Institute for Immunology and Transfusion Medicine, University Medicine of Greifswald, 17475 Greifswald, Germany.
ZIK HIKE-Center for Innovation Competence, Humoral Immune Reactions in Cardiovascular, 17489 Greifswald, Germany.
Int J Mol Sci. 2018 Apr 2;19(4):1054. doi: 10.3390/ijms19041054.
For the last two decades, heparins have been widely used as anticoagulants. Besides numerous advantages, up to 5% patients with heparin administration suffer from a major adverse drug effect known as heparin-induced thrombocytopenia (HIT). This typical HIT can result in deep vein thrombosis, pulmonary embolism, occlusion of a limb artery, acute myocardial infarct, stroke, and a systemic reaction or skin necrosis. The basis of HIT may lead to clinical insights. Recent studies using single-molecule force spectroscopy (SMFS)-based atomic force microscopy revealed detailed binding mechanisms of the interactions between platelet factor 4 (PF4) and heparins of different lengths in typical HIT. Especially, SMFS results allowed identifying a new mechanism of the autoimmune HIT caused by a subset of human-derived antibodies in patients without heparin exposure. The findings proved that not only heparin but also a subset of antibodies induce thrombocytopenia. In this review, the role of SMFS in unraveling a major adverse drug effect and insights into molecular mechanisms inducing thrombocytopenia by both heparins and antibodies will be discussed.
在过去的二十年中，肝素被广泛用作抗凝剂。尽管肝素具有许多优点，但高达 5%的肝素使用者会出现一种称为肝素诱导的血小板减少症（HIT）的严重药物不良反应。这种典型的 HIT 可导致深静脉血栓形成、肺栓塞、肢体动脉闭塞、急性心肌梗死、中风以及全身性反应或皮肤坏死。HIT 的基础可能会导致临床洞察。最近使用基于单分子力谱（SMFS）的原子力显微镜的研究揭示了典型 HIT 中血小板因子 4（PF4）与不同长度肝素之间相互作用的详细结合机制。特别是，SMFS 结果证明了一种新的机制，即由患者体内无肝素暴露的一部分人类来源的抗体引起的自身免疫性 HIT。这些发现证明，不仅肝素，而且一部分抗体也会导致血小板减少症。在这篇综述中，将讨论 SMFS 在揭示主要药物不良反应以及肝素和抗体诱导血小板减少症的分子机制方面的作用。
