estropipate and Thrombosis

Platelets play a central role in the arrest of bleeding. The ability of platelets to engage with extracellular matrix proteins of the subendothelium has long been recognized as a pivotal platelet attribute, underpinning adequate hemostasis. The propensity of platelets to rapidly bind and functionally respond to collagen was one of the earliest documented events in platelet biology. The receptor primarily responsible for mediating platelet/collagen responses was identified as glycoprotein (GP) VI and successfully cloned in 1999. Since that time, this receptor has held the attention of many research groups, and through these efforts, we now have an excellent understanding of the roles of GPVI as a platelet- and megakaryocyte-specific adheso-signaling receptor in platelet biology. GPVI is considered a viable antithrombotic target, as data obtained from groups across the world is consistent with GPVI being less involved in physiological hemostatic processes but participating in arterial thrombosis. This review will highlight the key aspects of GPVI contributions to platelet biology and concentrate on the interaction with recently identified ligands, with a focus on fibrin and fibrinogen, discussing the role of these interactions in the growth and stability of thrombi. We will also discuss important therapeutic developments that target GPVI to modulate platelet function while minimizing bleeding outcomes.

Topics: Blood Platelets; Collagen; Fibrin; Hemorrhage; Humans; Platelet Activation; Platelet Membrane Glycoproteins; Thrombosis

Although much has been established concerning the overall structure and function of fibrinogen, much less has been known about its two αC regions, each consisting of an αC-connector and an αC-domain, but new information has been accumulating. This review summarizes the state of our current knowledge of the structure and interactions of fibrinogen's αC regions. A series of studies with isolated αC regions and their fragments demonstrated that the αC-domain forms compact ordered structures consisting of N- and C-terminal subdomains including β sheets and suggested that the αC-connector has a poly(L-proline) type II structure. Functionally, the αC-domains interact intramolecularly with each other and with the central region of the molecule, first demonstrated by electron microscopy and then quantified by optical trap force spectroscopy. Upon conversion of fibrinogen into fibrin, the αC-domains switch from intra- to intermolecular interactions to form ordered αC polymers. The formation of αC polymers occurs mainly through the homophilic interaction between the N-terminal subdomains; interaction between the C-terminal subdomains and the αC-connectors also contributes to this process. Considerable evidence supports the idea that the αC-regions accelerate fibrin polymerization and affect the final structure of fibrin clots. The interactions between αC-regions are important for the mechanical properties of clots, increasing their stiffness and extensibility. Conversion of fibrinogen into fibrin results in exposure of multiple binding sites in its αC regions, providing interaction of fibrin with different proteins and cell types during hemostasis and wound healing. This heretofore mysterious part of the fibrinogen molecule is finally giving up its secrets.

Topics: Estrone; Fibrin; Fibrinogen; Humans; Peptide Fragments; Polymers; Protein Structure, Tertiary; Thrombosis

Although fibrinolytic enzymes and thrombolytic agents help in cardiovascular disease treatment, those currently available have several side effects. This warrants the search for safer alternatives. Several natural cysteine protease preparations are used in traditional medicine to improve platelet aggregation and thrombosis-related diseases. Hence, this study aimed to investigate the effect of ficin, a natural cysteine protease, on fibrin(ogen) and blood coagulation. The optimal pH (pH 7) and temperature (37 °C) for proteolytic activity were determined using the azocasein method. Fibrinogen action and fibrinolytic activity were measured both electrophoretically and by the fibrin plate assay. The effect of ficin on blood coagulation was studied by conventional coagulation tests: prothrombin time (PT), activated partial thromboplastin time (aPTT), blood clot lysis assay, and the κ-carrageenan thrombosis model. The Aα, Bβ, and γ bands of fibrinogen are readily cleaved by ficin, and we also observed a significant increase in PT and aPTT. Further, the mean length of the infarcted regions in the tails of Sprague-Dawley rats was shorter in rats administered 10 U/mL of ficin than in control rats. These findings suggest that natural cysteine protease, ficin contains novel fibrin and fibrinogenolytic enzymes and can be used for preventing and/or treating thrombosis-associated cardiovascular disorders.

Topics: Animals; Anticoagulants; Carrageenan; Cysteine Proteases; Estrone; Fibrin; Fibrinogen; Fibrinolytic Agents; Ficain; Rats; Rats, Sprague-Dawley; Thrombosis