Platelets and the permeability of fibrin network developed in human plasma

Gelder, James M. van; Nair, C H; Dhall, D.P.

doi:10.1016/0049-3848(93)90143-c

Cited by 2 publications

(1 citation statement)

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“…Although the rheology of this fibrin gel was not reported, perfusion data suggest that the network also greatly differs from the one we report herein. In support of our proposal that PF4 mediates a specific pattern of polymerization, confocal micrographs illustrate that the network surrounding platelets differs from that of a "typical" fibrin clot (37) and, providing that retraction had been prevented, has a low permeability (60).…”

Section: Discussionmentioning

confidence: 77%

Platelet Factor 4 (CXCL4) Seals Blood Clots by Altering the Structure of Fibrin

Amelot

Tagzirt

Ducouret

et al. 2007

Journal of Biological Chemistry

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Platelet factor-4 (PF4/CXCL4) is an orphan chemokine released in large quantities in the vicinity of growing blood clots. Coagulation of plasma supplemented with a matching amount of PF4 results in a translucent jelly-like clot. Saturating amounts of PF4 reduce the porosity of the fibrin network 4.4-fold and decrease the values of the elastic and loss moduli by 31-and 59-fold, respectively. PF4 alters neither the cleavage of fibrinogen by thrombin nor the cross-linking of protofibrils by activated factor XIII but binds to fibrin and dramatically transforms the structure of the ensuing network. Scanning electron microscopy showed that PF4 gives rise to a previously unreported pattern of polymerization where fibrin assembles to form a sealed network. The subunits constituting PF4 form a tetrahedron having at its corners a RPRH motif that mimics (in reverse orientation) the Gly-His-Arg-Pro-amide peptides that co-crystallize with fibrin. Molecular modeling showed that PF4 could be docked to fibrin with remarkable complementarities and absence of steric clashes, allowing the assembly of irregular polymers. Consistent with this hypothesis, as little as 50 M the QVRPRHIT peptide derived from PF4 affects the polymerization of fibrin.In addition to catalyzing the conversion of fibrinogen to fibrin, thrombin activates the G protein-coupled protease-activated receptor 1, triggering platelet adhesion and activation (1, 2). Following activation, large quantities of platelet factor-4 (PF4/CXCL4), 3 a major component of the ␣-granules (15-20 g/10 9 platelets), are released into the vicinity of growing blood clots, such that amounts in excess of 5 g/ml are found in serum (3, 4). PF4 is an asymmetrically associated homo-tetrameric (70 residues/subunit) chemokine that interacts with a variant of CXCR3. The physiologic function of PF4 is not fully understood even if one of the first clues to the existence of endogenous angiogenesis inhibitors came with the observation that it inhibits endothelial cell proliferation (5). PF4 is otherwise mainly known for binding polysulfated glycosaminoglycans such as heparin and has been extensively studied for its role in heparin-induced thrombocytopenia (6). Generally speaking, PF4 binds to glycosaminoglycans, modulating their activity. Both pro-coagulant and anti-coagulant properties for PF4 have been reported. PF4 accelerates the activation of the anticoagulant protein C (7, 8); in contrast, studies on transgenic mice demonstrate that whereas PF4 contributes to thrombus formation, PF4-null mice had no overt bleeding diathesis (9).Fibrinogen is a M r 340,000 glycoprotein consisting of a pair of ␣-, ␤-, and ␥-chains. The molecule comprises two outer D-nodules connected through coiled-coil domains to a central E-nodule (10, 11). The E-nodule includes all six NH 2 termini, and each D-nodule contains the COOH terminus of the ␤-and ␥-chains folded into globular domains, namely ␤C and ␥C (12, 13). Fibrin formation is initiated by a thrombin-catalyzed removal of two peptides (fibrinopeptides A) from t...

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Section: Discussionmentioning

confidence: 77%