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<p>With the advent of complement inhibition therapy, the severe thrombotic complications of paroxysmal nocturnal hemoglobinuria (PNH)—once described as the most vicious acquired thrombophilic state—no longer pose the same imminent clinical threat. Nevertheless, thrombotic events still occur, albeit at much lower frequency, raising both clinical and mechanistic questions. Among the most pressing are: Under what circumstances does anti-complement therapy fail to prevent thrombosis, and which patient- or therapy-specific factors contribute to this risk? When and where should anticoagulation, anti-platelet therapy, or even prophylaxis be considered? At a mechanistic level, what are the drivers of complement-mediated thrombosis in PNH, and how do they differ from those in other thrombotic conditions involving complement activation? This review addresses these questions by summarizing current evidence on complement-induced thrombosis, integrating clinical and experimental findings. It highlights unresolved issues, including when complement blockade is insufficient and explores the distinction between complement-driven thrombotic states, such as PNH, and intrinsic complement-related diseases without thrombotic complications, such as C3 glomerulopathy. Finally, it proposes a pragmatic framework for anticoagulation and prophylaxis and provides an outlook on critical directions for basic and clinical research, with the goal of further elucidating the complex interplay between complement activation and thrombosis.</p>

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Thrombosis in paroxysmal nocturnal hemoglobinuria in the complement inhibitor era: mechanisms, risk stratification, and clinical management

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Bruno Fattizzo,
  • Christoph Q. Schmidt

摘要

With the advent of complement inhibition therapy, the severe thrombotic complications of paroxysmal nocturnal hemoglobinuria (PNH)—once described as the most vicious acquired thrombophilic state—no longer pose the same imminent clinical threat. Nevertheless, thrombotic events still occur, albeit at much lower frequency, raising both clinical and mechanistic questions. Among the most pressing are: Under what circumstances does anti-complement therapy fail to prevent thrombosis, and which patient- or therapy-specific factors contribute to this risk? When and where should anticoagulation, anti-platelet therapy, or even prophylaxis be considered? At a mechanistic level, what are the drivers of complement-mediated thrombosis in PNH, and how do they differ from those in other thrombotic conditions involving complement activation? This review addresses these questions by summarizing current evidence on complement-induced thrombosis, integrating clinical and experimental findings. It highlights unresolved issues, including when complement blockade is insufficient and explores the distinction between complement-driven thrombotic states, such as PNH, and intrinsic complement-related diseases without thrombotic complications, such as C3 glomerulopathy. Finally, it proposes a pragmatic framework for anticoagulation and prophylaxis and provides an outlook on critical directions for basic and clinical research, with the goal of further elucidating the complex interplay between complement activation and thrombosis.