Antiplatelet-anticoagulant, APAC, a mimic of endogenous heparin, is an antithrombotic with von Willebrand factor-mediated characteristics

IF 3.7 3区医学 Q1 HEMATOLOGY

Thrombosis research Pub Date : 2025-04-12 DOI:10.1016/j.thromres.2025.109318

Annukka Jouppila , Ilja Nevola , Marja Lemponen , Tomi Mattila , Riitta Lassila

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引用次数: 0

Abstract

Background

We have conjugated selected number of unfractionated heparin (UFH) chains to human albumin core to mimic mast-cell heparin proteoglycans (HEP-PG). Indeed, APAC, dual antiplatelet and anticoagulant, as HEP-PG, has inhibited collagen- (CIPA) and thrombin-induced platelet aggregation, being simultaneously an anticoagulant. In several animal models of arterial thrombosis, APAC has provided vascular-injury-associated local antithrombotic properties mediated by von Willebrand factor (VWF).

Aims

We compared the structure-function effects of APAC with those of UFH in vitro, and when supplemented in blood studied platelet and VWF-dependency and anticoagulation.

Methods

We assessed the total thrombosis formation analysis system (T-TAS) and coagulation (rotational thromboelastometry, ROTEM) in blood, and thrombin generation and aggregation in platelet-rich plasma. We studied aggregation responses of APAC to collagen, ristocetin, ADP, and potential synergism with cangrelor, P2Y12 receptor antagonist. Finally, heparin-neutralizing role of platelet factor 4 (PF4) on antiplatelet and anticoagulant functions of APAC was investigated.

Results

APAC concentration-dependently exceeded the anticoagulant and antithrombotic action of UFH in ROTEM, and platelet thrombus formation under arterial blood flow over collagen/tissue factor. APAC uniquely inhibited CIPA. While ADP- and ristocetin-induced aggregation were unaffected by APAC, we detected synergism with cangrelor for CIPA. Disruption of the tertiary structure of APAC reverted its mode of action to anticoagulation only, alike UFH. PF4 neutralized antithrombotic actions of APAC.

Conclusion

The structure-function of APAC conveys dual and unique antiplatelet and anticoagulant actions in flowing blood over collagen and beyond. Our studies confirmed the inhibitory role of APAC on VWF functions and fibrin formation.

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抗血小板抗凝剂，APAC，内源性肝素的模拟物，是一种具有血管性血友病因子介导特性的抗血栓药

我们已经将一些未分离的肝素（UFH）链偶联到人白蛋白核心，以模拟肥大细胞肝素蛋白多糖（HEP-PG）。事实上，APAC，双重抗血小板和抗凝剂，如HEP-PG，抑制胶原蛋白（CIPA）和凝血酶诱导的血小板聚集，同时是一种抗凝剂。在几种动脉血栓形成的动物模型中，APAC提供了由血管性血友病因子（VWF）介导的血管损伤相关的局部抗血栓特性。目的比较APAC与UFH在体外的结构-功能作用，并在血液中添加APAC后，研究APAC对血小板和vwf的依赖性及抗凝作用。方法评价血中总血栓形成分析系统（T-TAS）和凝血（旋转血栓弹性测量，ROTEM），以及富血小板血浆中凝血酶的产生和聚集。我们研究了APAC对胶原蛋白、瑞斯托霉素、ADP的聚集反应，以及与P2Y12受体拮抗剂canrelor的潜在协同作用。最后，探讨血小板因子4 （PF4）对APAC抗血小板和抗凝功能的肝素中和作用。结果在ROTEM中，apac浓度依赖性地超过了UFH的抗凝和抗血栓作用，并在动脉血流超过胶原/组织因子的情况下形成血小板血栓。亚太地区独有地抑制CIPA。虽然ADP和里斯托司汀诱导的聚集不受APAC的影响，但我们发现了与康格乐对CIPA的协同作用。APAC三级结构的破坏使其作用模式恢复为抗凝血，类似于UFH。PF4中和APAC的抗血栓作用。结论APAC具有独特的抗血小板和抗凝血双重功能。我们的研究证实了APAC对VWF功能和纤维蛋白形成的抑制作用。

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 research 医学-外周血管病

CiteScore

14.60

自引率

4.00%

发文量

364

审稿时长

31 days

期刊介绍： Thrombosis Research is an international journal dedicated to the swift dissemination of new information on thrombosis, hemostasis, and vascular biology, aimed at advancing both science and clinical care. The journal publishes peer-reviewed original research, reviews, editorials, opinions, and critiques, covering both basic and clinical studies. Priority is given to research that promises novel approaches in the diagnosis, therapy, prognosis, and prevention of thrombotic and hemorrhagic diseases.