Prethrombin-1 as a Drug Substance Promoting Hemostasis with Reduced Risk of Thrombosis.

IF 5 2区医学 Q1 HEMATOLOGY Thrombosis and haemostasis Pub Date : 2024-06-12 DOI:10.1055/s-0044-1787720

Johann Georg Graus, Michael Prückler, Helga Bergmeister, Christoph Mader, Alexandru Trefilov, Richard Gölles, Marianne Kunschak, Wolfgang Schramm

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Abstract

Introduction: Prethrombin-1 is a Gla-domain lacking enzymatically inactive split product that results from the cleavage of fragment 1 from prothrombin by thrombin in a feedback reaction.

Methods: A prethrombin-1 preparation derived from human plasma was tested for its hemostatic and thrombogenic properties. Animal models of nail clipping (for rabbits) and tail clipping (for mice) were developed to measure blood loss in FVIII-inhibitor or rivaroxaban anticoagulated rabbits and mice, respectively. A modified Wessler test was used in rabbits to assess the thrombogenic potential by Wessler score and clot weight. Studies were performed in groups of three to six for prethrombin-1 dose escalation and comparison with prothrombin, Beriplex®, FEIBA®, and saline as a control. Data were analyzed using t-statistics or the Mann Whitney U test as applicable.

Results: Prethrombin-1 has excellent hemostatic properties in anticoagulated mouse and rabbit bleeding models. Wessler tests suggest that in contrast to activated and nonactivated prothrombin complexes, prethrombin-1 has negligible thrombogenic potential.

Conclusion: The thrombin zymogen prethrombin-1 promotes hemostasis with reduced risk of thrombosis. Prethrombin-1 may have potential to become a life-saving treatment for patients who bleed or are at risk of bleeding.

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前凝血酶原-1 作为一种药物物质，可促进止血并降低血栓形成的风险。

导言：凝血酶原-1 是凝血酶在反馈反应中裂解凝血酶原片段 1 后产生的一种缺乏酶活性的 Gla-domain分裂产物：方法：对从人血浆中提取的凝血酶原-1制剂进行了止血和血栓形成特性测试。建立了剪指甲（兔子）和剪尾巴（小鼠）的动物模型，分别测量 FVIII 抑制剂或利伐沙班抗凝兔子和小鼠的失血量。对兔子采用改良的韦斯勒试验，通过韦斯勒评分和血块重量评估血栓形成的可能性。研究以三至六只为一组，进行凝血酶原-1剂量递增，并与凝血酶原、贝瑞普力®、FEIBA®和作为对照的生理盐水进行比较。数据分析采用t统计或曼-惠特尼U检验（Mann Whitney U test）：结果：凝血酶原-1 在抗凝小鼠和兔出血模型中具有优异的止血性能。韦斯勒试验表明，与活化和非活化凝血酶原复合物相比，凝血酶原-1 的致血栓潜力可以忽略不计：结论：凝血酶原酶原凝血酶原-1能促进止血，降低血栓形成的风险。凝血酶原-1 有可能成为挽救出血患者或有出血风险的患者生命的一种治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Thrombosis and haemostasis 医学-外周血管病

CiteScore

11.90

自引率

9.00%

发文量

140

审稿时长

1 months

期刊介绍： Thrombosis and Haemostasis publishes reports on basic, translational and clinical research dedicated to novel results and highest quality in any area of thrombosis and haemostasis, vascular biology and medicine, inflammation and infection, platelet and leukocyte biology, from genetic, molecular & cellular studies, diagnostic, therapeutic & preventative studies to high-level translational and clinical research. The journal provides position and guideline papers, state-of-the-art papers, expert analysis and commentaries, and dedicated theme issues covering recent developments and key topics in the field.