Assays of fibrin network properties altered by VKAs in atrial fibrillation – importance of using an appropriate coagulation trigger

Michal Ząbczyk; Margareta Blombäck; Jacek Majewski; Grzegorz Karkowski; Hakan N. Wallen; Anetta Undas; Shu He

doi:10.1160/TH14-07-0591

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(04): 851-861
DOI: 10.1160/TH14-07-0591

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Assays of fibrin network properties altered by VKAs in atrial fibrillation – importance of using an appropriate coagulation trigger

Michal Ząbczyk

¹Department of Cardiac Surgery, Anaesthesiology and Experimental Cardiology, Institute of Cardiology, Jagiellonian University, Medical College and John Paul II Hospital, Kraków, Poland

²Department of Molecular Medicine and Surgery/Coagulation Research, Karolinska Institutet, Stockholm, Sweden

,

Margareta Blombäck

²Department of Molecular Medicine and Surgery/Coagulation Research, Karolinska Institutet, Stockholm, Sweden

³Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

,

Jacek Majewski

⁴Department of Electrocardiology, Institute of Cardiology, Jagiellonian University, Medical College and John Paul II Hospital, Kraków, Poland

,

Grzegorz Karkowski

⁴Department of Electrocardiology, Institute of Cardiology, Jagiellonian University, Medical College and John Paul II Hospital, Kraków, Poland

,

Hakan N. Wallen

³Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

,

Anetta Undas

¹Department of Cardiac Surgery, Anaesthesiology and Experimental Cardiology, Institute of Cardiology, Jagiellonian University, Medical College and John Paul II Hospital, Kraków, Poland

,

Shu He

³Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

› Author Affiliations

Abstract

Summary

Atrial fibrillation (AF) is a prothrombotic condition, involving increased thrombin generation and fibrinogen concentrations. Vitamin K antagonists (VKAs) prevent arterial thromboembolism if optimal anticoagulation is achieved by individualised drug doses, assessed by determining the Prothrombin time-related International Normalized Ratio (Pt-INR). There is evidence that formation of tight-laced fibrin networks is pathogenic in prothrombotic diseases. This study was performed among AF patients, to test whether long-term treatment with VKAs affects the structure of fibrin networks, and whether the effect is altered by employing different coagulation triggers: exogenous thrombin (1 IU/ml), 10 pM tissue factor (TF) or a commercial Pt-INR reagent (containing 400-fold more TF). In the thrombin-based method, fibrin network porosity (scanning electron microscopy) and liquid permeability (flow measurements) correlated inversely to fibrinogen concentrations, while positive correlations to the degree of anticoagulation were shown with the Pt-INR reagent. In the method with 10 pM TF, the two above relationships were detected, though the influence of Pt-INR was more profound than that of fibrinogen concentrations. Moreover, greater shortening of clot lysis time (CLT) arose from more permeable clots. As a coagulation trigger, 10 pM TF vs exogenous thrombin or the Pt-INR reagent is more informative in reflecting the in vivo process from thrombin generation to fibrin formation. Since fibrin network permeability rose in parallel to elevations of INR and shortening of CLT in AF patients, antithrombotic effects on prevention of thrombotic complications may be achieved from impairment of thrombin generation, resulting in formation of permeable clots susceptible to fibrinolysis.

Keywords

Atrial fibrillation - vitamin K antagonists - fibrin network permeability - Pt-INR - coagulation trigger

Full Text

References

References
1 Roldán V, Marín F, Blann AD. et al. Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation. Eur Heart J 2003; 24: 1373-1380.
2 Li-Saw-Hee FL, Blann AD, Gurney D. et al. Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation. Effects of cardioversion and return of left atrial function. Eur Heart J 2001; 22: 1741-1747.
3 Lip GY, Lim HS. Atrial fibrillation and stroke prevention. Lancet Neurol 2007; 06: 981-993.
4 Ansell J, Hirsh J, Hylek E. et al. American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 Suppl 160-198.
5 Keeling D, Baglin T, Tait C. et al. British Committee for Standards in Haematology. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol 2011; 154: 311-324.
6 Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82: 165-174.
7 Stavrou E, Schmaier AH. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb Res 2010; 125: 210-215.
8 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
9 He S, Johnsson H, Zabczyk M. et al. Fibrinogen depletion after plasma-dilution: impairment of proteolytic resistance and reversal via clotting factor concentrates. Thromb Haemost 2014; 111: 417-428.
10 Undas A, Ariëns RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31: e88-e99.
11 Blombäck M, He S, Bark N. et al. Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. Br J Haematol 2011; 152: 758-765.
12 He S, Blombäck M, Bark N. et al. The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis. Thromb Haemost 2010; 103: 1076-1084.
13 He S, Cao H, Antovic A. et al. Modifications of flow measurement to determine fibrin gel permeability and the preliminary use in research and clinical materials. Blood Coagul Fibrinolysis 2005; 16: 61-67.
14 Blombäck B, Okada M. Fibrin gel structure and clotting time. Thromb Res 1982; 25: 51-70.
15 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.
16 Lee AJ, Lowe GD, Woodward M. et al. Fibrinogen in relation to personal history of prevalent hypertension, diabetes, stroke, intermittent claudication, coronary heart disease, and family history: the Scottish Heart Health Study. Br Heart J 1993; 69: 338-342.
17 Rooth E, Wallen NH, Blombäck M. et al. Decreased fibrin network permeability and impaired fibrinolysis in the acute and convalescent phase of ischemic stroke. Thromb Res 2011; 127: 51-56.
18 Undas A. Fibrin clot properties and their modulation in thrombotic disorders. Thromb Haemost 2014; 112: 32-42.
19 Antovic A, Perneby C, Ekman GJ. et al. Marked increase of fibrin gel permeability with very low dose ASA treatment. Thromb Res 2005; 116: 509-517.
20 Pieters M, Undas A, Marchi R. et al. Factor XIII and Fibrinogen Subcommittee of the Scientific Standardisation Committee of the International Society for Thrombosis and Haemostasis. An international study on the standardization of fibrin clot permeability measurement: methodological considerations and implications for healthy control values. J Thromb Haemost 2012; 10: 2179-2181.
21 Castoldi E, Rosing J. Thrombin generation tests. Thromb Res 2011; 127 (Suppl. 03) 21-25.
22 Gatt A, van Veen JJ, Bowyer A. et al. Wide variation in thrombin generation in patients with atrial fibrillation and therapeutic International Normalized Ratio is not due to inflammation. Br J Haematol 2008; 142: 946-952.
23 Barcellona D, Vannini ML, Fenu L. et al. Warfarin or acenocoumarol: which is better in the management of oral anticoagulants?. Thromb Haemost 1998; 80: 899-902.