Response to “Features of Postpartum Hemorrhage-Associated Thrombotic Microangiopathy and Role of Short-Term Complement Inhibition”: Still a Long Way to Go

We read with interest the work entitled "Features of Postpartum Hemorrhage-Associated Thrombotic Microangiopathy and Role of Short-Term Complement Inhibition" (1Kaufeld J.K. Kühne L. Schönermarck U. Bräsen J.H. von Kaisenberg C. Beck B.B. et al.Features of Postpartum Hemorrhage-Associated Thrombotic Microangiopathy and Role of Short-Term Complement Inhibition.Kidney International Reports. 2024; ([Internet]. 23 janv)Abstract Full Text Full Text PDF Scopus (0) Google Scholar). The authors contend that patients in the post-partum presenting with thrombotic microangiopathy (TMA) may benefit from short-term C5 inhibition. Several lines of argumentation tend to mitigate this claim. First and foremost, no comparison is provided between patients who received C5 inhibition (72.5%) and those treated without these agents. Therefore, in the absence of a control group, the author's conclusion rests heavily on the assumption that the outcome of kidney function following postpartum TMA is poor. This hypothesis is not supported by the current literature. In one multicenter retrospective investigation reporting on patients with post-partum TMA, including pre-eclampsia (PE, n=33) and postpartum hemorrhage (PPH, n=20), Meibody et al recorded a median eGFR of 82 mL/min, 89.5 mL/min (86–92) at 12-month follow-up, respectively. None but 2 patients with PE received eculizumab (2Meibody F. Jamme M. Tsatsaris V. Provot F. Lambert J. Frémeaux-Bacchi V. et al.Post-partum acute kidney injury: sorting placental and non-placental thrombotic microangiopathies using the trajectory of biomarkers.Nephrol Dial Transplant. 1 sept. 2020; 35: 1538-1546Crossref PubMed Scopus (0) Google Scholar). In fact, the final kidney function course depended primarily on the occurrence of cortical necrosis with a median last follow-up eGFR of 6 mL/min (5-31). However, patients experiencing cortical necrosis would not be considered eligible to receive a complement inhibitor trial, given the potentially irreversible nature of kidney lesions, further narrowing down the expected gains from C5 inhibition. Finally, the understanding of the paper's results may fall within the scope of what authors have termed the "modifier gene" concept whereby the disease results from the interaction of genetic predisposition and a second "hit", in this case pregnancy and its complications (3Leon J. LeStang M.B. Sberro-Soussan R. Servais A. Anglicheau D. Frémeaux-Bacchi V. et al.Complement-driven hemolytic uremic syndrome.Am J Hematol. jan 2023; 22Google Scholar,4Nobile G. Doreille A. Raymond L. Robert T. Dancer M. Mesnard L. et al.Role of the I416L Variant of Complement Factor I in Thrombotic Microangiopathy Among Patients of African Ancestry.Kidney Int Rep. oct 2023; 8: 2136-2140Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). This conceptual framework is suggested by the supplementary appendix wherein the authors distinguish pathogenic variants from risk haplotypes. Unfortunately, not only is this assumption not spelled out explicitly, but the authors claim quite oppositely that none of the patients with PPH exhibited susceptibility variants. Pending robust clinical evidence, we the current use of complement inhibitors should be grounded on the implementation of fast track genetic testing to identify the small fraction of patients with pathogenic variants who have demonstrated proven benefit from these treatments in the short and long term (5Doreille A. Rafat C. Rondeau E. Mesnard L. How I treat thrombotic microangiopathy in the era of rapid genomics.Blood. 8 nov 2022; (blood.2022015583)Google Scholar). The interaction between coagulation and complement cascades in the management of thrombotic microangiopathies related to postpartum hemorrhageKidney International ReportsPreviewWe read with great interest the report by Kaufeld and colleagues who studied the impact of short-term complement inhibition in patients with thrombotic microangiopathy (TMA) associated with postpartum hemorrhage (PPH)1. We agree with the authors regarding the need to propose a pragmatic management model by presenting a real-world cohort of patients affected by this infrequent complication. Nonetheless, we believe that some aspects deserve further discussion.