In platelets, phosphatidylserine (PS) is present exclusively in the inner leaflet of the membrane bilayer. Upon activation with some agonists, platelets externalize PS and provide a procoagulant surface. Exposure of PS is accompanied by the release of PS-rich procoagulant membrane fragments called platelet-derived microvesicles. Deficiency of PS exposure and microvesiculation leads to an inherited bleeding disorder, Scott syndrome. Increased microvesicles have been detected in conditions associated with either arterial or venous thrombosis. These associations suggest that, while they may be necessary for normal hemostasis, elevated microvesicles predispose to thrombosis. We have identified lactadherin and Del-1 (developmentally expressed locus-1) as mediators of microvesicles clearance. Lactadherin and Del-1 are present in circulating microvesicles and promotes their phagocytosis by macrophages in a concentration-dependent manner in vitro. Lactadherin-deficient mice have increased microvesicles in the circulation and an enhanced thrombin generation in their plasma. Furthermore, in a light-dye-induced endothelial cell injury/thrombosis model, lactadherin-deficient mice have increased thrombotic tendency compared to wild type littermate controls. Our goals in the current proposal are to define the mechanism(s) of microvesicles clearance and its relation to thrombosis. We will also test the hypothesis that impaired clearance of the microvesicles per sh leads to a hypercoagulable state in antiphospholipid antibody syndrome.
The specific aims of this proposal are to further characterize the role of lactadherin and Del-1 in the clearance of microvesicles in vivo and to test the hypothesis that microvesicles causes thrombosis in antiphospholipid syndrome.
Narrative When platelets are activated, they release small membrane fragments called microvesicles. These vesicles promote blood clotting and some individuals with thrombosis have increased microvesicles in their blood. We will test whether these microvesicles causes blood clotting because of defective clearance. Consequences of thrombosis such as myocardial infarction, stroke and peripheral arterial occlusion are the leading causes of morbidity and mortality among veterans. Our research has a major bearing on the understanding of the role of platelet-derived microvesicles in atherothrombosis.
|Zhou, Yuan; Cai, Wei; Zhao, Zilong et al. (2018) Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice. Blood 131:563-572|
|Weiss, Nicole H; Johnson, Clinesha D; Contractor, Ateka et al. (2017) Racial/ethnic differences moderate associations of coping strategies and posttraumatic stress disorder symptom clusters among women experiencing partner violence: a multigroup path analysis. Anxiety Stress Coping 30:347-363|
|Weiss, Nicole H; Duke, Aaron A; Overstreet, Nicole M et al. (2016) Intimate partner aggression-related shame and posttraumatic stress disorder symptoms: The moderating role of substance use problems. Aggress Behav 42:427-40|
|Song, Jihyun; Yoon, Donghoon; Christensen, Robert D et al. (2015) HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis. J Mol Med (Berl) 93:857-66|
|Nguyen, Trung C; Gushiken, Francisca; Correa, Juliana I et al. (2015) A recombinant fragment of von Willebrand factor reduces fibrin-rich microthrombi formation in mice with endotoxemia. Thromb Res 135:1025-30|
|Hellmuth, Julianne C; Jaquier, Véronique; Swan, Suzanne C et al. (2014) Elucidating posttraumatic stress symptom profiles and their correlates among women experiencing bidirectional intimate partner violence. J Clin Psychol 70:1008-21|
|Flanagan, Julianne C; Jaquier, Véronique; Overstreet, Nicole et al. (2014) The mediating role of avoidance coping between intimate partner violence (IPV) victimization, mental health, and substance abuse among women experiencing bidirectional IPV. Psychiatry Res 220:391-6|
|Sullivan, Tami P; McPartland, Tara; Price, Carolina et al. (2013) Relationship self-efficacy protects against mental health problems among women in bidirectionally aggressive intimate relationships with men. J Couns Psychol 60:641-7|
|Thiagarajan, Perumal; Afshar-Kharghan, Vahid (2013) Platelet transfusion therapy. Hematol Oncol Clin North Am 27:629-43|
|Pongas, Georgios; Dasgupta, Swapan Kumar; Thiagarajan, Perumal (2013) Antiplatelet factor 4/heparin antibodies in patients with gram negative bacteremia. Thromb Res 132:217-20|
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