Distinct and concerted functions of von Willebrand factor and fibrinogen in mural thrombus growth under high shear flow

Abstract

Using a perfusion chamber and confocal laser scanning microscopy, we analyzed the interplay of von Willebrand factor (VWF) and fibrinogen during thrombus growth on a collagen surface under physiologic high shear rate conditions. During initial thrombogenesis, platelet thrombi were constructed totally by VWF, not by fibrinogen. Fibrinogen accumulated predominantly inside the growing thrombi as a function of time, whereas the thrombus surfaces directly exposed to flow were occupied constantly by VWF throughout the observation period. In perfusion of afibrinogenemia (AF) blood lacking both plasma and platelet fibrinogen, the final height and volume of thrombi were significantly reduced compared with controls, albeit the area of surface coverage was normal. The impaired thrombus growth in AF was only partially corrected by the addition of purified fibrinogen to AF blood, whereas the addition of purified VWF to blood of severe von Willebrand disease (VWD) completely normalized the defective thrombus growth in this disease.Thus, the initial 2-dimensional thrombus expansion involves only VWF, whereas the time-dependent accumulation of fibrinogen, released from activated platelets, acts as a core adhesive ligand, increasing thrombus strength and height and resulting in 3-dimensional thrombus development against rapid blood flow. (Blood. 2002;100:3604-3610)

Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

“…The role of JNK1 in relation to GPIbvWF-mediated platelet activation in thrombus formation is in accordance with previous work (47) showing that, at high shear rates, vWF is predominantly distributed at the outer areas of thrombi, whereas fibrinogen is present in the inner area. In contrast, at low shear rates, only fibrinogen appears in thrombi.…”

Warfarin-Intractable, Intraatrial Thrombogenesis in A 52-Year-Old Woman with Mitral Stenosis and Chronic Atrial Fibrillation

“…This is the first report that histologically demonstrates the interplay between platelet aggregates and fibrin clots in intraatrial thrombi, although increased plasma levels of both fibrin D-dimer and platelet beta-thromboglobulin have been shown in AF patients (Lip et al 1996). In contrast to our findings, thrombogenesis at a high shear rate has been experimentally characterized by localizations of fibrinogen in the inner areas and platelet thrombi mediated through von Willebrand factor at the outer surfaces (Matsui et al 2002). By using left atrial thrombectomy specimens from a woman with mitral stenosis and chronic AF, we demonstrated that warfarin-intractable, intraatrial thrombogenesis occurred in a stepwise fashion on the endocardium involving platelet aggregate/fibrin clot complex formation.…”

Expression of the von Willebrand Factor in Atrial Endocardium is Increased in Atrial Fibrillation Depending on the Extent of Structural Remodeling

“…Our observations may be consistent with the report by Matsui et al in which fibrinogen and/or fibrin are mainly involved in thrombus growth rather than initial platelet adhesion to the thrombogenic surfaces. 34 …”