A monthly roundup of key articles in other journals

Genotyped RHD+ red cells for D-positive patients with sickle cell disease with conventional RHD and unexpected anti-D. Chou ST, Mewha J, Friedman DF, et al., Blood. 2024; epub ahead of print. Genotyping donors could alleviate risks associated with transfusing patients with sickle cell disease while conserving supplies of rare Rh-negative blood. In patients with sickle cell disease (SCD), regular transfusion can drive alloimmunization. When these patients have conventional RHD alleles, exposure to variant D antigens from Black donors may trigger anti-D formation. Anti-D variant antibodies generally subside within a few months, at which point the patients could theoretically return to receiving (non-variant) D-positive units; however, there is lingering concern around the possibility of recurrence. Chou et al. hypothesized that alloimmunization in patients with conventional RHD variants was the result of an immune response mounted against a D-like structural epitope expressed on donor blood cells, and that donor RHD genotyping could mitigate the risk of secondary immunization in this population. To explore this hypothesis, the team recruited five patients with SCD, with conventional RHD variants, on chronic red cell exchange, and with a history of anti-D. Participants were transfused with RHD-genotyped red blood cells (RBCs) from donors who self-identified as Black. For the first two visits, all participants received one D+ RHD genotyped unit, increasing incrementally by one at each subsequent visit until they reached a maximum of six D+ units by visit 7. The cumulative total number of D+ RHD genotyped RBCs transfused over the study period ranged from 11 to 22. Of the total 72 D+ units transfused over the study, 62 were from donors who had conventional RHD, five were homozygous for a variant encoding a one amino acid change that does not result in loss or alteration of a clinically relevant epitope (RHD*DAU0), and five were heterozygous for this variant and conventional RHD. None of the patients showed reemergence of anti-D antibodies while receiving red cell exchange using units from genotyped donors. One patient did develop unexpected anti-E and one developed anti-C, both of which were likely due to donor variant alleles. There was no notable difference in hemoglobin and sickle hemoglobin levels when comparing the red cell exchanges performed under this study and the six that occurred prior to study enrollment, indicating that cell survival was not negatively impacted. While the study only tracked a small number of patients for a relatively short period of time, the findings indicate that patients with resolved anti-D due to transfusion with D-variant units can be safely returned to D-positive transfusion protocols by genotyping both the patient and donors. This approach could have a beneficial impact for rare blood inventories. ♦♦♦ Restrictive versus liberal transfusion in patients with type 1 or type 2 myocardial infarction: a prespecified analysis of the myocardial ischemia and transfusion (MINT) trial. DeFilippis AP, Abbott JD, Herbert BM, et al. Circulation. 2024; epub ahead of print. The potential risk of harm of a restrictive transfusion strategy observed in the Myocardial Ischemia and Transfusion (MINT) trial is driven by patients with type 1 myocardial infarction. In the MINT trial, patients with type 1 or type 2 myocardial infarction and randomized to a restrictive transfusion strategy had a relative risk of myocardial infarction or death of 1.15 (95% confidence interval (CI), 0.99 to 1.34; p = 0.07) compared with those randomized to a liberal approach. But type 1 and type 2 myocardial infarction involve distinct pathophysiologies and may thus exhibit different responses and susceptibilities to transfusion. DeFilippis et al. report a prespecified subgroup analysis of the MINT trial, stratifying patients by myocardial infarction type. The enrolled population included 1460 patients with type 1 and 1955 patients with type 2 myocardial infarction. Baseline characteristics were largely balanced across the two groups, but patients with type 2 myocardial infarction had more chronic illness including a history of anemia and had a lower rate of prior coronary artery disease. The primary outcome of all-cause death or nonfatal myocardial infarction at 30 days occurred at similar rates in patients with type 1 and type 2 myocardial infarction (16.0% vs. 15.4%, p = .64). In patients with type 1 myocardial infarction, the primary outcome occurred at a higher rate in patients randomized to a restrictive strategy (18.2% vs. 13.8%; RR 1.32, 95% confidence interval [CI] 1.04–1.67), consistent with the overall findings in the MINT trial. All-cause death, cardiac death at 30 days, and cardiac death at 6 months were also higher in the restrictive arm. In contrast, there were no significant differences in any of the primary or secondary outcomes in patients with type 2 myocardial infarction assigned to a restrictive versus liberal strategy. Nonetheless, the statistical test for a differential effect of transfusion strategy by myocardial infarction type was not significant (interaction = 0.16). In summary, the MINT data suggest consideration of a liberal transfusion approach among patients with type 1 myocardial infarction. ♦♦♦ Improving normothermic machine perfusion and blood transfusion through biocompatible blood silicification. Lei C, Lia Z, Mab S, et al. Proc Natl Acad Sci USA. 2024; 121(35): e2322418121. Biosilicification can shield RBCs from immunological and environmental damage without negatively impacting mechanical, structural, and oxygen carrying capacity. Normothermic machine perfusion (NMP) of donor organs increases their longevity and transplantation success rate. The oxygen carriers that are pumped through the tissues throughout this process can be artificial (i.e., hemoglobin-based carriers) or natural (RBCs) each of which has strengths and weaknesses. With the goal of improving the suitability of RBCs for NMP by decreasing antigen cross-reactivity and improving cryopreservation, Lei et al. biosilicified RBCs, generating a universal, scalable technology. Silicified RBCs (Si-RBCs) showed biological properties almost identical to native RBCs. Si-RBCs deformability (shear modulus, bending rigidity, and surface-to-volume ratio)—crucial for flow through capillaries—remained similar to that observed in native RBCs as was stretching response to external tensile forces. There was a small increase in rigidity, however, this did not notably impact flow. The silica coat effectively shielded RBCs following exposure to hemolytic toxins and protected cells against mechanical damage induced by freeze-thaw cycles. Following exposure to liquid nitrogen for 2 h and a slow thaw, native RBCs demonstrated a recovery rate of 38.1% compared with 96.9% for the Si-RBCs. The silica shield also abrogated agglutination mediated by anti-A, anti-B, or anti-D. In animal models including rabbit, mouse, and rat, the silicification process abolished molecular antibody-antigen recognition and its accompanying immune response and showed similar oxygen carrying capacity and safety profiles as native RBCs. Lastly, the authors evaluated xenotransfusion of human blood into mice. Native RBCs drove a demonstrable increase in ALT and AST in the serum indicating hepatocellular disease. The magnitude of this effect was approximately three times lower following transfusion with Si-RBCs. In a 20% transfusion experiment, both Si-RBC transfusion and PBS controls showed normal physiological signs and good biosafety, whereas transfusion with native RBCs resulted in liver damage and inflammation. In sum, Si-RBCs escape immune activation while maintaining oxygen transport function, providing universal compatibility in a simple, reliable, and scalable format. ♦♦♦ Efficacy and safety of daratumumab in multiresistant immune-mediated thrombotic thrombocytopenic purpura. Weisinger J, Bouzid R, Ranta D, et al. Br J Haematol. 2024; epub ahead of print. In a small case series of treatment-refractory patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), daratumumab shows durable efficacy. There is a lack of robust evidence to support effective treatment options in patients with iTTP and refractory to rituximab. While the role of plasma cells in iTTP pathogenesis is not well-established, case reports indicate that daratumumab—a monoclonal anti-CD38 antibody—may be a useful addition to the armament. Here, Weisinger et al. describe the clinical course of seven patients with multiresistant iTTP treated with daratumumab. The French Thrombotic Microangiopathies Reference Center identified four female and three male patients with iTTP who were considered refractory to rituximab and other immunosuppressive therapies and had been treated with daratumumab while in clinical response (preemptively; n = 8) or during acute disease (n = 1) (median age = 62 years; median three prior lines of therapy). Six of the individuals had ADAMTS13 levels in the undetectable range at daratumumab initiation, the seventh patient had an ADAMTS13 activity level of 22%. Prior to daratumumab administration, five patients had detectable anti-ADAMTS13 antibodies. Daratumumab regimens were not standardized; a median of six infusions were given per patient, with one patient continuing on monthly infusions at the time of analysis. The cohort of seven patients experienced nine daratumumab-treated iTTP episodes over the study period. Three patients showed complete recovery; a partial recovery was observed in five of the episodes; and one patient failed to show a response. The estimated median time to ADAMTS13 response after daratumumab administration was 28 days. Following initial response to daratumumab, two of the cohort experienced three relapses. Both of these patients had shown no response to rituximab, previously. At 12 months, median relapse-free survival was 56%. Daratumumab-related adverse events were recorded in five cases, all of which were infusion reactions. No severe or unexpected adverse reactions were reported. The results support further investigations of treatment strategies targeting plasma cells in patients who are refractory to B-cell depleting therapy. Further work is needed to confirm the findings and identify optimal regimens. ♦♦♦ Major reduction in occurrence of anti-c and anti-E in pregnancy after more than 10 years of preventive matched transfusion with most benefit for c-matching. Luken JS, Folman CC, Meekers JH, et al., Br J Haematol. 2024; 205(4): 1599–1604. Implementing a cE-matched transfusion policy in women under 45 years old may reduce the incidence of anti-c and anti-E, with implications for rates of hemolytic disease of the fetus and newborn (HDFN). Matching for common blood cell surface antigens can reduce the risk of developing HDFN in at-risk women. In 2004, the Netherlands introduced guidelines recommending K-negative units for transfusion in women under 45 years old. These guidelines were extended in 2011 to include preventative c- and E- matching. Luken et al. performed an observational cohort study to determine the impact of this recommendation. Data were obtained from a national screening program encompassing 4 million pregnant women in their first trimester between 2002 and 2022. In total, anti-c was detected in 1428 pregnancies; anti-E in 3662; and both anti-c and anti-E were identified in 456 pregnancies. The incidence of anti-c, anti-E, and reference antibodies decreased across the study period. Between 2002–2004, anti-c occurred at a rate of 46.8 per 100,000 pregnancies, decreasing to 30.4 per 100,000 between 2020–2022 (RR 0.65, 95% CI 0.54–0.7). The decrease in anti-c was strongest in pregnancies by a c-negative father, suggesting that c-matching was responsible for the change. Anti-E also decreased over this period, from 122.1 per 100,000 to 89.9 per 100,000 (RR 0.74, 95% CI 0.66–0.84). Again, the decrease in anti-E was highest for pregnancies with an E-negative father. Because anti-E can also occur without prior exposure, the authors adjusted the observed rates according to the calculated prevalence of naturally occurring anti-E (45.9/100,000 in D-negative pregnancies). A slightly greater magnitude of reduction remained (decreasing from 76.2/100,000 in 2002–2004 to 44/100,000 in 2020–2022 [RR 0.56, 95% CI 0.48–0.67]). The occurrence of anti-E was highest in women with a c-negative phenotype (CCDee) between 2002–2004, and this group saw the greatest reduction in anti-E following implementation of matching (decreasing from 244.2 to 149.2 [RR 0.61, 95% CI 0.50–0.74]). Furthermore, in women with the CCDee phenotype the decrease in combined anti-c and anti-E was greater than anti-E and anti-c alone. In sum, extension of Dutch guidelines for transfusion in women under 45 years old resulted in a decreased rate of alloimmunization, and thus a decreased risk of developing HDFN in pregnancy.