Thrombosis and platelet activation play a central role in stroke pathogenesis, and antiplatelet and anticoagulant therapies are central to stroke prevention. However, whether haematological traits contribute equally to all ischaemic stroke subtypes is uncertain. Furthermore, identification of associations with new traits may offer novel treatment opportunities. The aim of this research was to ascertain causal relationships between a wide range of haematological traits and ischaemic stroke and its subtypes. We obtained summary statistics from 27 published genome-wide association studies of haematological traits involving over 375 000 individuals, and genetic associations with stroke from the MEGASTROKE Consortium (n = 67 000 stroke cases). Using two-sample Mendelian randomization we analysed the association of genetically elevated levels of 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells) and 49 haemostasis traits (including clotting cascade factors and markers of platelet function) with risk of developing ischaemic (AIS), cardioembolic (CES), large artery (LAS), and small vessel stroke (SVS). Several factors on the intrinsic clotting pathway were significantly associated (P < 3.85 × 10-4) with CES and LAS, but not with SVS (e.g. reduced factor VIII activity with AIS/CES/LAS; raised factor VIII antigen with AIS/CES; and increased factor XI activity with AIS/CES). On the common pathway, increased gamma (γ') fibrinogen was significantly associated with AIS/CES. Furthermore, elevated plateletcrit was significantly associated with AIS/CES, eosinophil percentage of white cells with LAS, and thrombin-activatable fibrinolysis inhibitor activation peptide antigen with AIS. We also conducted a follow-up analysis in UK Biobank, which showed that amongst individuals with atrial fibrillation, those with genetically lower levels of factor XI are at reduced risk of AIS compared to those with normal levels of factor XI. These results implicate components of the intrinsic and common pathways of the clotting cascade, as well as several other haematological traits, in the pathogenesis of CES and possibly LAS, but not SVS. The lack of associations with SVS suggests thrombosis may be less important for this stroke subtype. Plateletcrit and factor XI are potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their possible aetiological roles.

中文翻译：

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血液学特征在缺血性中风及其亚型风险中的作用。

血栓形成和血小板活化在中风发病机制中发挥着核心作用，抗血小板和抗凝治疗是中风预防的核心。然而，血液学特征是否对所有缺血性卒中亚型的影响相同尚不确定。此外，识别与新特征的关联可能提供新的治疗机会。本研究的目的是确定多种血液学特征与缺血性中风及其亚型之间的因果关系。我们从 MEGASTROKE 联盟（n = 67 000 例中风病例）中获得了 27 项已发表的涉及超过 375 000 名个体的血液学特征的全基因组关联研究的汇总统计数据，以及与中风的遗传关联。使用两个样本孟德尔随机化，我们分析了 36 种血细胞性状（血小板、成熟/未成熟红细胞和骨髓/淋巴/复合白细胞）和 49 种止血性状（包括凝血级联因子和血小板标记物）遗传升高水平的关联。功能），有发生缺血性（AIS）、心源性栓塞（CES）、大动脉（LAS）和小血管卒中（SVS）的风险。内在凝血途径上的几个因素与 CES 和 LAS 显着相关（P < 3.85 × 10-4），但与 SVS 无关（例如，AIS/CES/LAS 降低因子 VIII 活性；AIS/CES 升高因子 VIII 抗原；并通过 AIS/CES 增加因子 XI 活性）。在共同途径上，γ (γ') 纤维蛋白原增加与 AIS/CES 显着相关。此外，升高的血小板压积与AIS/CES、LAS白细胞中的嗜酸性粒细胞百分比以及AIS的凝血酶可激活的纤溶抑制剂激活肽抗原显着相关。我们还在英国生物银行进行了一项后续分析，结果表明，在房颤患者中，与 XI 因子水平正常的人相比，XI 因子基因水平较低的人患 AIS 的风险较低。这些结果暗示了 CES 和可能的 LAS（但不是 SVS）发病机制中凝血级联的内在和常见途径的组成部分，以及其他几种血液学特征。与 SVS 缺乏关联表明血栓形成对于这种中风亚型可能不太重要。血小板比容和因子 XI 是缺血性中风二级预防的潜在易处理的新靶标，而因子 VIII 和 γ' 纤​​维蛋白原需要进一步基于人群的研究来确定其可能的病因学作用。