The Effects of the Contact Activation System on Hemorrhage.
The Effects of the Contact Activation System on Hemorrhage.
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DOI：
10.3389/fmed.2017.00121
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发表时间：
2017
影响因子：
3.9
通讯作者：
Feener EP
中科院分区：
文献类型：
--
作者：
Simão F;Feener EP
接触激活系统（CAS）通过多种机制对凝血产生影响，调节内在和外在凝血级联以及纤维蛋白溶解和血小板活化。虽然 CAS 对凝血的影响（以活化部分凝血活酶时间缩短来衡量）已有充分记录，但导致血浆前激肽释放酶 (PPK) 或因子 XII (FXII) 表达缺陷的基因突变与自发性出血或手术期间出血风险增加无关。这些蛋白质的缺陷往往几十年来都未被诊断出来，并在以后的常规凝血检测中被发现，没有明显的临床表型。人们对 CAS 作为抗血栓治疗的潜在安全靶标越来越感兴趣，这在很大程度上来自对诱发血栓形成的动物模型的研究，这些研究表明 PPK 或 FXII 的缺陷可以减少血栓形成，而不增加出血。对健康动物的基因靶向和药理学研究已证实 PPK 和 FXII 阻断不会引起凝血病。这些发现支持以下结论：止血不需要 CAS。然而，虽然 FXII 和 PPK 的缺陷不会显着影响与周围伤口相关的出血，但最近的报告表明这些蛋白质可以促进视网膜和大脑的出血。玻璃体内注射血浆激肽释放酶（PKal）会引起视网膜出血，脑内注射PKal会增加颅内出血。 PPK 缺乏和 PKal 抑制可改善糖尿病动物脑血管损伤后血肿的形成。此外，PPK 和 FXII 缺陷对血栓性大脑中动脉闭塞小鼠的组织纤溶酶原激活剂介导的溶栓治疗引起的脑出血具有保护作用。因此，虽然 CAS 不是止血所必需的，但它的抑制可能提供减少视网膜和大脑出血的机会。与 CAS 对出血影响相关的机制和潜在临床意义的表征需要进一步考虑 PPK 和 FXII 对出血的影响，超出其对凝血级联的假定影响。在这里，我们回顾了 CAS 对出血和止血机制影响的实验和临床证据。
The contact activation system (CAS) exerts effects on coagulation via multiple mechanisms, which modulate both the intrinsic and extrinsic coagulation cascades as well as fibrinolysis and platelet activation. While the effects of the CAS on blood coagulation measured as activated partial thromboplastin time shortening are well documented, genetic mutations that result in deficiencies in the expression of either plasma prekallikrein (PPK) or factor XII (FXII) are not associated with spontaneous bleeding or increased bleeding risk during surgery. Deficiencies in these proteins are often undiagnosed for decades and detected later in life during routine coagulation assays without an apparent clinical phenotype. Increased interest in the CAS as a potentially safe target for antithrombotic therapies has emerged, in large part, from studies on animal models with provoked thrombosis, which have shown that deficiencies in PPK or FXII can reduce thrombus formation without increasing bleeding. Gene targeting and pharmacological studies in healthy animals have confirmed that PPK and FXII blockade does not cause coagulopathies. These findings support the conclusion that CAS is not required for hemostasis. However, while deficiencies in FXII and PPK do not significantly affect bleeding associated with peripheral wounds, recent reports have demonstrated that these proteins can promote hemorrhage in the retina and brain. Intravitreal injection of plasma kallikrein (PKal) induces retinal hemorrhage and intracerebral injection of PKal increases intracranial bleeding. PPK deficiency and PKal inhibition ameliorates hematoma formation following cerebrovascular injury in diabetic animals. Moreover, both PPK and FXII deficiency are protective against intracerebral hemorrhage caused by tissue plasminogen activator-mediated thrombolytic therapy in mice with thrombotic middle cerebral artery occlusion. Thus, while the CAS is not required for hemostasis, its inhibition may provide an opportunity to reduce hemorrhage in the retina and brain. Characterization of the mechanisms and potential clinical implications associated with the effects of the CAS on hemorrhage requires further consideration of the effects of PPK and FXII on hemorrhage beyond their putative effects on coagulation cascades. Here, we review the experimental and clinical evidence on the effects of the CAS on bleeding and hemostatic mechanisms.