Fibrinogen counteracts the antiadhesive effect of fibrin‐bound plasminogen by preventing its activation by adherent U937 monocytic cells

Abstract

Summary Background Fibrinogen and plasminogen strongly reduce adhesion of leukocytes and platelets to fibrin clots, highlighting a possible role for these plasma proteins in surface-mediated control of thrombus growth and stability. In particular, adsorption of fibrinogen on fibrin clots renders their surfaces non-adhesive, while the conversion of surface-bound plasminogen to plasmin by transiently adherent blood cells results in degradation of a superficial fibrin layer, leading to cell detachment. Although the mechanisms whereby these proteins exert their antiadhesive effects are different, the outcome is the same: the formation of a mechanically unstable surface that does not allow firm cell attachment. Objectives Since fibrin clots in circulation are exposed to both fibrinogen and plasminogen, their combined effect on adhesion of monocytic cells was examined. Methods Fibrin gels were coated with plasminogen and its activation by adherent U937 monocytic cells in the presence of increasing concentrations of fibrinogen was examined by either measuring 125I-labeled fibrin degradation products or plasmin amidolytic activity. Results Unexpectedly, the antiadhesive effects of two fibrin binding proteins were not additive; in fact, in the presence of fibrinogen, the effect of plasminogen was strongly reduced. An investigation of the underlying mechanism revealed that fibrinogen prevented activation of fibrin-bound plasminogen by cells. Confocal microscopy showed that fibrinogen accumulates in a thin superficial layer of a clot, where it exerts its blocking effect on activation of plasminogen. Conclusion The results point to a complex interplay between the fibrinogen- and plasminogen-dependent antiadhesive systems, which may contribute to the mechanisms that control the adhesiveness of a fibrin shell on the surface of hemostatic thrombi.

Deposition of fibrinogen on the surface of in vitro thrombi prevents platelet adhesion

“…Therefore, the conclusions and models generated in our previous studies of fibrinogen deposition on hard surfaces such as mica or glass [28,29] should provide guidance for future analyses. Likewise, our present studies and previous low resolution demonstration that fibrinogen accumulates in a thin superficial layer of fibrin clots [27] may guide future analyses of spatial distribution of fibrinogen and other proteins on the flow surface of thrombi in vivo .…”

“…The underlying mechanism of this process involves the adsorption of intact fibrinogen in a thin superficial layer of fibrin clots [27] and its self-assembly leading to the formation of a nanoscale (~10 nm) multilayer matrix [28,29]. The fibrinogen matrix is extensible, which makes it incapable of transducing strong mechanical forces via cellular integrins, resulting in weak intracellular signaling and infirm cell adhesion [16,28,29].…”

Role of fibrinogen in acute ischemic kidney injury

“…We therefore anticipated that fibrinogen might disturb cell functions that are considered instrumental in stress resistance and tubular repair. Antiadhesive effects of fibrinogen have previously been described in other cell types and have mainly been interpreted as a mechanism to limit uncontrolled thrombus growth (23,24). In vivo, we could not find any significant changes in adhesion-dependent injury and repair processes such as tubular cell detachment or epithelial repopulation of denuded basement membranes.…”

Fibrinogen matrix deposited on the surface of biomaterials acts as a natural anti-adhesive coating

“…We and other groups have shown that pure fibrin, which is a highly adhesive substrate for platelets and leukocytes, loses its capacity to support cell adhesion in the presence of soluble fibrinogen or after coating of fibrin clots with fibrinogen (19,22,45). The mechanism by which fibrinogen neutralizes the adhesion-promoting capacity of fibrin is evidently the deposition of the nonadhesive fibrinogen multilayer on its surface.…”