Bleeding hearts.
Bleeding hearts.
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心在滴血。
DOI：
10.1182/blood-2008-11-188508
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发表时间：
2009
期刊：
影响因子：
20.3
通讯作者：
N. Mackman
中科院分区：
文献类型：
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作者：
N. Mackman
止血，即止血，是通过结合血小板(一次止血)和激活凝血级联反应(二次止血)实现的。小鼠的遗传学研究表明，由于胚胎发育期间血管形成缺陷和出生后止血缺陷，外源性凝血途径的组成部分(组织因子和FVII)或普通凝血途径(Fx、Fv和FII)的“敲除”与生命不相容。然而，小鼠可以在没有纤维蛋白原(凝血级联的终点)或没有蛋白酶激活受体4(PAR-4)的情况下存活。2重要的是，纤维蛋白原和PAR-4共同缺陷的小鼠出生后因失控出血而死亡。3这些观察结果与凝血酶是凝血级联中的中心丝氨酸蛋白酶的概念一致，并在纤维蛋白原的切割和血小板的激活中发挥关键作用。
外源性和共同的凝血途径是止血所必需的。血管损伤后FVIIa：组织因子(TF)复合体的形成导致FX活化为FXA，FXA与其辅因子FVA一起将凝血酶原裂解为凝血酶。..。
止血的概念很容易被设想在刀割伤的环境中，血管被切断，凝血系统通过暴露于组织因子而被激活。大多数人没有考虑到的是，在日常生活中，整个身体的血管很可能会自动破裂。如果要设计止血系统，为所有血管提供基本保护，并为重要器官和器官中的血管提供额外保护将是有益的，因为在这些器官中，血管更有可能受到重复机械应力的破坏，例如心脏。事实上，组织因子是由围绕较大血管的外膜成纤维细胞和血管平滑肌细胞以及围绕毛细血管的周细胞表达的，因此为所有血管提供基本的止血保护。组织因子也以组织特异性的方式表达，在大脑和心脏中水平较高。这种表达模式与高水平组织因子为这些重要器官提供额外止血保护的设计是一致的。这一观点首先得到支持，因为观察到经基因改造表达极低水平组织因子(∼1%)的小鼠出现组织特异性止血缺陷，尤其是心脏。4，5在表达极低水平FVII(∼1%)和低水平FX(约5.5%)的小鼠中也观察到类似的止血缺陷。4，6相反，缺乏FVIII或FIX的小鼠存活到成年，心脏中没有止血缺陷。然而，血友病A(FVIII缺乏)或血友病B(FIX缺乏)的患者经常在组织因子表达水平较低的组织(即关节和骨骼肌)发生自发性出血，并在受伤后出现大量出血。这些观察表明，对于心脏止血来说，外源性和普通凝血途径而不是内在途径是重要的。
在这一期的《血液》杂志上，Mullins和他的同事使用Poly I：C诱导的Mx1-Cre系统在成年小鼠中从基因上消除FII。这是一个优雅的方法来研究FII在止血中的作用。正如预期的那样，FII的丢失与凝血酶原时间和激活的部分凝血酶原时间的深刻影响有关。给予Poly I：C后，循环FII水平迅速下降，小鼠在7天内均匀死亡。如果一个人相信止血在所有组织中都是平等的，那么这些小鼠的大多数器官都会出血。相反，这份报告中令人兴奋的观察结果是，缺乏循环FII的小鼠表现出组织特异性出血。对39只小鼠的尸检分析显示，大多数小鼠有心脏出血，大约50%有颅内出血。低水平FII表达的小鼠(10%-20%)在1岁时心脏也有轻微的止血缺陷。这些急性和慢性FII缺陷小鼠的表型与组织因子、FVII和FX水平低的小鼠的表型非常相似。对小鼠组织因子的药理抑制也会导致心脏和大脑出血。7这些研究支持止血并不等同于所有组织的观点。
抗凝治疗是为了在不影响止血的情况下减少血栓形成。然而，不足为奇的是，抗凝药的主要副作用是出血。新的抗凝血剂已经开发出来，可以选择性地靶向凝血酶或FXA。8目前的研究表明，在药物作用下，凝血酶活性降低到临界值以下可能会影响心脏和大脑的止血。
Hemostasis, the arrest of bleeding from an injured blood vessel, is mediated by binding of platelets (primary hemostasis) and activation of the coagulation cascade (secondary hemostasis). Genetic studies in mice have demonstrated that “knock-out” of components of the extrinsic coagulation pathway (tissue factor and fVII) or the common coagulation pathway (fX, fV and fII) is not compatible with life due to defective vessel formation during embryonic development and hemostatic defects after birth. 1 However, mice can survive without fibrinogen, the end point of the coagulation cascade, or without protease activated receptor 4 (PAR-4), which mediates thrombin activation of platelets in mice.2 Importantly, mice with a combined deficiency of both fibrinogen and PAR-4 die after birth due to uncontrolled hemorrhage.3 These observations are consistent with the notion that thrombin is the central serine protease in the coagulation cascade and plays critical roles in both cleavage of fibrinogen and activation of platelets.
The extrinsic and common coagulation pathways are essential for hemostasis. Formation of the fVIIa:tissue factor (TF) complex after vessel injury leads to activation of fX to fXa, which, together with its cofactor fVa, cleaves prothrombin to thrombin. ...
The concept of hemostasis is easy to envisage in settings such as a knife cut where blood vessels are severed and the clotting system is activated by exposure to tissue factor. What is not considered by most people is that in daily life there are likely to be “spontaneous” breaks in blood vessels throughout the body. If one were to design a hemostatic system, it would be beneficial to provide a basic protection to all blood vessels, as well as additional protection to blood vessels in vital organs and organs in which blood vessels are more likely to be damaged by repetitive mechanical stress, such as the heart. Indeed, tissue factor is expressed by adventitial fibroblasts and vascular smooth muscle cells surrounding larger blood vessels and pericytes surrounding capillaries and thus provides basic hemostatic protection to all blood vessels. Tissue factor is also expressed in a tissue-specific manner, with high levels in the brain and heart. This pattern of expression is consistent with a design in which high levels of tissue factor provide additional hemostatic protection to these vital organs. Support for this idea was first provided by the observation that mice engineered to express very low levels of tissue factor (∼1%) exhibited tissue-specific hemostatic defects, particularly in the heart.4,5 Similar hemostatic defects were observed in mice expressing very low levels of fVII (∼1%) and low levels of fX (approximately 5.5%).4,6 In contrast, mice lacking either fVIII or fIX survive to adulthood and have no hemostatic defects in their hearts. However, patients with hemophilia A (fVIII deficiency) or hemophilia B (fIX deficiency) often experience spontaneous hemorrhages in tissues with low levels of tissue factor expression (ie, joints and skeletal muscle) and have excessive hemorrhage after injury. These observations indicate that the extrinsic and common coagulation pathways but not the intrinsic pathway are important for cardiac hemostasis.
In this issue of Blood, Mullins and colleagues use the poly I:C-inducible Mx1-Cre system to genetically eliminate FII in adult mice. This is an elegant approach to study the role of fII in hemostasis. As expected, loss of fII was associated with a profound effect on the prothrombin time and the activated partial prothrombin time. Administration of poly I:C led to a rapid reduction in circulating fII levels and uniform death of the mice within 7 days. If one believes that hemostasis is equal in all tissues, one would expect hemorrhage in the majority of organs in these mice. Rather, the exciting observation in this report is that mice lacking circulating fII exhibit tissue-specifichemorrhage. Postmortem analysis of 39 mice revealed that the majority had cardiac hemorrhage, and approximately 50% had intracranial hemorrhage. Mice expressing low levels of fII (10%-20%) also had a mild hemostatic defect in their hearts at 1 year of age. The phenotype of these acute and chronic fII-deficient mice is remarkably similar to the phenotypes of mice with low levels of tissue factor, fVII and fX. Pharmacological inhibition of tissue factor in mice also leads to hemorrhage in the heart and brain.7 These studies support the idea that hemostasis is not equal in all tissues.
Anticoagulant therapy is designed to reduce thrombosis without affecting hemostasis. However, not surprisingly, the major side effect of anticoagulant drugs is hemorrhage. New anticoagulants have been developed that selectively target thrombin or fXa. 8 The current study demonstrates that pharmacologic reduction in thrombin activity below a critical threshold could compromise cardiac and brain hemostasis.