Subscribe to RSS
DOI: 10.1055/s-0029-1214153
Assessment of Thrombin Generation: Useful or Hype?
Publication History
Publication Date:
23 March 2009 (online)
![](https://www.thieme-connect.de/media/sth/200901/lookinside/thumbnails/10.1055-s-0029-1214153-1.jpg)
ABSTRACT
Thrombin plays an important role in hemostasis through its multiple functions across blood coagulation, platelet activation, and fibrinolysis. The measurement of thrombin generation is therefore viewed as a potentially useful test that could be applied to the screening, monitoring, and/or diagnosis of hemostatic abnormalities. Indeed, advances in thrombin generation assays have created significant interest and debate as to whether they may provide a more physiologically relevant testing system than do traditional coagulation tests. A variety of thrombin generation assays, including commercially available systems, have been investigated for their correlation with hypocoagulable and hypercoagulable states. Although there is an extensive body of literature that has investigated the application of thrombin generation assays, some limitations remain. These include poor standardization of reagents and methods and a lack of large prospective studies that demonstrate clear relationships between thrombin generation with bleeding and thrombosis phenotypes, as well as with monitoring anticoagulation. Whether thrombin generation assays become more “useful” than “hype” will require well-designed, large, prospective multicenter trials using standardized methods.
KEYWORDS
Thrombin generation assays - hemostasis - laboratory testing - thrombosis - bleeding
REFERENCES
- 1 Hemker H C, Beguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost. 1995; 74 134-138
- 2 Lippi G, Favaloro E J. Activated partial thromboplastin time: new tricks for an old dogma. Semin Thromb Hemost. 2008; 34 604-611
- 3 Davie E W, Ratnoff O D. Waterfall sequence for intrinsic blood clotting. Science. 1964; 145 1310-1312
- 4 Macfarlane R G. An enzyme cascade in the blood clotting mechanism, and its function as a a biochemical amplifier. Nature. 1964; 202 498-499
- 5 Osterud B, Rapaport S I. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci U S A. 1977; 74 5260-5264
- 6 Sanders N L, Bajaj S P, Zivelin A, Rapaport S I. Inhibition of tissue factor/factor VIIa activity in plasma requires factor X and an additional plasma component. Blood. 1985; 66 204-212
- 7 Gailani D, Broze Jr G J. Factor XI activation in a revised model of blood coagulation. Science. 1991; 253 909-912
- 8 Hoffman M, Monroe III D M. A cell-based model of hemostasis. Thromb Haemost. 2001; 85 958-965
- 9 McVey J H. Tissue factor pathway. Best Pract Res Clin Haematol. 1999; 12 361-372
- 10 Crawley J T, Zanardelli S, Chion C K, Lane D A. The central role of thrombin in hemostasis. J Thromb Haemost. 2007; 5(Suppl 1) 95-101
- 11 Righini M, Perrier A, De Moerloose P, Bounameaux H. D-dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost. 2008; 6 1059-1071
- 12 Stegnar M, Vene N, Bozic M. Do haemostasis activation markers that predict cardiovascular disease exist?. Pathophysiol Haemost Thromb. 2003; 33 302-308
- 13 Macfarlane R G, Biggs R. A thrombin generation test; the application in haemophilia and thrombocytopenia. J Clin Pathol. 1953; 6 3-8
- 14 Pitney W R, Dacie J V. A simple method of studying the generation of thrombin in recalcified plasma; application in the investigation of haemophilia. J Clin Pathol. 1953; 6 9-14
- 15 Baglin T. The measurement and application of thrombin generation. Br J Haematol. 2005; 130 653-661
- 16 Hemker H C, Wielders S, Kessels H, Beguin S. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost. 1993; 70 617-624
- 17 Hemker H C, Willems G M, Beguin S. A computer assisted method to obtain the prothrombin activation velocity in whole plasma independent of thrombin decay processes. Thromb Haemost. 1986; 56 9-17
- 18 Tappenden K A, Gallimore M J, Evans G, Mackie I J, Jones D W. Thrombin generation: a comparison of assays using platelet-poor and -rich plasma and whole blood samples from healthy controls and patients with a history of venous thromboembolism. Br J Haematol. 2007; 139 106-112
- 19 Stief T W. Influence of the surface on thrombin generation. Int J Lab Hematol. 2008; 30 269-277
- 20 Hemker H C, Al Dieri R, De Smedt E, Beguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost. 2006; 96 553-561
- 21 van Veen J J, Gatt A, Makris M. Thrombin generation testing in routine clinical practice: are we there yet?. Br J Haematol. 2008; 142 889-903
- 22 Berntop E, Salvagno G L. Standardization and clinical utility of thrombin generation assays. Semin Thromb Hemost. 2008; 34 670-682
- 23 Dargaud Y, Beguin S, Lienhart A et al.. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost. 2005; 93 475-480
- 24 Varadi K, Turecek P L, Schwarz H P. Thrombin generation assay and other universal tests for monitoring haemophilia therapy. Haemophilia. 2004; 10(Suppl 2) 17-21
- 25 Beltran-Miranda C P, Khan A, Jaloma-Cruz A R, Laffan M A. Thrombin generation and phenotypic correlation in haemophilia A. Haemophilia. 2005; 11 326-334
- 26 Turecek P L, Varadi K, Keil B et al.. Factor VIII inhibitor-bypassing agents act by inducing thrombin generation and can be monitored by a thrombin generation assay. Pathophysiol Haemost Thromb. 2003; 33 16-22
- 27 Rugeri L, Beguin S, Hemker C et al.. Thrombin-generating capacity in patients with von Willebrand's disease. Haematologica. 2007; 92 1639-1646
- 28 Beguin S, Keularts I, Al Dieri R et al.. Fibrin polymerization is crucial for thrombin generation in platelet-rich plasma in a VWF-GPIb-dependent process, defective in Bernard-Soulier syndrome. J Thromb Haemost. 2004; 2 170-176
- 29 Beguin S, Kumar R, Keularts I et al.. Fibrin-dependent platelet procoagulant activity requires GPIb receptors and von Willebrand factor. Blood. 1999; 93 564-570
- 30 Reverter J C, Beguin S, Kessels H et al.. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and “clinical restenosis”. J Clin Invest. 1996; 98 863-874
- 31 Al Dieri R, Peyvandi F, Santagostino E et al.. The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding. Thromb Haemost. 2002; 88 576-582
- 32 al Dieri R, Alban S, Beguin S, Hemker H C. Thrombin generation for the control of heparin treatment, comparison with the activated partial thromboplastin time. J Thromb Haemost. 2004; 2 1395-1401
- 33 Al Dieri R, Alban S, Beguin S, Hemker H C. Fixed dosage of low-molecular-weight heparins causes large individual variation in coagulability, only partly correlated to body weight. J Thromb Haemost. 2006; 4 83-89
- 34 Gerotziafas G T, Elalamy I, Depasse F, Perzborn E, Samama M M. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost. 2007; 5 886-888
- 35 Gerotziafas G T, Depasse F, Chakroun T et al.. Comparison of the effect of fondaparinux and enoxaparin on thrombin generation during in-vitro clotting of whole blood and platelet-rich plasma. Blood Coagul Fibrinolysis. 2004; 15 149-156
- 36 Beilfu ACommentStCommentEndCommentBody, Grandoch M, Wenzel F et al.. Differential effects of factor IIa inhibitors on the endogenous thrombin potential. Ther Drug Monit. 2008; , September 26 (Epub ahead of print)
- 37 Wegert W, Graff J, Kaiser D et al.. Effects of antiplatelet agents on platelet-induced thrombin generation. Int J Clin Pharmacol Ther. 2002; 40 135-141
- 38 Ignjatovic V, Summerhayes R, Yip Y Y, Monagle P. The in vitro anticoagulant effects of danaparoid, fondaparinux, and lepirudin in children compared to adults. Thromb Res. 2008; 122 709-714
- 39 Gatt A, van Veen J J, Woolley A M et al.. Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro. Thromb Haemost. 2008; 100 350-355
- 40 Brodin E, Seljeflot I, Arnesen H et al.. Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment. Thromb Res. 2009; 123 573-579
- 41 Gatt A, van Veen J J, 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
- 42 Curvers J, Thomassen M C, Rimmer J et al.. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb Haemost. 2002; 88 5-11
- 43 Duchemin J, Pittet J L, Tartary M et al.. A new assay based on thrombin generation inhibition to detect both protein C and protein S deficiencies in plasma. Thromb Haemost. 1994; 71 331-338
- 44 Gardiner C, Machin S J, Mackie I J. Measuring thrombin generation based sensitivity to activated protein C using an automated coagulometer (ACL 9000). Int J Lab Hematol. 2008; 30 261-268
- 45 Tchaikovski S N, van Vliet H A, Thomassen M C et al.. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost. 2007; 98 1350-1356
- 46 Regnault V, Beguin S, Lecompte T. Calibrated automated thrombin generation in frozen-thawed platelet-rich plasma to detect hypercoagulability. Pathophysiol Haemost Thromb. 2003; 33 23-29
- 47 Rosenkranz A, Hiden M, Leschnik B et al.. Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost. 2008; 99 331-337
- 48 Regnault V, Beguin S, Wahl D et al.. Thrombinography shows acquired resistance to activated protein C in patients with lupus anticoagulants. Thromb Haemost. 2003; 89 208-212
- 49 Lecompte T, Wahl D, Perret-Guillaume C et al.. Hypercoagulability resulting from opposite effects of lupus anticoagulants is associated strongly with thrombotic risk. Haematologica. 2007; 92 714-715
- 50 Eichinger S, Hron G, Kollars M, Kyrle P A. Prediction of recurrent venous thromboembolism by endogenous thrombin potential and D-dimer. Clin Chem. 2008; 54 2042-2048
- 51 Besser M, Baglin C, Luddington R, van Hylckama Vlieg A, Baglin T. High rate of unprovoked recurrent venous thrombosis is associated with high thrombin-generating potential in a prospective cohort study. J Thromb Haemost. 2008; 6 1720-1725
- 52 van Hylckama Vlieg A, Christiansen S C, 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
Murray AdamsPh.D. M.A.I.M.S.
School of Human Life Sciences, University of Tasmania
Tasmania 7250, Australia
Email: Murray.Adams@utas.edu.au