Fibrins

Fibrin, a biopolymer similar to collagen, is involved in the natural blood-dotting process. Fibrinogen, which is a 360 kDa protein, composed of three pairs of polypeptide chains is the source of fibrin. The structure of fibrin can be divided into three major sections consisting of a central domain composed of fibrinopeptide E with two pairs of fibrinopeptide A and B molecules and two terminal domains of fibrinopeptide D. Spontaneous fibrillogenesis is the formation of a linear fibril by 

It is believed that using fibrin as a cell-deliveiy vehicle is limited by fibrin s low mechanical properties and low hydration capacity (Lee and Mooney, 2001). For this reason, efforts were made to add biomacromolecules to the fibrin gel to improve its biocompatibility. Yang et al. (2011) report the s5mthesis and potential applications of hybrid molecules composed of fibrinogen coupled to the reducing ends of short-chain hyaluronic acids (sHAs) by reductive amination (Fig. 16.9). 

The sHA-fibrinogen gel was examined for its ability to encapsulate and support the differentiation of chondrocyte-like cells. Experimental data surest that the three-dimensional gel is a better support than the fibrin gel for chondrogenesis induction. 

In another studies, droplet-hydrogel composites consisting of a fibrin matrix doped with a perfluorocarbon double emulsion were generated. These composites were proposed as a uniquely bioactive platform that enables the noninvasive regulation, both spatially and temporally, of biochemical and mechanical stimuli 

Finally, Fibrin glue prepared by fibrinogen hydrolysis was proposed as vehicle for the release of bioactive adeno-associated virus (Lee et al., 2011). 

Once the generation of plasmin is completed, fibrin is cleaved into small soluble monomers, introducing carboxy-terminal lysine residues. Both tPA and uPA contain lysine binding sites that permit further binding to fibrin and thus regeneration of plasmin and more fibrin removal. 

The problem of the clotting of blood has also evoked a voluminous literature, whose contributors include phyaologists and phyadans as well as chemists no attempt can be made to review it comprehendvely here. A recent critical review is ven by Chargaff (1945) additional material is cited by Wdhlisch (1940) and Quick (1942). This discusdon is limited to the final step in the clotting process, the reaction between fibrinogen and thrombin to form a solid structure of fibrin. 

Whereas in gelatin gels the network structure appears to involve associations of specific loci spaced far apart on the rodlike parent molecule and in denatured proteins the associations appear to be nonspecific, occurring anywhere along the polypeptide cluun in the fibrin structure both types of associations seem to be involved. The specific linkages differ from those of gelatin in that they are irreverdble and are probably primary chemical bonds. 

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They release adenosine diphosphate [58-64-0 (ADP) and thromboxane [57576-52-0] which results in vascular contraction and, indirectiy, in the formation of fibrin clot. Platelet transfusions are indicated for patients with thrombocytopenia, ie, a shortage of healthy platelets or thrombocytopathy, ie, platelet malignancy associated with spontaneous hemorrhages. 

These steioids aie capable of preventing or suppressing the development of the sweUing, redness, local heat, and tenderness which characterize inflammation. They inhibit not only the acute symptoms of the inflammatory process, such as edema, fibrin deposition, and capillary dilatation, but also the chronic manifestations. There is evidence that glucocorticoids induce the synthesis of a protein that inhibits phosphoHpase A 2 (60), diminishing the release of arachidonic acid from phosphoHpids (Fig. 2), thereby reducing chemotaxis and inflammation. 

Thrombin, the two-chain derivative of the prothrombin molecule, has a molecular weight of approximately 37,000 daltons. Its proteolytic properties induce the conversion of fibrinogen to fibrin to produce the initial visible manifestation of coagulation, the soluble fibrin clot. In addition, thrombin influences the activity of Factors V, VIII, and XIII and plasmin. Thrombin affects platelet function by inducing viscous metamorphosis and the release reaction with subsequent aggregation. 

Factor II. Prothrombin is a vitamin K-dependent compound synthesized by the Hver. When prothrombin is activated it is cleaved at two sites, resulting in a two-chain molecule linked by a disulfide bond that has a molecular weight of 37,000 daltons. Thrombin is the serine protease that initiates the conversion of soluble fibrinogen into fibrin. 

Factor XIII. Factor XIII circulates in the blood as a zymogen composed of two pairs of different polypeptide chains designated A and B. Inert Factor XIII has a molecular weight of 350,000 daltons and is converted to its active transglutaminase form in the presence of thrombin and calcium. Activated Factor XIII, Xllla, induces an irreversible amide exchange reaction between the y-glutamine and S-lysine side chains of adjacent fibrin... 

The high affinity LBS is involved in the interaction of plasminogen with fibrin, a2-antiplasmin, and a plasmin inhibitor called histidine-rich glycoprotein. It has been observed that plasminogen activation takes place on the surface of fibrin and that a2-antiplasmin competitively inhibits the plasminogen—fibrin interaction at the high affinity LBS. 

The actions of plasmin on both fibrin and fibrinogen have been studied extensively. Plasmin cleaves fibrin and fibrinogen into a family of fragments known as fibrinogen and fibrin (FDP-fdp) degradation products. 

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... 

Prourokinase is a single-chain protein containing 411 amino acids (261,265,274,275). In clinical uses scu-PA does not bind to fibrin only and its use causes a decreased plasma fibrinogen of 80%. Its half-life in the circulation is 5 min. It is cleared by the fiver. It is used at 40—70 mg over 1 h and heparin is needed simultaneously. Fibrin specificity and thrombolytic efficacy are similar to that of t-PA. 

Thrombolytic Enzymes. Although atherosclerosis and the accompanying vascular wall defects are ultimately responsible for such diseases as acute pulmonary embolism, arterial occlusion, and myocardial infarction, the lack of blood flow caused by a fibrin clot directly results in tissue injury and in the clinical symptoms of these devastating diseases (54). Thrombolytic enzyme therapy removes the fibrin clot by dissolution, and has shown promise in the treatment of a number of thrombo-occlusive diseases (60). 

Streptokinase. The fibrinolytic activity of streptokinase, isolated from strains of hemolytic Streptococci, was first demonstrated in 1933 (63). Streptokinase is a secreted protein product inasmuch as filtrates free of demonstrable bacteria were found to dissolve fibrin clots with rapidity. 

Streptokinase dissolves such fibrin clots, thereby permitting effective antibiotic therapy (201). 

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