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  • Title: Evidence that fibrinogen γ' directly interferes with protofibril growth: implications for fibrin structure and clot stiffness.
    Author: Allan P, Uitte de Willige S, Abou-Saleh RH, Connell SD, Ariëns RA.
    Journal: J Thromb Haemost; 2012 Jun; 10(6):1072-80. PubMed ID: 22463367.
    Abstract:
    BACKGROUND: Fibrinogen contains an alternatively spliced γ-chain (γ'), which mainly exists as a heterodimer with the common γA-chain (γA/γ'). Fibrinogen γ' has been reported to inhibit thrombin and modulate fibrin structure, but the underlying mechanisms are unknown. OBJECTIVE: We aimed to investigate the molecular mechanism underpinning the influence of γ' on fibrin polymerization, structure and viscoelasticity. METHODS: γA/γA and γA/γ' fibrinogens were separated using anion exchange chromatography. Cross-linking was controlled with purified FXIIIa and a synthetic inhibitor. Fibrin polymerization was analyzed by turbidity and gel-point time was measured using a coagulometer. We used atomic force microscopy (AFM) to image protofibril formation while final clot structure was assessed by confocal and scanning electron microscopy. Clot viscoelasticity was measured using a magnetic microrheometer. RESULTS: γA/γ' fibrin formed shorter oligomers by AFM than γA/γA, which in addition gelled earlier. γA/γ' clots displayed a non-homogenous arrangement of thin fibers compared with the uniform arrangements of thick fibers for γA/γA clots. These differences in clot structure were not due to thrombin inhibition as demonstrated in clots made with reptilase. Non-cross-linked γA/γA fibrin was approximately 2.7 × stiffer than γA/γ'. Cross-linking by FXIIIa increased the stiffness of both fibrin variants; however, the difference in stiffness increased to approximately 4.6 × (γA/γA vs. γA/γ'). CONCLUSIONS: Fibrinogen γ' is associated with the formation of mechanically weaker, non-uniform clots composed of thin fibers. This is caused by direct disruption of protofibril formation by γ'.
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