Thrombin generation in patients after acute deep-vein thrombosis

Arina J. ten Cate-Hoek; ArneW J. H. Dielis; Henri M. H. Spronk; Rene van Oerle; Karly Hamulyak; Martin H. Prins; Hugo ten Cate

doi:10.1160/TH08-02-0099

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 100(02): 240-245
DOI: 10.1160/TH08-02-0099

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Thrombin generation in patients after acute deep-vein thrombosis

Arina J. ten Cate-Hoek

¹Department of Internal Medicine, Division of Hematology, University Hospital Maastricht, Maastricht, the Netherlands

³Department of Epidemiology, Maastricht University, Maastricht, the Netherlands

,

ArneW J. H. Dielis

²Department of Internal Medicine, Laboratory for Clinical Thrombosis and Hemostasis, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands

,

Henri M. H. Spronk

²Department of Internal Medicine, Laboratory for Clinical Thrombosis and Hemostasis, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands

,

Rene van Oerle

¹Department of Internal Medicine, Division of Hematology, University Hospital Maastricht, Maastricht, the Netherlands

,

Karly Hamulyak

¹Department of Internal Medicine, Division of Hematology, University Hospital Maastricht, Maastricht, the Netherlands

,

Martin H. Prins

³Department of Epidemiology, Maastricht University, Maastricht, the Netherlands

,

Hugo ten Cate

²Department of Internal Medicine, Laboratory for Clinical Thrombosis and Hemostasis, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands

› Institutsangaben

Abstract

Summary

Thrombin generation measurement may be of value for assessing the risk of venous thromboembolism, but its long term profile has not been assessed in patients. We evaluated thrombin generation by Calibrated Automated Thrombogram (CAT) in plasma during follow up of 104 consecutive patients after an acute episode of deep venous thrombosis. Blood was drawn three times over the course of 24 months. Thrombin generation was measured in absence and presence of thrombomodulin and compared to a reference range derived from thrombin generation curves in 137 healthy volunteers. Thrombin generation of patients showed significantly higher endogenous thrombin potential (ETP) and peak height compared to the reference population. Differences were more pronounced in assays triggered with I pM TF. Inhibition by thrombomodulin was attenuated in patients off anticoagulants as compared to the reference population (21 % vs.42.2%, p<0.0001); inhibition in patients on anticoagulant treatment was less pronounced (9.7%, p<0.000l). Protein C activity, protein S antigen as well as free protein S showed highly negative correlation with ETP in all patients. A significant negative relation was found between FVIII levels and thrombomodulin induced reduction of ETP and peak height. In conclusion, thrombin generation by CAT reflects changes in coagulation status in patients following athromboembolic event and is most sensitive at CAT analysis triggered with I pM TEA role for factor VIII as an important attributable cause of hypercoagulability is reflected by the reduced inhibitory effect of thrombomodulin at high factor VIII levels.

Keywords

Deep vein thrombosis - factor VIII - hypercoagulability - thrombin

Volltext

Referenzen

References
1 Kearon C. Long-term management of patients after venous thromboembolism. Circulation 2004; 110 (Suppl. 09) I10-18.
2 Piovella F, Crippa L, Barone M. et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002; 87: 515-522.
3 Prandoni P, Lensing AW, Prins MH. et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955-960 Summary for patients in: Ann Intern Med 2002; 137: I32..
4 Palareti G, Legnani C, Cosmi B. et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002; 87: 7-12.
5 Palareti G, Legnani C, Cosmi B. et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 2003; 108: 313-318.
6 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-462.
7 Legnani C, Cini M, Cosmi B. et al. Risk of deep vein thrombosis: interaction between oral contraceptives and high factor VIII levels. Haematologica 2004; 89: 1347-1351.
8 Kreuz W, Stoll M, Junker R. et al. Familial elevated factor VIII in children with symptomatic venous thrombosis and post-thrombotic syndrome: results of a multicenter study. Arterioscler Thromb Vasc Biol 2006; 26: 1901-1906.
9 Meijers JC, Tekelenburg WL, Bouma BN. et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
10 van Hylckama Vlieg A, van der Linden IK. et al. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95: 3678-3682.
11 Van Hylckama Vlieg A, Christiansen SC, Luddington R. et al. Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence. Br J Haematol 2007; 138: 769-774.
12 Hron G, Kollars M, Binder BR. et al. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. J Am Med Assoc 2006; 296: 397-402.
13 Couturaud F, Duchemin J, Leroyer C. Groupe d'Etude de la Thrombose de Bretagne Occidentale (G.E.T.B.O). Thrombin generation in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. A pilot study. et al. Thromb Haemost 2008; 99: 223-228.
14 Gatt A, van Veen JJ, Cooper P. et al. Protein C deficiency screening using a thrombin generation assay - an upgrade. Thromb Haemost 2007; 98: 691-692.
15 Lincz LF, Lonergan A, Scorgie FE. et al. Endogenous thrombin potential for predicting risk of venous thromboembolism in carriers of factor V Leiden. Pathophysiol Haemost Thromb 2006; 35: 435-439.
16 Geerts WH, Pineo GF, Heit JA. et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 338S-400S.
17 van Veen JJ, Gatt A, Cooper PC. et al. Corn trypsin inhibitor in fluorogenic thrombin-generation measurements is only necessary at low tissue factor concentrations and influences the relationship between factor VIII coagulant activity and thrombogram parameters. Blood Coagul Fibrinolysis 2008; 19: 183-189.
18 Dargaud Y, Luddington R, Baglin TP. Elimination of contact factor activation improves measurement of platelet-dependent thrombin generation by calibrated automated thrombography at low-concentration tissue factor. J Thromb Haemost 2006; 04: 1160-1161.
19 Hackeng TM, Seré KM, Tans G. et al. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA 2006; 103: 3106-3111.
20 Dargaud Y, Trzeciak MC, Bordet JC. et al. Use of calibrated automated thrombinography +/- thrombomodulin to recognise the prothrombotic phenotype. Thromb Haemost 2006; 96: 562-567.
21 Penning-van Beest FJ, Gómez García EB, van der Meer FJ. et al. Levels of vitamin K-dependent procoagulant and anticoagulant proteins in over-anticoagulated patients. Blood Coagul Fibrinolysis 2002; 13: 733-739.