Metabolism-mediated thrombotic microangiopathy and B12

Goubran, Hadi; Ragab, Gaafar; Sabry, Waleed

doi:10.1016/bs.vh.2022.01.002

Cited by 1 publication

(1 citation statement)

References 49 publications

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“…The last process evaluated, hyperhomocysteinemia, while being reported to be associated to TMA in other settings 53 has not been shown in our results as being part of the TMA mechanisms induced by “emicizumab plus aPCC”. The mechanisms linking hyperhomocysteinemia with TMA, while not fully understood, involve abnormal red cell and platelet production and endothelial dysfunction 54 which, although ultimately linked to the existence of a hypercoagulable state 55 , 56 , might affect upstream of the mechanisms predicted for “emicizumab plus aPCC”.…”

Section: Discussionmentioning

confidence: 99%

Application of systems biology to identify pharmacological mechanisms of thrombotic microangiopathy evoked by combined activated prothrombin complex concentrate and emicizumab

Valls

Wagg

Paz‐Priel³

et al. 2023

Sci Rep

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Emicizumab is a bispecific monoclonal antibody that substitutes for the function of missing or deficient factor VIII (FVIII) in people with hemophilia A (PwHA). Long-term safety and efficacy of emicizumab have been demonstrated in several clinical trials. Nevertheless, in the first of these, three cases of thrombotic microangiopathy (TMA) occurred in PwHA treated with emicizumab receiving high doses of activated prothrombin complex concentrate (aPCC), a bypassing agent used for treating breakthrough bleeds when FVIII neutralizing antibodies (inhibitors) make FVIII replacement ineffective. The aim of the present work is to offer a method to elucidate the pathophysiological and pharmacological mechanisms involved in this treatment-induced TMA. Systems biology and machine learning-based Therapeutic Performance Mapping System is a validated in silico technology that allowed us to construct models of potential mechanisms behind induced TMA. Two drug combinations were modeled and assessed: emicizumab plus aPCC and emicizumab plus recombinant activated factor VII (another bypassing agent). Our models showed that both combinations were related to activation of the coagulation cascade. However, mechanisms involved mainly in platelet activation and possibly in complement activation were detected only for emicizumab plus aPCC, potentially explaining the occurrence of TMA only in this combination.

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