Fibrin‐stabilizing Factor Inhibitors

Abstract

The hydrolytic removal of the fibrinopeptides from fibrinogen changes the properties of the protein in several respects. The previously water-soluble molecules now assemble to form a gel which can be redispersed in certain media.l The cleavage of the fibrinopeptides also causes unmasking of the crosslinking sites of the protein. Under the influence of fibrinoligase (activated fibrin-stabilizing factor; FSF * ) , the fibrin gel is rapidly cross-linked via the open sites, to form an insoluble structure. The new material is a polymeric network wherein the single fibrin molecules are held together by covalent bonds. Although only about two covalent bonds are formed per mole of fibrin," the process imparts great elasticity and mechanical strength to the clot by the additional changes that the protein undergoes as a consequence of the covalent bond formation.3 Partial inhibition of the cross-linking reaction by certain compounds results in a mechanically weaker fibrin with enhanced plasmin dige~tibility.'-~ It is thus conceivable that inhibitors of fibrin crosslinking could be valuable prophylacttic or therapeutic agents in thrombotic diseases. Presumed Pathway of Transpeptidation and Inhibition of Fibrin Cross-linkingIn 1962, Lorand and coworkers proposed that transpeptidation should be considered as a probable mechanism for cross-linking. In an overall sense, an amino group of one fibrin molecule would, under the catalytic influence of fibrinoligase, react as a nucleophile with an activated carbonyl group of a neighboring fibrin molecule forming an amide bond between the two fibrin units. Since each molecule would carry both amino and carbonyl groups, the chain of cross-linking would be propagated. Although several components may

Transamidase kinetics. Amide formation in the enzymic reactions of thiol esters with amines

“…for C14H22NOSI;C,44.43;H,5.85;N,3.69%). (Lorand et al, 1968) This was prepared in one step by the method of Nilsson et al (1971). The crude crystalline base (about 5g) was dissolved in ethanol (150ml), then anhydrous diethyl ether (500ml) was admixed, followed by the addition of a saturated solution of fumaric acid in ethanol until no further precipitate was formed.…”

Syntheses and Transglutaminase-Catalyzed Incorporation of Novel Spin-Labeled Primary Amines into Proteins

“…The reason for this anamoly is not clear at present. Previously, in studies of structural requirements for inhibitors of fibrin-stabilizing factor, namely, transglutaminase, Nilsson et al, prepared various dansyl derivatives of primary amines as potential inhibitors for factor-XIIIa-mediated cross-linking of fibrin molecules (27). They found that the dansyl derivative with a pentamethylene chain (dansylcadaverine) had an optimal activity, whereas the dansyl derivative with a trimethylene chain had virtually no activity at all.…”

Sol Sherry Lecture in Thrombosis

“…85 As mentioned before, the factor XIIIa-catalyzed covalent attachment of ␣ 2 PI to fibrin significantly contributes to lytic resistance. 40,41 In fact, the hemorrhagic manifestations in patients with ␣ 2 PI deficiency are being attributed to the excessive digestibility of the clot. 86 The antibody to ␣ 2 PI was shown to be effective in promoting clot lysis in vitro and thrombolysis in vivo in animal models.…”