Erik R Vandendries | PubMed Health

PubMed2006

Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis.

Thrombin, a central mediator of hemostasis and thrombosis, converts fibrinogen to fibrin and is a potent platelet activator. Activated platelets provide a surface for assembly of the tenase and prothrombinase complexes required for thrombin generation. The role of thrombin-induced platelet activation in platelet accumulation and its interplay with fibrin deposition during thrombus assembly has not been fully defined. We studied these processes during laser-induced thrombus formation by using real-time digital fluorescence microscopy in mice lacking protease-activated receptor-4 (Par4), which is necessary for thrombin responsiveness in mouse platelets. Juxtamural platelet accumulation immediately after laser injury was not different in wild-type and Par4(-/-) mice. However, subsequent growth of platelet thrombi was markedly diminished in Par4(-/-) mice. At the time of maximal thrombus size in wild type, platelet accumulation was more than 10-fold higher in wild type than in Par4(-/-) mice. P-selectin expression, a marker of platelet activation, was reduced and delayed in Par4(-/-) thrombi. In contrast to platelet activation and accumulation, the rate and amount of fibrin deposition, predominantly intramural and juxtamural in this model, were indistinguishable in Par4(-/-) and wild-type mice. These results suggest that platelet activation by thrombin is necessary for normal propagation of a platelet thrombus at a distance from the injured vessel wall and hence for normal thrombus growth. However, platelet activation by thrombin is unnecessary for initial and limited accumulation of platelets at or near the vessel wall, and this limited accumulation of platelets and/or platelet-independent mechanism(s) of thrombin generation are sufficient for normal fibrin deposition in this model.

Animals↗

PubMed2006

Drug-associated disease: hematologic dysfunction.

Hematologic dysfunction, including thrombocytopenia, anemia, neutropenia, thromboses, and coagulopathy, occur commonly during critical illnesses. A major challenge is to identify drug-induced causes of hematologic dysfunction. Given the wide variety of drug-induced hematologic effects, clinicians always should consider any concomitant drugs in the differential diagnosis of acquired hematologic dysfunction. The most severe effects include drug-induced aplastic anemia, heparin-induced thrombocytopenia, and drug-induced thrombotic microangiopathy. Certain drugs are associated with multiple hematologic effects. For example, cisplatin can cause hemolytic uremia syndrome and erythropoietin deficiency, and quinine can precipitate immune-mediated thrombocytopenia, immune-mediated thrombocytopenia, and thrombotic microangiopathy.

Anemia, Aplastic↗

PubMed2004

Role of P-selectin and PSGL-1 in coagulation and thrombosis.

P-selectin and PSGL-1 are cell adhesion molecules, regulating the initial interactions between leukocytes and the blood vessel wall as well as between activated platelets and leukocytes. P-selectin is expressed on activated endothelial cells and platelets, while its major ligand PSGL-1 is expressed on leukocytes. Multiple studies have shown that these adhesion molecules are required for the normal recruitment of leukocytes during an inflammatory reaction. More recently, these adhesion molecules have been implicated in recruitment of leukocytes and leukocyte microparticles to thrombi. The P-selectin- and PSGL-1-dependent delivery of circulating microparticles to thrombi appears to be important for normal tissue factor accumulation and fibrin generation in thrombi.

Blood Coagulation↗