delayed hemolytic transfusion reactions and hyperhe- molysis in patients with sickle cell disease.
Study
Boonyasampant et al. 2015
Dumas et al. 2016 Chonat et al. 2018
Vlachaki et al. 2018 Unnikrishnan et al. 2019 Chonat et al. 2020 Floch et al. 2020
Mpinganzima et al. 2020 Sivapalaratnam et al. 2019
Lee et al. 2020
Hair et al. 2021
Drug investigated
Eculizumab
Eculizumab
Eculizumab Eculizumab Eculizumab Eculizumab Eculizumab
Eculizumab Tocilizumab
Tocilizumab
Eculizumab and
Dose
1200 mg weekly x 4 weeks followed by every 2 weeks for 2 more doses
900 mg x 2 dosed 1 week apart
600mgx2 900mgx1 900mgx1
600 mg weekly x 4 weeks 1-3 doses
900 mg x 2 dosed 6 days apart 8 mg/kg daily x 2 days
8 mg/kg daily x 4 days
900 mg x 3
8 mg/kg x 1
Number of patients
1
3
1 1 1 1 18
1 1
1
1
Adverse events
None reported
1 death secondary to
severe pulmonary infection None reported
None reported
None reported
None reported
3 patient deaths (2 from complications of encapsulated bacterial infection)
None reported None reported
Seizure (in the setting of methemoglobinemia secondary to hemoglobin-based oxygen carrier)
None reported
Tocilizumab
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