Asymmetrical Forces Dictate the Distribution and Morphology of Platelets in Blood Clots

Abstract

Primary hemostasis consists in the activation of platelets, which spread on the exposed extracellular matrix at the injured vessel surface. Secondary hemostasis, the coagulation cascade, generates a fibrin clot in which activated platelets and other blood cells get trapped. Active platelet-dependent clot retraction reduces the clot volume by extruding the serum. Thus, the clot architecture changes with time of contraction, which may have an important impact on the healing process and the dissolution of the clot, but the precise physiological role of clot retraction is still not completely understood. Since platelets are the only actors to develop force for the retraction of the clot, their distribution within the clot should influence the final clot architecture. We analyzed platelet distributions in intracoronary thrombi and observed that platelets and fibrin co-accumulate in the periphery of retracting clots in vivo. A computational mechanical model suggests that asymmetric forces are responsible for a different contractile behavior of platelets in the periphery versus the clot center, which in turn leads to an uneven distribution of platelets and fibrin fibers within the clot. We developed an in vitro clot retraction assay that reproduces the in vivo observations and follows the prediction of the computational model. Our findings suggest a new active role of platelet contraction in forming a tight fibrin- and platelet-rich boundary layer on the free surface of fibrin clots.

Blood clot contraction: Mechanisms, pathophysiology, and disease

“…Collectively, contracting platelets induce dramatic remodeling of the fibrin network by decreasing the clot volume, as well as increasing its density and stiffness associated with reduced porosity and permeability of the clot. The contraction of blood clots is a spatially heterogeneous process, such that the peripheral part of the macroscopic clot contracts faster and the shrinkage propagates toward the center [ 21 ] since platelets pull uniformly in all directions but there is asymmetry because the contractile forces acting on the periphery are not compensated [ 21 , 24 ].

Figure 2 Time-lapse images of a contracting platelet that causes bending, kinking, and agglomeration of a single fibrin fiber.

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Platelet functional responses and signalling: the molecular relationship. Part 1: responses.

“…Recent studies suggested that contraction may play a role in re-arranging thrombus architecture, e.g. expelling procoagulant platelets to the platelet thrombus periphery to form fibrin there [27], organizing ischemic thrombi [82], or increasing platelet concentration at the fibrin clot periphery, also mechanically increasing local fibrin density [83].…”

Incorporation of Fibrin, Platelets, and Red Blood Cells into a Coronary Thrombus in Time and Space

“…3,8 An in silico model for clot contraction can account for this redistribution of clot components. 8 Moreover, other studies demonstrated the presence of a fibrin biofilm on the surface of in vitro clots, wound clots, and in thrombi, which prevents microbial invasion. 9 The presence of fibrin on the surface also impairs fibrinolysis.…”

“…6 Additional effects of clot contraction have been established through studies ex vivo, in vitro, and in silico. 3,7,8 Procoagulant platelets move to the surface of in vitro and in vivo clots during clot contraction, where they facilitate fibrinogen transformation to fibrin. 7 Studies of human coronary artery thrombi also showed platelets and fibrin on the surface, demonstrating clot contraction in vivo.…”

“…7 Studies of human coronary artery thrombi also showed platelets and fibrin on the surface, demonstrating clot contraction in vivo. 3,8 An in silico model for clot contraction can account for this redistribution of clot components. 8 Moreover, other studies demonstrated the presence of a fibrin biofilm on the surface of in vitro clots, wound clots, and in thrombi, which prevents microbial invasion.…”