Dept. of Science & Engineering
Oregon Health & Science University
The prevention and treatment of cardiovascular disease complications, including occlusive blood clots responsible for heart attacks and strokes, are projected to cost Americans more than $500 billion in 2010. While therapeutic strategies have been employed to prevent occlusive events, the most effective antithrombotic agents are accompanied by unintended bleeding side effects. In order to develop new approaches that distinguish pathological events (thrombosis) from physiological clotting (hemostasis), there exists a need for a deeper understanding of the interactions between the major players involved in hemostasis and thrombosis: platelets, coagulation factors and extracellular matrix (ECM) components. In this thesis, we employed flow chamber studies, clotting assays and biochemical and microscopy techniques in order to identify the mechanisms governing the molecular interactions between platelets, coagulation factors and the ECM. The ECM participates in the crucial event of platelet recruitment to the vascular wall after injury. Recent studies have described the ability of the ECM component collagen to accelerate coagulation factor XII (FXII) activation, thus contributing directly to blood coagulation. Due to the parallel mechanisms employed by collagen and fellow ECM protein, laminin, in platelet interactions, we hypothesized that laminin contributes to coagulation in an analogous manner. Results showed that laminin shortened plasma clotting times in a FXII-dependent manner and accelerated FXII activation in the presence of prekallikrein and high molecular weight kininogen. Factor XI (FXI) has been shown to play a critical role in clot growth and stability in vivo. While FXI binding to platelet glycoprotein (GP)Ib/IX/V has been demonstrated, its ability to localize FXI to the growing clot or promote its activity has yet to be demonstrated. Results here identify a second platelet receptor for FXI: apolipoprotein E receptor 2 (ApoER2), which exists in a complex with GPIb/IX/V. Protein C is the zymogen precursor to activated protein C (APC), which plays a regulatory role in blood coagulation by inactivating cofactors essential for thrombin production. These pro-coagulant cofactors assemble onto the platelet surface, and although APC has been shown to bind to the platelet surface, results described here extend these findings by identifying two receptors, GPIb/IX/V and ApoER2, that mediate platelet-protein C/APC interactions.
Div. of Biomedical Engineering
School of Medicine
Adams, Tara Chantal, "Novel mechanisms mediating platelet, coagulation and extracellular matrix interactions in the presence of shear" (2010). Scholar Archive. 365.