Download PDF
Thromb Haemost 2011; 106(05): 901-907
DOI: 10.1160/TH11-04-0254
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Thrombin generation and activated protein C resistance in the absence of factor V Leiden correlates with the risk of recurrent venous thromboembolism in women aged 18–65 years

Kristina Sonnevi
1   Department of Internal Medicine, Karolinska Institutet Södersjukhuset, Stockholm, Sweden
,
Svetlana N. Tchaikovski
2   Cardiovascular Reasearch Institute Maastricht, Maastricht, Netherlands
5   Department of Gynecology, Otto-von-Guericke University, Magdeburg, Germany
,
Margareta Holmström
3   Hematology Centre Karolinska University, Karolinska Institutet, Stockholm, Sweden
,
Jan Rosing
2   Cardiovascular Reasearch Institute Maastricht, Maastricht, Netherlands
,
Katarina Bremme
4   Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
,
Gerd Lärfars
1   Department of Internal Medicine, Karolinska Institutet Södersjukhuset, Stockholm, Sweden
› Author Affiliations Financial support: This study was supported by research-grants (ALF) from Stockholms Läns Landsting.
Further Information

Publication History

Received: 19 April 2011

Accepted after major revision:29 July 2011

Publication Date:
23 November 2017 (online)

  PDF Download  Permissions and Reprints

Summary

Identification of patients at high risk of recurrence after a first event of venous thromboembolism (VTE) remains difficult. Resistance to activated protein C (APC) is a known risk factor for VTE, but data on the risk of recurrence is controversial. We wanted to investigate whether APC resistance in the absence of factor V Leiden, determined with global coagulation test such as the thrombin generation assay, could be used as a marker for increased risk of recurrent VTE among women 18–65 years old after a first event of VTE. In a cohort of 243 women with a first event of VTE, plasma was collected after discontinuation of anticoagulant treatment and the patients were followed up for 46 months (median). Thrombin generation was measured via calibrated automated thrombography, at 1 pM and 10 pM of tissue factor (TF). In women without factor V Leiden (n=117), samples were analysed in the absence and in the presence of APC. Increase in ETP (endogenous thrombin potential) and peak height analysed in the presence of APC correlated significantly with higher risk of recurrence. At 1 pM, peak height correlated with increased risk of recurrence. In conclusion, high thrombin generation in the presence of APC, in women after a first event of VTE is indicative for an increased risk of a recurrence. We also found that thrombin generation at low TF (1 pM) is correlated with the risk of recurrence. Our data suggest that APC resistance in the absence of factor V Leiden is a risk factor for recurrent VTE.

Keywords

APC-resistance - thrombin generation - venous thrombosis - recurrence - women
 

  • References

  • 1 Fowkes FJ, Price JF, Fowkes FG. Incidence of diagnosed deep vein thrombosis in the general population: systematic review. Eur J Vasc Endovasc Surg 2003; 25: 1-5.
    CrossrefPubMedGoogle Scholar
  • 2 Cushman M, Tsai AW, White RH. et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117: 19-25.
    CrossrefPubMedGoogle Scholar
  • 3 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-593.
    CrossrefPubMedGoogle Scholar
  • 4 Kyrle PA, Minar E, Bialonczyk C. et al. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004; 350: 2558-2563.
    CrossrefPubMedGoogle Scholar
  • 5 Christiansen SC, Lijfering WM, Helmerhorst FM. et al. Sex difference in risk of recurrent venous thrombosis and the risk profile for a second event. J Thromb Haemost 2010; 8: 2159-2168.
    CrossrefPubMedGoogle Scholar
  • 6 Le Gal G, Kovacs MJ, Carrier M. et al. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost 2010; 104: 498-503.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Rosing J, Middeldorp S, Curvers J. et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036-2040.
    CrossrefPubMedGoogle Scholar
  • 8 Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010; 126: 5-11.
    CrossrefPubMedGoogle Scholar
  • 9 Pesavento R, Villalta S, Prandoni P. The postthrombotic syndrome. Intern Emerg Med 2009; 5: 185-192.
    PubMedGoogle Scholar
  • 10 Douketis JD, Gu CS, Schulman S. et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med 2007; 147: 766-774.
    CrossrefPubMedGoogle Scholar
  • 11 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 13 Tripodi A, Legnani C, Chantarangkul V. et al. High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism. J Thromb Haemost 2008; 6: 1327-1333.
    CrossrefPubMedGoogle Scholar
  • 14 Bergrem A, Dahm AE, Jacobsen AF. et al. Resistance to activated protein C is a risk factor for pregnancy-related venous thrombosis in the absence of the F5 rs6025 (factor V Leiden) polymorphism. Br J Haematol 2011; 12: 1365-2141.
    PubMedGoogle Scholar
  • 15 Tournier A, Wahl D, Chaouat A. et al. Calibrated automated thrombography demonstrates hypercoagulability in patients with idiopathic pulmonary arterial hypertension. Thromb Res 2010; 126: e418-422.
    CrossrefPubMedGoogle Scholar
  • 16 Tchaikovski SN, van Vliet HA, Thomassen MC. et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost 2007; 98: 1350-1356.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Tans G, Vlieg AvH, Thomassen M. et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 2003; 122: 465-470.
    CrossrefPubMedGoogle Scholar
  • 18 Wallentin L, Yusuf S, Ezekowitz MD. et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975-983.
    CrossrefPubMedGoogle Scholar
  • 19 Wieloch M, Sjalander A, Frykman V. et al. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011; 5: 26
    PubMedGoogle Scholar
  • 20 Curvers J, Thomassen MC, Nicolaes GA. et al. Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol 1999; 1: 88-94.
    PubMedGoogle Scholar
  • 21 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
    CrossrefPubMedGoogle Scholar
  • 22 Holmberg K, Persson ML, Uhlen M. et al. Pyrosequencing analysis of thrombosis-associated risk markers. Clin Chem 2005; 51: 1549-1552.
    CrossrefPubMedGoogle Scholar
  • 23 Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost 2010; 8: 445-453.
    CrossrefPubMedGoogle Scholar
  • 24 Maurissen LF, Castoldi E, Simioni P. et al. Thrombin generation-based assays to measure the activity of the TFPI-protein S pathway in plasma from normal and protein S-deficient individuals. J Thromb Haemost 2010; 8: 750-758.
    CrossrefPubMedGoogle Scholar
  • 25 de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-1276.
    PubMedGoogle Scholar
  • 26 Tripodi A, Legnani C, Lemma L. et al. Abnormal Protac-induced coagulation inhibition chromogenic assay results are associated with an increased risk of recurrent venous thromboembolism. J Thromb Thrombolysis 2010; 30: 215-219.
    CrossrefPubMedGoogle Scholar
  • 27 Dielis AW, Castoldi E, Spronk HM. et al. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost 2008; 6: 125-131.
    PubMedGoogle Scholar
  • 28 de Visser MC, van Hylckama Vlieg A, Tans G. et al. Determinants of the APTT- and ETP-based APC sensitivity tests. J Thromb Haemost 2005; 3: 1488-1494.
    CrossrefPubMedGoogle Scholar
  • 29 Liestol S, Sandset PM, Mowinckel MC. et al. Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants. J Thromb Haemost 2007; 5: 2204-2210.
    CrossrefPubMedGoogle Scholar
  • 30 Palareti G, Cosmi B, Legnani C. et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355: 1780-1789.
    CrossrefPubMedGoogle Scholar
  • 31 Douketis J, Tosetto A, Marcucci M. et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 2010; 153: 523-531.
    CrossrefPubMedGoogle Scholar