P-selectin is Central to Venous Thrombosis Pathogenesis

静脉血栓形成(VT)是一个全国性的健康问题，在过去的20年里以恒定的速度发生，每年至少有25万例发生。据估计，每年约有300,000至600,000人住院，多达50,000人死亡，与深静脉血栓形成和肺栓塞有关。慢性静脉功能不全是静脉血栓形成的后遗症，影响大约40万至50万皮肤溃疡患者，600万至700万皮肤淤积变化患者，随着时间的推移，高达28%的严重髂股深静脉血栓患者将发展为严重的浮肿和皮肤变化，可能导致静脉溃疡。简而言之，VT花费了卫生系统数十亿美元。选择素是黏蛋白样糖蛋白细胞黏附分子，由活化的内皮细胞和血小板表达，介导白细胞-血小板、白细胞-内皮细胞和白细胞-白细胞的相互作用。初步数据表明，P-选择素与室性心动过速相关炎症和血栓反应的启动和维持在时间上是相关的。我们的研究假设包括：P-选择素与室性心动过速炎症和血栓形成放大随意相关；单独抑制P-选择素或与其他药物联合应用将减少炎症和血栓形成，而不会出现全身抗凝并发症；抑制P-选择素将刺激确实形成的血栓的溶栓，从而增强其他纤溶剂。我们将以三个具体目标来解决这些假说：具体目标1：确定与静脉血栓形成相关的炎症机制是否涉及P-选择素。这将用表达高水平循环可溶性P-选择素的转基因小鼠来研究，以及阻断多余的可溶性P-选择素的效果。然后，他们将与服用可溶性P-选择素的野生型小鼠和遗传缺乏P-选择素的小鼠进行对比。具体目的2：评价P-选择素的抑制作用以及其他抗血栓药物治疗室性心动过速的疗效，包括抑制Xa因子和直接抑制凝血酶。此外，联合用药以确定哪种或哪种药对无抗凝活性的室性心动过速提供最佳治疗。具体目标3：确定直接抑制P-选择素是否能增强自发和药物诱导的血栓溶解，并明确P-选择素抑制是否会损害纤维蛋白沉积或增加纤溶。这些研究将明确P-选择素在室性心动过速的发病机制、治疗和溶栓中的作用。

Venous thrombosis (VT) is a national health concern, occurring at a constant rate over the past 20 years, with an annual incidence of at least 250,000 cases. It is estimated that deep venous thrombosis and pulmonary embolism are associated with approximately 300,000 to 600,000 hospitalizations and as many as 50,000 deaths per year. Chronic venous insufficiency, the sequela of venous thrombosis, affects approximately 400,000 to 500,000 patients with skin ulceration, 6 to 7 million patients with skin stasis changes, and up to 28 percent of patients with significant iliofemoral DVT over time will develop severe edema and skin changes which may lead to venous ulceration. VT in short costs the health system billions of dollars. Selectins are mucin like glycoprotein cell adhesion molecules that are expressed by activated endothelial cells and platelets and mediate leukocyte-platelet, leukocyte-endothelial cell, and leukocyte-leukocyte interactions. Preliminary data suggest that P-selectin is temporally related to the initiation and maintenance of the inflammatory and thrombotic response associated with VT. Our research hypotheses include: P-selectin is casually related to VT inflammation and thrombosis amplification; inhibition of P-selectin alone or augmented with other agents will decrease inflammation and thrombosis without systemic anticoagulant complications; and P-selectin inhibition will stimulate thrombolysis of thrombus that does form, augmenting other fibrinolytic agents. We will address these hypotheses with three specific aims: Specific Aim 1: To determine if the mechanism of inflammation associated with venous thrombosis involves P-selectin. This will be investigated using genetically altered mice which express high levels of circulating soluble P-selectin, and the effect of blocking the excess soluble P-selectin. They will then be contrasted to wild type mice administered soluble P-selectin, and mice genetically lacking P- selectin. Specific Aim 2: To assess P-selectin inhibition and to test the efficacy of other antithrombotic agents for VT treatment, agents with different mechanisms of action including inhibition of factor Xa and direct thrombin inhibition. Additionally, to combine agents to determine which agent or agents offer the best treatment for VT without anticoagulant activity. Specific Aim 3: To determine if direct P-selectin inhibition augments both spontaneous and pharmacologically induced thrombolysis and specifically to determine if P-selectin inhibition impairs fibrin deposition or increases fibrinolysis. These studies will define the role of P-selectin in VT pathogenesis, treatment and thrombolysis.