Alpha-Defensins in perioperative thrombosis

围手术期血栓形成中的α-防御素

• 批准号: 8903553
• 负责人: Abd Alroof HIGAZI
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903553
• 关键词: Address; Adherence; Alteplase; Anticoagulants; Attenuated; Biological Markers; Bone Marrow Transplantation; Carotid Arteries; Clinical; Clinical Medicine; Coagulation Process; Colchicine; Complex; Confocal Microscopy; Cytolysis; Cytoplasmic Granules; Data; Defensins; Deposition; Disease; Dose; Drug usage; Embolism; Enzymes; Equilibrium; Femoral vein; Fibrin; Fibrinogen; Fibrinolysis; Gene Dosage; Gene Expression; Genetic; Guidelines; Health; Hemorrhage; Hemostatic function; Human; In Vitro; Individual; Infection; Infection prevention; Inflammation; Investigation; Link; Lung; Measures; Mechanics; Mediator of activation protein; Medical; Methods; Mus; Natural Immunity; Nature; Neutrophil Activation; Operative Surgical Procedures; Outcome; Patients; Peptides; Perioperative; Permeability; Plasma; Plasma Cells; Platelet Activation; Play; Populations at Risk; Postoperative Period; Postphlebitic Syndrome; Prevention; Process; Property; Prophylactic treatment; Proteins; Publishing; Resistance; Risk; Risk Estimate; Risk Factors; Risk Reduction; Role; Scanning Electron Microscopy; Structure; Thromboembolism; Thrombosis; Thrombus; Transgenic Mice; Venous; Venous Thrombosis; Wound Healing; alpha-Defensins; antimicrobial peptide; base; biophysical techniques; crosslink; effective intervention; in vivo; inhibitor/antagonist; injured; insight; meetings; neutrophil; novel; novel strategies; polymerization; prevent; prophylactic; protein expression; reconstitution; research study

DESCRIPTION (provided by applicant): Surgery increases the risk of thrombosis but prevention and management of thromboembolic disease in the perioperative period is complicated by the risk of hemorrhage. Neutrophils (PMNs) play a vital role in wound healing, but their contribution to perioperative thrombosis and implications for thromboprophylaxis are unclear. Adherence of PMNs to wounds and to the vasculature generates a unique localized sequestrum enriched in enzymes and antimicrobial peptides protected from plasma inhibitors that contribute to innate immunity in part through the orderly formation and dissolution of fibrin. We posit that post-operative and persistent inflammation disrupt this balance, predisposing to thrombosis by promoting formation and persistence of fibrin. We have previously observed that alpha-defensins (α-def), antimicrobial peptides that constitute 5% of total human PMN protein that are released upon activation, promote clotting and inhibit fibrinolysis. The absence of α-def in murine PMNs has hindered a better understanding of how these peptides contribute to thromboembolic disease in the perioperative setting. Using a novel transgenic mouse that expresses PMN α-def (Def++), we show that α-def circulates in a complex with fibrinogen and promotes polymerization and retraction of fibrin in vitro, deposits in the vasculature, induces occlusive arterial and venous thrombosis, and inhibits lysis of pulmonary emboli in vivo. These pathogenic properties can be prevented and possibly reversed by preventing α-def release using colchicine. We now propose an integrated approach to understanding the mechanism and implications of PMN α-def on perioperative thrombosis by examining: a) The biophysical effects of α-def on clot formation and structure~ b) The mechanism of accelerated thrombosis and impaired fibrinolysis in Def++ mice and the salutary effect of blocking α-def release~ and c) The utility of α-def gene and protein expression as biomarkers of risk for venous thrombosis and post-thrombotic syndrome. These studies will provide insight into an unappreciated contribution of PMN α-def to arterial and venous thrombosis, identify novel genetic and protein biomarkers of patients at risk for surgery related thrombosis and provide evidence for the use of a safe and effective intervention to prevent thrombosis in the perioperative period.

描述（由申请人提供）：手术增加血栓形成的风险，但围手术期血栓栓塞性疾病的预防和处理因出血的风险而复杂化。中性粒细胞（pmn）在伤口愈合中起着至关重要的作用，但它们对围手术期血栓形成的贡献及其对血栓预防的影响尚不清楚。pmn粘附在伤口和脉管系统上，产生独特的局部固壁，富含酶和抗菌肽，免受血浆抑制剂的保护，血浆抑制剂部分通过纤维蛋白的有序形成和溶解促进先天免疫。