Concomitant administration of emicizumab and activated prothrombin complex concentrate (aPCC) may activate the coagulation cascade and lead to thrombotic microangiopathy (TMA) in patients with hemophilia A, according to an article published in Scientific Reports.
The aim of the study was to investigate the pathophysiological and pharmacological mechanisms underlying the occurrence of TMA reported in hemophilia patients treated with emicizumab and prothrombin complex concentrate.
The researchers used systems biology and the machine learning-based Therapeutic Performance Mapping System, a validated in silico technology, to construct models of potential mechanisms behind treatment-induced TMA.
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The following drug combinations were analyzed: emicizumab and aPCC as well as emicizumab and recombinant activated factor VII. Both aPCC and recombinant activated factor VII are used to treat breakthrough bleeds when factor VIII neutralizing antibodies (inhibitors) make factor VIII replacement ineffective.
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According to the results, both drug combinations may cause the activation of the coagulation cascade. However, only the mix of emicizumab and aPCC triggered mechanisms involved in platelet activation and possibly complement activation.
“Although bypassing agents are indicated for both prophylaxis and bleeding episodes, the use of more than 100 U/kg/24 h of aPCC for 24 h or more for people with hemophilia A on emicizumab should be avoided, and recombinant activated factor VII should be the first option used to treat bleeds,” Valls and colleagues noted.
“Our insights into the underlying mechanisms involved in drug-induced TMA may be used to inform the design of targeted experimental studies, which will further assess the specific effects of “emicizumab plus aPCC” on the activities of the proteins identified explicitly as modified by this combination, and how these changes mechanistically drive TMA.”
Emicizumab is a bispecific monoclonal antibody that acts as a substitute for the missing or deficient factor VIII in patients with hemophilia A. Its long-term efficacy and safety have been demonstrated in many clinical trials.
Reference
Valls R, Wagg J, Paz-Priel I, et al. Application of systems biology to identify pharmacological mechanisms of thrombotic microangiopathy evoked by combined activated prothrombin complex concentrate and emicizumab. Sci Rep. Published online June 21, 2023. doi:10.1038/s41598-023-36891-x
