Fibrin Cross-linking

Controversy exists over whether intravitreally injected tPA can diffuse across the retina to act on the site of thrombosis. Some authors also question whether thrombolytic therapy can have any effect in older cases of central vein occlusion where the thrombus has formed fibrin cross linking and become organized. It has been suggested that such treatment would be more effective if applied closer to the time of onset of the retinal vein occlusion. 

Fibrin cross-links. The structures at the top are parts of two separate fibrin molecules. The polypeptide backbones are shown on the far left and the far right. 

Lorand, L. Rule, N. G. Ong, H. H. Furlanetto, R. Jacobsen, A. Downey, J. Oner, N. Bruner-Lorand, J. Amine specificity in transpeptidation inhibition of fibrin cross-linking, fizocfemwiry 1968,7,1214-1223. 

The degradation of fibrin by plasmin is more complex because the fibrin molecule is a cross-linked polymer. Fragments released include D—D dimer or D2 (two cross-linked D fragments) with a molecular weight of 160,000 daltons, D2E, which is beHeved to be the principally released fragment in vivo, and... 

FIGURE 15.5 The cascade of activation steps leading to blood clotting. The intrinsic and extrinsic pathways converge at Factor X, and the final common pathway involves the activation of thrombin and its conversion of fibrinogen into fibrin, which aggregates into ordered filamentous arrays that become cross-linked to form the clot. 

Figure 51-1. The pathways of blood coagulation. The intrinsic and extrinsic pathways are indicated. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. New observations (dotted arrow) include the finding that complexes of tissue factor and factor Vila activate not only factor X (in the classic extrinsic pathway) but also factor IX in the intrinsic pathway, in addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). (PK, prekallikrein HK, HMW kininogen PL, phospholipids.) (Reproduced, with permission, from Roberts HR, Lozier JN New perspectives on the coagulation cascade. Hosp Pract [Off Ed] 1992Jan 27 97.)...

Figure 51-5. Formation of a fibrin clot. A Thrombin-induced cleavage of Arg-Gly bonds of the Aaand B(3 chains of fibrinogen to produce fi-brinopeptides (left-hand side) and the a and p chains of fibrin monomer (right-hand side). B Cross-linking of fibrin molecules by activated factor XIII (factor Xllla).

FIGURE 8-3. The physiologic clotting cascade. Clot formation beginning with vessel or tissue injury. Tissue injury starts the complex process involving clotting factors and resulting in cross-linked fibrin. This is a schematic of the factors and steps involved in the process. 

D7. Deitcher, S. R., and Eisenberg, P. R., Elevated concentrations of cross-linked fibrin degradation products in plasma. An early marker of gram-negative bacteremia. Chest 103, 1107-1112... 

D-Dimer) (Other cross linked fibrin degradation products)... 

Measurement of a peptide released by the action of plasmin on both cross-linked and non-cross-linked fibrin, which is called Bp 15-42, is useful for the assessment of fibrinolytic activity (94). 

By far the most widely measured marker of hemostatic activation is D-dimer, which is a product formed by the action of plasmin on cross-linked fibrin (95). D-dimer levels in plasma are generally elevated in DIC. The consumption of platelets and coagulation proteins as a result of thrombin generation leads to the deposition of fibrin thrombi at multiple organ sites. This triggers fibrinolysis with an increase in the formation of fibrin degradation products, which can cause bleeding at multiple sites. Because DIC can have a variety of causes and may coexist with systemic fibrinolysis, such as in pulmonary embolism or deep vein thrombosis, the d-Dimer test is not specific for DIC (95). 

XIII Fibrin-stabilizing factor Both Activated form cross-links fibrin, forming a hard clot... 

Figure 12.4 Terminal steps of a blood clot (haemostatic plug) cross-linked fibrin molecules bind together platelets and red blood cells congregated at the site of damage, thus preventing loss of any more blood...

Simultaneously, activation of the extrinsic coagulation cascade occurs as a result of exposure of blood to the thrombogenic lipid core and endothelium, which are rich in tissue factor. This pathway ultimately leads to the formation of a fibrin clot composed of fibrin strands, cross-linked platelets, and trapped red blood cells. 

The most important reaction in blood clotting is the conversion, catalyzed by thrombin, of the soluble plasma protein fibrinogen (factor 1) into polymeric fibrin, which is deposited as a fibrous network in the primary thrombus. Thrombin (factor 11a) is a serine proteinase (see p. 176) that cleaves small peptides from fibrinogen. This exposes binding sites that spontaneously allow the fibrin molecules to aggregate into polymers. Subsequent covalent cross-linking of fibrin by a transglutaminase (factor Xlll) further stabilizes the thrombus. 

Active thrombin not only converts fibrinogen into fibrin, but also indirectly promotes its own synthesis by catalyzing the activation of factors V and Vlll. In addition, it catalyzes the activation of factor Xlll and thereby triggers the cross-linking of the fibrin. 

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