Blood clot contraction differentially modulates internal and external fibrinolysis

Abstract

Clot contraction influences the rate of fibrinolysis in vitro. Internal fibrinolysis is enhanced ∼2‐fold in contracted vs. uncontracted blood clots. External fibrinolysis is ∼4‐fold slower in contracted vs. uncontracted blood clots. Contraction can modulate lytic resistance and potentially the clinical outcome of thrombosis. Summary BackgroundFibrinolysis involves dissolution of polymeric fibrin networks that is required to restore blood flow through vessels obstructed by thrombi. The efficiency of lysis depends in part on the susceptibility of fibrin to enzymatic digestion, which is governed by the structure and spatial organization of fibrin fibers. How platelet‐driven clot contraction affects the efficacy of fibrinolysis has received relatively little study. ObjectiveHere, we examined the effects of clot contraction on the rate of internal fibrinolysis emanating from within the clot to simulate (patho)physiological conditions and external fibrinolysis initiated from the clot exterior to simulate therapeutic thrombolysis. MethodsClot contraction was prevented by inhibiting platelet myosin IIa activity, actin polymerization or platelet‐fibrin(ogen) binding. Internal fibrinolysis was measured by optical tracking of clot size. External fibrinolysis was determined by the release of radioactive fibrin degradation products. Results and ConclusionsClot contraction enhanced the rate of internal fibrinolysis ∼2‐fold. In contrast, external fibrinolysis was ~4‐fold slower in contracted clots. This dichotomy in the susceptibility of contracted and uncontracted clots to internal vs. external lysis suggests that the rate of lysis is dependent upon the interplay between accessibility of fibrin fibers to fibrinolytic agents, including clot permeability, and the spatial proximity of the fibrin fibers that modulate the effects of the fibrinolytic enzymes. Understanding how compaction of blood clots influences clot lysis might have important implications for prevention and treatment of thrombotic disorders.

Effects of Diabetes Mellitus on Fibrin Clot Structure and Mechanics in a Model of Acute Neutrophil Extracellular Traps (NETs) Formation

“…Firstly, a small number of platelets was introduced in the plasma clots due to platelet contamination in the isolated neutrophils. However, this was only 2% of the normal concentration of platelets in the blood and previous studies show that this small number will not have a relevant effect on clot properties [ 31 ]. We chose to study plasma clots instead of clots formed from whole blood to focus our study on the effects on the fibrin network, without potential confounding by other cells.…”

Rupture of blood clots: Mechanics and pathophysiology

“…6C and section S11). Second, less compacted and more obstructive thrombi experience much higher shear stresses acting on the thrombus in the blood flow, making them predisposed to rupture (section S12), especially when the hydrodynamic forces work in combination with fibrinolysis, which is highly dependent on the extent of clot contraction ( 27 ). Apparently, the rupture resistance of clots and thrombi determines the incidence of thrombotic embolism in pathological conditions associated with changes in cellular and molecular blood composition, such as hypo- or hyperfibrinogenemia, variations in platelet or leucocyte count, hematocrit, etc.…”

Visualizing thrombosis to improve thrombus resolution

“…The formation of polyhedrocytes is due to their mechanical compression by the contractile forces generated by platelets and transmitted through the fibrin network. The most obvious physiologic consequences of the compaction of deformed RBCs include densification and impermeability of the clot for pathogens and fibrinolytic enzymes 1 and altered susceptibility to external and internal fibrinolysis 30 . As a matter of fact, the polyhedrocytes are a hitherto unknown natural morphologic variant of RBCs, which have been studied under the microscope since the time of Jan Swammerdam, Marcello Malpighi, and Anthony van Leeuwenhoek.…”