Plasma fibrin clot properties in the G20210A prothrombin mutation carriers following venous thromboembolism: the effect of rivaroxaban

Agnieszka Janion-Sadowska; Joanna Natorska; Jakub Siudut; Michal Zabczyk; Andrzej Stanisz; Anetta Undas

doi:10.1160/TH17-01-0060

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(09): 1739-1749
DOI: 10.1160/TH17-01-0060

Coagulation and Fibrinolysis

Schattauer GmbH

Plasma fibrin clot properties in the G20210A prothrombin mutation carriers following venous thromboembolism: the effect of rivaroxaban

Authors

Agnieszka Janion-Sadowska

¹Intensive Cardiac Care Unit, Świetokrzyskie Cardiology Centre, Kielce, Poland
Joanna Natorska

²Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland

³Krakow Centre for Medical Research and Technologies, John Paul II Hospital, Krakow, Poland
Jakub Siudut

²Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland

³Krakow Centre for Medical Research and Technologies, John Paul II Hospital, Krakow, Poland
Michal Zabczyk

²Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
Andrzej Stanisz

⁴Department of Bioinformatic and Telemedicine, Jagiellonian University Medical College, Krakow, Poland
Anetta Undas

²Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland

³Krakow Centre for Medical Research and Technologies, John Paul II Hospital, Krakow, Poland

Abstract

Summary

We sought to investigate whether the G20210A prothrombin mutation modifies plasma fibrin clot properties in patients after venous thromboembolism (VTE) and how rivaroxaban treatment affects these alterations. We studied 34 prothrombin mutation heterozygous carriers and sex- and age-matched 34 non-carriers, all at least three months since the first VTE episode, before and during treatment with rivaroxaban. Clot permeability (K_s) and clot lysis time (CLT) with or without elimination of thrombin activatable fibrinolysis inhibitor (TAFI) were assessed at baseline, 2–6 hours (h) after and 20–25 h after intake of rivaroxaban (20 mg/day). At baseline, the prothrombin mutation group formed denser clots (K_s −12 %, p=0.0006) and had impaired fibrinolysis (CLT +14 %, p=0.004, and CLT-TAFI +13 %, p=0.03) compared with the no mutation group and were similar to those observed in 15 healthy unrelated prothrombin mutation carriers. The G20210A prothrombin mutation was the independent predictor for K_s and CLT before rivaroxaban intake. At 2–6 h after rivaroxaban intake, clot properties improved in both G20210A carriers and non-carriers (K_s +38 %, and +37 %, CLT −25 % and −25 %, CLT-TAFI −20 % and −24 %, respectively, all p<0.001), but those parameters were worse in the prothrombin mutation group (K_s −12.8 %, CLT +17 %, CLT-TAFI +13 %, all p<0.001). Rivaroxaban concentration correlated with fibrin clot properties. After 20–25 h since rivaroxaban intake most clot properties returned to baseline. Rivaroxaban-related differences in clot structure were confirmed by scanning electron microscopy images. In conclusion, rivaroxaban treatment, though improves fibrin clot properties, cannot abolish more prothrombotic fibrin clot phenotype observed in prothrombin mutation carriers following VTE.

Keywords

Fibrin clot - fibrinolysis - prothrombin mutation - rivaroxaban - venous thromboembolism

Full Text

References

References
1 Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015; 12: 464-474.
2 Rosendaal FR, Doggen CJ, Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-708.
3 Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009; 07 (Suppl. 01) 301-304.
4 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-3703.
5 Colucci M, Binetti BM, Tripodi A. et al. Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism. Blood 2004; 103: 2157-2161.
6 Pollak ES, Lam HS, Russell JE. The G20210A mutation does not affect the stability of prothrombin mRNA in vivo. Blood 2002; 100: 359-362.
7 Kyrle PA, Mannhalter C, Béguin S. et al. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol 1998; 18: 1287-1291.
8 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21: 131-142.
9 Aleman MM, Walton BL, Byrnes JR. et al. Elevated prothrombin promotes venous, but not arterial, thrombosis in mice. Arterioscler Thromb Vasc Biol 2013; 33: 1829-1836.
10 Butenas S, van’t Veer C, Mann KG. „Normal” thrombin generation. Blood 1999; 94: 2169-2178.
11 Wolberg AS, Monroe DM, Roberts HR. et al. Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood 2003; 101: 3008-3013.
12 Franchini M, Mannucci PM. Direct oral anticoagulants and venous thromboembolism. Eur Respir Rev 2016; 25: 295-302.
13 Lau YC, Xiong Q, Shantsila E. et al. Effects of non-vitamin K antagonist oral anticoagulants on fibrin clot and whole blood clot formation, integrity and thrombolysis in patients with atrial fibrillation. J Thromb Thrombolysis 2016; 42: 535-544.
14 Gulseth MP, Michaud J, Nutescu EA. Rivaroxaban: an oral direct inhibitor of factor Xa. Am J Health Syst Pharm 2008; 65: 1520-1529.
15 Varin R, Mirshahi S, Mirshahi P. et al. Whole blood clots are more resistant to lysis than plasma clots-greater efficacy of rivaroxaban. Thromb Res 2013; 131: e100-109.
16 Gerotziafas GT, Elalamy I, Depasse F. et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007; 05: 886-888.
17 Varin R, Mirshahi S, Mirshahi P. et al. Improvement of thrombolysis by Riva-roxaban, an anti-Xa inhibitor. Potential therapeutic importance in patients with thrombosis. Blood 2008; 112: 3031
18 Semeraro F, Incampo F, Ammollo CT. et al. Dabigatran but not rivaroxaban or apixaban treatment decreases fibrinolytic resistance in patients with atrial fibrillation. Thromb Res 2016; 138: 22-29.
19 Undas A, Zawilska K, Ciesla-Dul M. et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114: 4272-4278.
20 Zalewski J, Rychlak R, Góralczyk T. et al. Rivaroxaban concentration in patients with deep vein thrombosis who reported thrombus progression or minor hemorrhagic complications: first Polish experience. Pol Arch Med Wewn 2014; 124: 553-555.
21 Hemker HC. Thrombin generation in a reconstituted system: a comment. Thromb Haemost 2002; 87: 551-554.
22 Ząbczyk M, Majewski J, Karkowski G. et al. Vitamin K antagonists favourably modulate fibrin clot properties in patients with atrial fibrillation as early as after 3 days of treatment: Relation to coagulation factors and thrombin generation. Thromb Res 2015; 136: 832-838.
23 Undas A, Podolec P, Zawilska K. et al. Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke. Stroke 2009; 40: 1499-1501.
24 Siudut J, Świat M, Undas A. Altered fibrin clot properties in patients with cerebral venous sinus thrombosis: association with the risk of recurrence. Stroke 2015; 46: 2665-2668.
25 Pankiw-Bembenek O, Zalewski J, Goralczyk T. et al. A history of early stent thrombosis is associated with prolonged clot lysis time. Thromb Haemost 2012; 107: 513-520.
26 Hotaling NA, Bharti K, Kriel H. et al. A validated open source nanofiber diameter measurement tool. Biomaterials 2015; 61: 327-338.
27 Meltzer ME, Lisman T, de Groot PG. et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116: 113-121.
28 Foley JH, Kim PY, Mutch NJ. et al. Insights into thrombin activatable fibrinolysis inhibitor function and regulation. J Thromb Haemost 2013; (Suppl. 01) 306-315.
29 van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-2859.
30 Buller HR, Lensing AW, Prins MH. et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood 2008; 112: 2242-2247.
31 Ten Cate H, Hemker HC. Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate?. J Am Heart Assoc 2016; 05: e003553
32 Standeven KF, Grant PJ, Carter AM. et al. Functional analysis of the fibrinogen Aalpha Thr312Ala polymorphism: effects on fibrin structure and function. Circulation 2003; 107: 2326-2330.
33 Lim BC, Ariëns RA, Carter AM. et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361: 1424-1431.
34 Undas A, Góralczyk T. Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment. Adv Clin Exp Med 2016; 25: 1321-1330.
35 Undas A, Goralczyk T. Non-vitamin K antagonist oral anticoagulants in patients with severe inherited thrombophilia: a series of 33 patients. Blood Coagul Fibrinolysis. 2017 Epub ahead of print