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

Fazoil I. Ataullakhanov; Natalya M. Dashkevich; Ruzanna A. Ovsepyan; Tatiana A. Vuimo; Anna N. Balandina; Anna D. Kuprash; Dorzo-Cyren B. Ayusheev; Alexey I. Bernakevich; Elena I. Sinauridze

doi:10.1055/a-2516-7384

Thrombosis and Haemostasis, Table of Contents

CC BY 4.0 · Thromb Haemost
DOI: 10.1055/a-2516-7384

New Technologies, Diagnostic Tools and Drugs

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

Fazoil I. Ataullakhanov

¹Laboratory of Physiology and Biophysics of the Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia

²Physiology Department, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

,

Natalya M. Dashkevich

³Laboratory of Cell Hemostasis Mechanisms, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia

,

Ruzanna A. Ovsepyan

³Laboratory of Cell Hemostasis Mechanisms, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia

,

Tatiana A. Vuimo

⁴Scientific Department, Hematological Corporation HemaCore LLC, Moscow, Russia

,

Anna N. Balandina

⁵Laboratory of Blood Coagulation Regulation and Integral Phenotyping, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia

⁶Laboratory of Cell Hemostasis and Thrombosis, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Ministry of Healthcare, Moscow, Russia

,

Anna D. Kuprash

⁵Laboratory of Blood Coagulation Regulation and Integral Phenotyping, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia

⁶Laboratory of Cell Hemostasis and Thrombosis, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Ministry of Healthcare, Moscow, Russia

,

Dorzo-Cyren B. Ayusheev

⁷Department of Large Vessel Endoprosthetics, N.N. Priorov National Medical Research Center for Traumatology and Orthopedics, Ministry of Healthcare, Moscow, Russia

,

Alexey I. Bernakevich

⁸Clinical and Diagnostic Laboratory, N.N. Priorov National Medical Research Center for Traumatology and Orthopedics, Ministry of Healthcare, Moscow, Russia

,

Elena I. Sinauridze

¹Laboratory of Physiology and Biophysics of the Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia

⁹Laboratory of Biophysics, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Ministry of Healthcare, Moscow, Russia

› Author Affiliations

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.

Keywords

anticoagulants - blood coagulation - spatial clot growth rate - spatial thrombin distribution - Thrombodynamics-4D

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References

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Supplementary Material