Fibrin clot formation

Fig.7 Blood compatibility of PEU surfaces modified by MPEO-derived SMAs. A Simplified cascade model for material-induced blood coagulation highlighting three clotting pathways plasma fibrin formation, platelet aggregation, and hemolysis-inflammation, respectively characterized by B-C...

Thrombin Time (TT). To 0.1 ml of citrated plasma 0.1 ml of diethylbarbiturate-citrate buffer, pH 7.6 (Behring Werke, Marburg) is added and the mixture is incubated for 1 min at 37 °C. Then 0.1 ml of bovine test-thrombin (30 IU/ml, Behring Werke, Marburg) is added and the coagulometer is started. The time to clot formation is determined. The TT measures effects on fibrin formation. 

Reaction time (r) the time from sample placement in the cup until onset of clotting (defined as amplitude of 1 mm). This represents the rate of initial fibrin formation. 

Several new compounds have been reported that affect the formation of a fibrin clot. Aromatic diamidines, such as, 21, were reported to inhibit several proteolytic enzymes including thrombin.74 Concanavalin A (a globulin protein from the jack bean) inhibits fibrin formation by inhibiting the lipoprotein cofactor in the production of thrombin and thus decreasing the rate of thrombin production.75 Several antibiotics (penicillins and cephalosporins) have been reported to affect fibrin clot formation as well as platelet function. Cephalothin (22) has been shown to delay fibrin polymerization and thus prolong the activated partial thromboplastin time (APTT) and thrombin time tests.78... 

Figure 11.13 summarizes the entire clotting process initiation, major pathways, fibrin formation and fibrinolysis, clotting control pathways, and major associated diseases. 

Fibrinogen is converted to fibrin by the action of thrombin on the a and p chains of fibrinogen. The proteolytic scission events leading up to thrombin formation are complex (Figure 2). Thrombin hydrolyzes each chain at two specific Arg-Gly bonds to release two fibrinopeptides A (from a-chain) and two fibrinopeptides B (from /3-chain). The fibrinopeptides account for ca. 3% of the weight of fibrinogen. This proteolytic step, leading to fibrin formation is critical for clot formation. 

The inhibitory effect of infusion of low-molecular-weight heparin sodium during lensectomy, vitrectomy, and retinotomy on intraocular fibrin formation was demonstrated in a rabbit model (97). Similarly, the preventative effect of heparin on postoperative intraocular fibrin clot formation was evaluated in the rabbit after vitrectomy and cyclocryotherapy. A single anterior chamber injection of heparin supplemented in the infusion solution or a single intravenous injection each resulted in a statistically significant reduction in postoperative intraocular fibrin formation (98). No ocular bleeding complications developed postoperatively. 

Formation of a blood clot involves a complex cascade of enzymatically controlled reactions the penultimate step of which is the formation of thrombin. Thrombin then cleaves peptides from fibrinogen to form fibrin monomers that associate to form the fibrin clot. Fibrin clot formation is a carefully poised process whereby a relatively minor injury will not allow excessive bleeding and result in death and whereby excessive clot formation will not block blood flow and result in death. As will be seen by examination of the relevant molecular structures, regardless of the balance struck, the key process of clot formation is the hydrophobic association of fibrin monomers. In demonstrating this perspective, the same T,-based mean residue hydrophobicity plot will be used as was used above in Figure 7.9 for understanding the hydrophobic association of hemoglobin subunits. 

Figure 7.28. Stereo view of fibrinogen, ((xPy)2, showing three sites for intermolecular contacts resulting in formation of the fibrin clot (1) the end-to-end docking site for linear fiber growth that works in cooperation with association at the Ea site (2) the Ea site of the carboxyl-terminal y-globule hydrophobic domain, which provides for fibrin formation in a second dimension due to association with the GPRP of an a-amino terminus (at the central domain) that was exposed on removal of the 16 residue A peptide ...

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