Thrombin generation in patients with thrombotic microangiopathy in critical illnesses

Introduction. The development of thrombotic microangiopathy of critical illnesses (TTP-like syndrome) is traditionally considered from the standpoint of imbalance in the von Willebrand factor system — ADAMTS-13, while coagulation disorders remain poorly studied.

Aim: to study the dynamics of fibrin clot formation and thrombin generation in patients with TTP-like syndrome, as well as their relationship with the severity of endothelial activation/damage, the activity of natural anticoagulant systems and complement systems.

Materials and methods. A prospective observational cohort study included 76 patients who underwent surgical treatment for heart disease and developed TTP-like syndrome as a postoperative complication. Inclusion criteria: multiple organ failure, thrombocytopenia <100×10⁹/l three days after surgery, schistocytosis >1%. The dynamics of fibrin formation and thrombin generation were assessed using the Thrombodynamics test; concentrations of natural anticoagulants, markers of endothelial damage, and the activity of complement system components were also evaluated.

Results. The mortality rate was 40.8% (31 patients). The analysis of three models revealed: 1) the complement system determines thrombin generation; 2) an increase in the concentration of natural anticoagulants, primarily thrombomodulin, inhibits the generation of thrombin on the activator and the propagation of its activation wave; 3) the degree of endothelial damage, starting with desquamation of the glycocalyx (reflected in an increase in plasma concentrations of syndecan-1 and heparan sulfate) and ending with the destruction of intercellular contacts and necrosis of endothelial cells with the release of PECAM и VE-cadherin; 4) endotheliopathy leads to platelet activation and consumption, as well as tissue hypoxia.

Conclusion. TTP-like syndrome is characterized by inhibition of thrombin generation, the degree of which depends on the severity of endothelial damage. This is due to the activation of natural anticoagulant systems. Desquamation of the endothelial glycocalyx reduces its resistance to the terminal complement complex which increases endothelial damage. In parallel, complement-mediated activation of platelets occurs. Deep endothelial damage, as well as the development of arterial microthrombosis, despite low thrombin generation, lead to an increase in hypoxic organ damage and poorer treatment outcomes.

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