Download PDF
Thromb Haemost 2012; 108(02): 258-265
DOI: 10.1160/TH12-02-0098
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Flow-simulated thrombin generation profiles as a predictor of thrombotic risk among pre-menopausal women

Sumanas W. Jordan
1   Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
,
Matthew A. Corriere
2   Division of Vascular Surgery, Emory University, Atlanta, Georgia, USA
3   Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
,
Carla Y. Vossen
4   Departments of Clinical Epidemiology and Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, Netherlands
5   Division of Biomedical Genetics, Department of Medical Genetics at the University Medical Center Utrecht, Utrecht, Netherlands
,
Frits R. Rosendaal
4   Departments of Clinical Epidemiology and Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, Netherlands
,
Elliot L. Chaikof
1   Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
6   Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
7   Wyss Institute of Biologically Inspired Engineering of Harvard University, Boston, Massachusetts, USA
› Author Affiliations
Further Information

Publication History

Received: 19 February 2012

Accepted after major revision: 25 April 2012

Publication Date:
25 November 2017 (online)

    Permissions and Reprints

Summary

A large number of individuals are at risk for deep venous thrombosis (DVT) due to alterations in multiple coagulation factors and inhibitors secondary to malignancy, drug interactions, or other general medical conditions. Traditional metrics of haemostasis such as prothrombin time, partial thromboplastin time, and bleeding time, generally estimate anticoagulation status and bleeding risk rather than thrombosis risk. The objective of this study was to correlate a novel, systems-based metric of clotting potential to risk of DVT from a database derived from the Leiden Thrombophilia Study (LETS). We utilised a computational model of blood coagulation, which addresses the interplay between biochemical factors, blood flow, and physiologic surface initiation of coagulation, to calculate an individualised, systems-based metric of clotting potential, termed the flow-simulated thrombin generation (FSTG), for 210 pre-menopausal women in LETS. Both DVT and oral contraceptive (OC) use were associated with higher values of FSTG. We demonstrated a nearly three-fold increased risk of DVT for each standard deviation increase above the mean in FSTG determined under venous flow conditions, which remained highly predictive after adjustment for age and OC status (adjusted odds ratio 2.66; 95% confidence interval 1.69–4.19; p<0.0001). In conclusion, a systems-based screening approach that integrates biochemical factors and flow haemodynamics identifies small subgroups of patients at risk of thrombosis that may benefit from oral anticoagulants.

Keywords

Thrombosis - blood coagulation - computer simulation - thromboembolism
 

  • References

  • 1 Dentali F, Crowther M, Ageno W. Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: A meta-analysis. Blood 2006; 107: 2766-2773.
    CrossrefPubMedGoogle Scholar
  • 2 Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost 2001; 86: 395-403.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Bloemenkamp KWM, Helmerhorst FM, Rosendaal FR. et al. Venous thrombosis, oral contraceptives and high factor viii levels. Thromb Haemost 1999; 82: 1024-1027.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Mackie IJ, Piegsa K, Furs SA. et al. Protein s levels are lower in women receiving desogestrel-containing combined oral contraceptives (cocs) than in women receiving levonorgestrel-containing cocs at steady state and on cross-over. Br J Haematol 2001; 113: 898-904.
    CrossrefPubMedGoogle Scholar
  • 5 Quehenberger P, Loner U, Kapiotis S. et al. Increased levels of activated factor vii and decreased plasma protein s activity and circulating thrombomodulin during use of oral contraceptives. Thromb Haemost 1996; 76: 729-734.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Tans G, Curvers J, Middeldorp S. et al. A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost 2000; 84: 15-21.
    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 Rosing J, Tans G, Nicolaes GAF. et al. Oral contraceptives and venous thrombosis: Different sensitivities to activated protein c in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97: 233-238.
    CrossrefPubMedGoogle Scholar
  • 9 Favaloro EJ, McDonald D, Lippi G. Laboratory investigation of thrombophilia: The good, the bad, and the ugly. Semin Thromb Hemost 2009; 35: 695-710.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Pannucci CJ, Bailey SH, Dreszer G. et al. Validation of the caprini risk assessment model in plastic and reconstructive surgery patients. J Am Coll Surg 2011; 212: 105-112.
    CrossrefPubMedGoogle Scholar
  • 11 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.
    PubMedGoogle Scholar
  • 12 Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor-viii in effect of von-willebrand-factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
    CrossrefPubMedGoogle Scholar
  • 13 Vlieg AV, van der Linden IK, Bertina RM. et al. High levels of factor ix increase the risk of venous thrombosis. Blood 2000; 95: 3678-3682.
    PubMedGoogle Scholar
  • 14 Butenas S, van'tVeer C, Mann KG. ″Normal″ thrombin generation. Blood 1999; 94: 2169-2178.
    PubMedGoogle Scholar
  • 15 Murano G, Williams L, Miller-Andersson M. et al. Some properties of antithrombin-iii and its concentration in human plasma. Thromb Res 1980; 18: 259-262.
    CrossrefPubMedGoogle Scholar
  • 16 Novotny WF, Brown SG, Miletich JP. et al. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78: 387-393.
    PubMedGoogle Scholar
  • 17 Jordan SW, Chaikof EL. Simulated surface-induced thrombin generation in a flow field. Biophys J 2011; 101: 276-286.
    CrossrefPubMedGoogle Scholar
  • 18 Nakazawa G, Finn AV, Joner M. et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients - an autopsy study. Circulation 2008; 118: 1138-1145.
    CrossrefPubMedGoogle Scholar
  • 19 Brummel KE, Paradis SG, Butenas S. et al. Thrombin functions during tissue factor-induced blood coagulation. Blood 2002; 100: 148-152.
    CrossrefPubMedGoogle Scholar
  • 20 Martinelli I. Pros and cons of thrombophilia testing: Pros. J Thromb Haemost 2003; 01: 410-411.
    CrossrefPubMedGoogle Scholar
  • 21 Vandenbroucke JP, vanderMeer FJM, Helmerhorst FM. et al. Factor v leiden: Should we screen oral contraceptive users and pregnant women?. Br Med J 1996; 313: 1127-1130.
    CrossrefPubMedGoogle Scholar
  • 22 Wu O, Robertson L, Twaddle S. et al. Screening for thrombophilia in high-risk situations: A meta-analysis and cost-effectiveness analysis. Br J Haematol 2005; 131: 80-90.
    CrossrefPubMedGoogle Scholar
  • 23 Hemker HC, Wielders S, Kessels H. et al. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993; 70: 617-624.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 van Veen JJ, Gatt A, Makris M. Thrombin generation testing in routine clinical practice: Are we there yet?. Br J Haematol 2008; 142: 889-903.
    CrossrefPubMedGoogle Scholar
  • 25 Brummel-Ziedins K, Vossen CY, Rosendaal FR. et al. The plasma hemostatic proteome: Thrombin generation in healthy individuals. J Thromb Haemost 2005; 03: 1472-1481.
    CrossrefPubMedGoogle Scholar
  • 26 Hockin MF, Jones KC, Everse SJ. et al. A model for the stoichiometric regulation of blood coagulation. J Biol Chem 2002; 277: 18322-18333.
    CrossrefPubMedGoogle Scholar
  • 27 Kushak RI, Nestoridi E, Lambert J. et al. Detached endothelial cells and microparticles as sources of tissue factor activity. Thromb Res 2005; 116: 409-419.
    CrossrefPubMedGoogle Scholar
  • 28 Mallat Z, Hugel B, Ohan J. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques - a role for apoptosis in plaque thrombogenicity. Circulation 1999; 99: 348-353.
    CrossrefPubMedGoogle Scholar
  • 29 Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC. et al. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 1997; 96: 3534-3541.
    CrossrefPubMedGoogle Scholar
  • 30 Satta N, Toti F, Feugeas O. et al. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J Immunol 1994; 153: 3245-3255.
    PubMedGoogle Scholar
  • 31 Boehme MWJ, Galle P, Stremmel W. Kinetics of thrombomodulin release and endothelial cell injury by neutrophil-derived proteases and oxygen radicals. Immunology 2002; 107: 340-349.
    CrossrefPubMedGoogle Scholar
  • 32 Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial-cells. Thromb Haemost 1991; 65: 618-623.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Kunz G, Ireland HA, Stubbs PJ. et al. Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction. Blood 2000; 95: 569-576.
    PubMedGoogle Scholar