Heparin and Direct Oral Anticoagulants have Different Effects on the Phases of Activation and Spatial Spread of Blood Coagulation.

Abstract

Background:  Various reactions are involved in the phases of activation and further propagation of coagulation in space. The effects of different anticoagulants on these phases are unknown. Our aim was to study how different anticoagulants affect the activation and propagation phases of coagulation.

Materials and methods:  Coagulation in the presence of low-molecular-weight heparin (nadroparin), and direct oral thrombin or factor Xa inhibitors (dabigatran and rivaroxaban, respectively) was studied in vitro and ex vivo via a global blood coagulation assay (Thrombodynamics-4D), which allows simultaneous analysis of thrombin activity in space and the clot growth rate. The ex vivo measurements were carried out in dynamics (8-9 days). The presence of asymptomatic thrombosis after 7 to 8 days of treatment was determined for each group of patients via ultrasound of the lower extremities.

Results:  All the tested anticoagulants inhibited thrombin generation but resulted in different patterns of thrombin spatial distribution and clot growth. The reversible inhibitors-dabigatran and rivaroxaban-inhibited the initiation phase of coagulation, while further clot growth was altered moderately. Irreversible nadroparin weakly affected the initiation phase of thrombin generation, but unlike dabigatran and rivaroxaban, it could completely suppress spatial thrombin propagation. Asymptomatic thrombosis was observed in 0%, 11%, and 29% of the patients in the nadroparin, dabigatran, and rivaroxaban groups, respectively.

Conclusion:  Antithrombin-dependent and independent inhibitors act differently on different phases of coagulation. High concentrations of dabigatran or rivaroxaban are insufficient to completely prevent fibrin clot growth, but even small amounts of heparin completely suppress this growth, due to factor IXa inhibition.