title: Discrimination between platelet-mediated and coagulation-mediated mechanisms in a model of complex thrombus formation in vivo.
abstract: To study mechanisms of complex thrombus formation in vivo, and to compare the relative antithrombotic effects of anticoagulants and antiplatelet agents, a model was developed in baboons. Segments of collagen-coated tubing followed by two sequentially placed expansion chambers exhibiting disturbed flow patterns were exposed to native blood under laminar flow conditions. The device was incorporated for 1 hour into an exteriorized arteriovenous shunt in baboons under controlled blood flow (20 ml/min). Morphologic evaluation by scanning electron microscopy showed that thrombi associated with collagen were relatively rich in platelets but thrombi in the chambers were rich in fibrin and red cells. Deposition of indium 111-labeled platelets was continuously measured with a scintillation camera. Platelet deposition increased in a linear (collagen-coated segment) or exponential (chambers 1 and 2) fashion over time, with values after 40 minutes averaging 24.1 +/- 3.3 x 10(8) platelets (collagen segment), 16.7 +/- 3.4 x 10(8) platelets (chamber 1), and 8.4 +/- 2.4 x 10(8) platelets (chamber 2). Total fibrinogen deposition after 40 minutes was determined by using iodine 125-labeled baboon fibrinogen and averaged 0.58 +/- 0.14 mg in the collagen segment, 1.51 +/- 0.27 mg in chamber 1, and 0.95 +/- 0.25 mg in chamber 2. Plasma levels of beta-thromboglobulin (beta TG), platelet-factor 4 (PF4), and fibrinopeptide A (FPA) increased fourfold to fivefold after 60 minutes of blood exposure to the thrombotic device. Platelet deposition onto the collagen segment, chamber 1, and chamber 2 was linearly dependent on the circulating platelet count. Platelet accumulation in chamber 1 and chamber 2 was also dependent on the presence of the proximal collagen segment. An anticoagulating dose of standard heparin decreased platelet deposition in the chambers (p less than 0.05) but did not decrease deposition onto the collagen segment. Although beta TG and PF4 levels remained elevated after the administration of standard heparin, the elevation in plasma FPA was interrupted. Further evidence that the thrombotic process was dependent on platelets was provided by the finding that prostaglandin I2 at high concentration (35 ng/ml) decreased platelet deposition onto the collagen segment and in chambers 1 and 2, decreased beta TG and PF4 release, and reduced FPA formation. The combination of standard heparin and PGI2 produced the most potent inhibition of platelet thrombus formation and prevented the increases in plasma PF4, beta TG and FPA.
authors.affiliation: Department of Basic and Clinical Research, Institute of Scripps Clinic, La Jolla, CA 92037.
authors.forename: Y
authors.initials: Y
authors.lastname: Cadroy
authors.forename: T A
authors.initials: TA
authors.lastname: Horbett
authors.forename: S R
authors.initials: SR
authors.lastname: Hanson
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism; D005344:Fibrinopeptide A / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008297:Male; D008855:Microscopy, Electron, Scanning; D008954:Models, Biological; D010215:Papio; D010976:Platelet Count; D010978:Platelet Factor 4 / Q000378:metabolism; D001620:beta-Thromboglobulin / Q000378:metabolism
chemical_list: D007457:Iodine Radioisotopes; D001620:beta-Thromboglobulin; D005344:Fibrinopeptide A; D010978:Platelet Factor 4; D005340:Fibrinogen; D006493:Heparin; D003094:Collagen; D011464:Epoprostenol