Thrombin generation assays: Accruing clinical relevance

Current Opinion in Hematology

Volumn 11, Issue 3, 2004, Pages 170-175

  Hemker, H Coenraad ^a   Al Dieri, Raed ^a   Béguin, Suzette ^a  

^a MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

Hemophilia and von Willebrand disease; Lupus anticoagulant; Monitoring antithrombotics; Platelet poor and platelet rich plasma; Thrombin generation

Indexed keywords

ABCIXIMAB; ACETYLSALICYLIC ACID; ANTICOAGULANT AGENT; ANTIVITAMIN K; CLOPIDOGREL; DESMOPRESSIN; LOW MOLECULAR WEIGHT HEPARIN;

BLEEDING; BLOOD CLOTTING; CALIBRATION; CELL INTERACTION; FUNCTION TEST; HEMOPHILIA; HEMOSTASIS; HUMAN; INTERNATIONAL STANDARD UNIT; MEASUREMENT; MODEL; NONHUMAN; PRIORITY JOURNAL; REVIEW; THROMBIN TIME; THROMBOCYTE; THROMBOCYTE POOR PLASMA; THROMBOCYTE RICH PLASMA; THROMBOSIS; VON WILLEBRAND DISEASE;

BLOOD COAGULATION DISORDERS; BLOOD COAGULATION TESTS; BLOOD PLATELETS; HEMOSTASIS; HUMANS; THROMBIN; TIME FACTORS;

EID: 3242673971     PISSN: 10656251     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.moh.0000130314.33410.d7     Document Type: Review

References (56)

1. Hayem: Du Sang et de Ses Altérations Anatomiques. G. Masson Editeur; 1889:266-274.
2. Kyrle PA, Mannhalter C, Béguin S, et al.: Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol 1998, 18:1287-1291.
3. 11 platelets/L. The influence of platelets diminishes with increasing concentration of either FVIII or FIX.
4. Kakkar VV, Hoppenstead DA, Fareed J, et al.: Randomized trial of different regimens of heparins and in vivo thrombin generation in acute deep vein thrombosis. Blood 2002, 99:1965-1970.
5. Hemker HC, Béguin S: Phenotyping the clotting system. Thromb Haemost 2000, 84:747-751.
6. Mann KG, Brummel K, Butenas S: What is all that thrombin for? J Thromb Haemost 2003, 1:1504-1514.
7. Broze GJ Jr: Thrombin-dependent inhibition of fibrinolysis. Curr Opin Hematol 1996, 3:390-394.
8. Mattsson C, Bjorkman JA, Abrahamsson T, et al.: Local proCPU (TAFI) activation during thrombolytic treatment in a dog model of coronary artery thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (melagatran). Thromb Haemost 2002, 87:557-562.
9. Verstraete M: Clinical application of inhibitors of fibrinolysis. Drugs 1985, 29:236-261.
10. Ruf W, Dorfleutner A, Riewald M: Specificity of coagulation factor signaling. J Thromb Haemost 2003, 1:1495-1503.
11. Major CD, Santulli RJ, Derian CK, Andrade-Gordon P: Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice. Arterioscler Thromb Vasc Biol 2003, 23:931-939.
12. Jensen AH, Béguin S, Josso F: Factor V and VIII activation "in vivo" during bleeding: evidence of thrombin formation at the early stage of hemostasis. Pathol Biol (Paris) 1976, 24(suppl):6-10.
13. Undas A, Brummel K, Musial J, et al.: Blood coagulation at the site of micro-vascular injury: effects of low-dose aspirin. Blood 2001, 98:2423-2431.
14. Kessels H, Béguin S, Andree H, Hemker HC: Measurement of thrombin generation in whole blood: the effect of heparin and aspirin. Thromb Haemost 1994, 72:78-83.
15. Brummel KE, Paradis SG, Butenas S, Mann KG: Thrombin functions during tissue factor-induced blood coagulation. Blood 2002, 100:148-152
16. Monroe DM, Hoffman M, Roberts HR: Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002, 22:1381-1389.
17. Mann KG: Thrombin formation. Chest 2003, 124:4S-10S. This review provides a summary of the evolution of knowledge with respect to present-day concepts of TG via the TF pathway and its regulation, seen from a personalized standpoint.
18. Hoffman M, Monroe DM 3rd: A cell-based model of hemostasis. Thromb Haemost 2001, 85:958-965.
19. Hemker HC: Thrombin generation in a reconstituted system: a comment. Thromb Haemost 2002, 87:551-554.
20. Béguin S, Kumar R, Keularts I, et al.: Fibrin-dependent platelet procoagulant activity requires GPIb receptors and von Willebrand factor. Blood 1999, 93:564-570.
21. Béguin S, Lindhout T, Hemker HC: The effect of trace amounts of tissue factor on thrombin generation in platelet rich plasma: its inhibition by heparin. Thromb Haemost 1989, 61:25-29.
22. Hemker HC, Béguin S: Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995, 74:134-138. Published erratum appears in Thromb Haemost 1995, 74:1388.
23. Hemker HC, Béguin S: The love of the artist for his model: of thrombin generation. J Thromb Haemost 2004, 2:400-401.
24. Allen GA, Hoffman M, Roberts HR, Monroe DM 3rd: 2004. The dose-effect relations are determined between the concentration of a number of clotting factors and TG in a system consisting of platelets and TF-bearing monocytes and purified dotting factors. TG increases linearly with prothrombin concentration but reaches an upper limit at minimal concentrations of the other clotting factors. The authors explain this in terms of enzyme kinetics of the clotting process. We consider it to demonstrate diffusion limitation of cell-bound TG.
25. Heemskerk JW, Severs EM, Lindhout T: Platelet activation and blood coagulation. Thromb Haemost 2002, 88:186-193.
26. Reverter JC: Fondaparinux sodium. Drugs Today (Barc) 2002, 38:185-194.
27. Béguin S, Kumar R, Keularts I, et al.: Fibrin-dependent platelet procoagulant activity requires GPIb receptors and von Willebrand factor. Blood 1999, 93:564-570.
28. Béguin 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. Induction of fibrin polymerization during the lag phase of TG by a snake venom enzyme induces an immediate burst of TG that is inhibited by a monoclonal antibody against GPIb. Inhibition of polymerization decreases TG. So polymerizing fibrin interacts with VWF so as to activate GPIb and produce platelet procoagulant activity.
29. Hemker HC, Willems GM, Béguin 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.
30. Hemker HC, Wielders S, Kessels H, Béguin S: Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993, 70:617-624.
31. Mosesson MW: Antithrombin I: inhibition of thrombin generation in plasma by fibrin formation. Thromb Haemost 2003, 89:9-12. Thrombin substrate binding to fibrinogen is mediated through exosite 1. Nonsubstrate binding of thrombin to fibrin occurs at low affinity in the fibrin E domain and at high affinity to a variant gamma chain, found in -15[ref] of the fibrinogen molecules (fibrinogen 2). Fibrin formation (antithrombin I) thus inhibits the appearance of thrombin in the fluid phase and "high-affinity" thrombin-binding plays a dominant role in this process.
32. Kumar R, Béguin S, Hemker HC: The influence of fibrinogen and fibrin on thrombin generation: evidence for feedback activation of the clotting system by clot bound thrombin. Thromb Haemost 1994, 72:713-721.
33. de Bosch NB, Mosesson MW, Ruiz-Saez A, et al.: Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). Thromb Haemost 2002, 88:253-258.
34. Kumar R, Béguin S, Hemker HC: The effect of fibrin clots and clot-bound thrombin on the development of platelet procoagulant activity. Thromb Haemost 1995, 74:962-968.
35. Rijkers DT, Hemker HC, Tesser GI: Synthesis of peptide p-nitroanilides mimicking fibrinogen- and hirudin-binding to thrombin: design of slow reacting thrombin substrates. Int J Pept Protein Res 1996, 48:182-193.
36. Hemker HC, Giesen P, Al Dieri R, et al.: Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003, 33:4-15. By using a "slow" fluorogenic thrombin substrate and continuous comparison to a simultaneously run calibrator, TG can be monitored automatically, on line, in clotting PPP or PRP. The resulting thrombogram in PPP measures hypocoagulability (hemophilias, oral anticoagulants, heparins, and heparin-likes), direct inhibitors) and hypercoagulabilities (AT deficiency, prothrombin hyperexpression, protein C and S deficiency, factor V Leiden, oral contraceptives). In PRP it is diminished in thrombopathies, in von Willebrand disease, by antibodies blocking GPIIb-IIIa or GPIb, or by antiplatelet drugs like aspirin and clopidogrel.
37. Hemker HC, Béguin S: Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995, 74:134-138.
38. Rosing J, Tans G, Nicolaes GA, 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.
39. Sorensen B, Johansen P, Christiansen K, et al.: Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost 2003, 1:551-558. Whole blood thrombelastography was used according to the traditional technique but the data were mathematically treated to resemble TG curves. Changes of these curves appeared to be dependent on the nature and severity of the hemostatic deficit in hemophiliacs and could be normalized with recombinant factor VIIa.
40. Carr ME, Martin EJ, Kuhn JG, Spiess BD: Onset of force development as a marker of thrombin generation in whole blood: the thrombin generation time (TGT). J Thromb Haemost 2003, 1:1977-1983. Reports an assay that measures platelet contractile force as a surrogate marker of TG.
41. Shima M: Understanding the hemostatic effects of recombinant factor VIIa by clot wave form analysis. Semin Hematol 2004, 41:125-131.
42. Yamamoto J, Yamashita T, Ikarugi H, et al.: Gorog Thrombosis Test: a global in-vitro test of platelet function and thrombolysis. Blood Coagul Fibrinolysis 2003, 14:31-39. Reports a technique for testing ex vivo blood flow. Aggregation and the explosive TG result in occlusion. Occlusion time was dose-dependently inhibited by monoclonal antibody against GPIb, aurin tricarboxylic acid, monoclonal antibody against GPIIb/IIIa, a GPIIb/IIIa antagonist, argatroban, and anti-vWF, but not by antifibrinogen. The test also measures thrombolysis.
43. Hemker HC, Lindhout T: Interaction of platelet activation and coagulation. Fuster et al. 2004;to be published
44. Duchemin J, Pittet JL, 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.
45. Curvers J, Thomassen MC, 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.
46. Regnault V, Béguin S, Wahl D, et al.: Thrombinography shows acquired resistance to activated protein C in patients with lupus anticoagulants. Thromb Haemost 2003, 89:208-212. Using thrombinography, APC resistance can be demonstrated in patients with lupus anticoagulants. A long time lag is observed before the thrombin burst (lupus anticoagulant effect) together with a marked inability of APC to diminish the thrombin activity. The effects were more outspoken in the presence of phospholipids from patients' platelets than with added phospholipids.
47. 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. The relation between clotting factor concentration, the ETP, and the severity of bleeding was investigated in patients with congenital deficiency of factors II, V, VII, X XI, and XII. In all the patients with severe bleeding, the ETP was less than 20[ref] of normal. Bleeding tendency was absent or mild in patients with an ETP of 30[ref] or higher.
48. Reverter JC, Béguin 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 7quot;clinical restenosis." J Clin Invest 1996, 98:863-874.
49. Keularts IM, Hamulyak K, Hemker HC, Béguin S: The effect of DDAVP infusion on thrombin generation in platelet-rich plasma of von Willebrand type 1 and in mild haemophilia A patients. Thromb Haemost 2000, 84:638-642.
50. Turecek PL, 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. A TG assay seems suitable for monitoring the pharmacokinetics of inhibitor bypassing agents during treatment and possibly for predicting responses to treatment.
51. Varadi K, Negrier C, Berntorp E, et al.: Monitoring the bioavailability of FEIBA with a thrombin generation assay. J Thromb Haemost 2003, 1:2374-2380. A TG assay enables the pharmacodynamic and pharmacokinetic properties of factor VIII-inhibitor bypassing therapies to be monitored, thus helping to optimize treatment.
52. Azar AJ, Cannegieter SC, Deckers JW, et al.: Optimal intensity of oral anticoagulant therapy after myocardial infarction. J Am Coll Cardiol 1996, 27:1349-1355.
53. Al Dieri R, Wagenvoord R, van Dedem GW, et al.: The inhibition of blood coagulation by heparins of different molecular weight is caused by a common functional motif: the C-domain. J Thromb Haemost 2003, 1:907-914. For any type of heparin, the capacity to inhibit the coagulation process in plasma is primarily determined by the concentration of the AT-binding pentasaccharide with 12 or more sugar units at its nonreducing end, ie, the structure that induces antithrombin activity. Antifactor Xa activity hardly influences either ETP or APTT.
54. Al Dieri R, Alban S, Béguin S, Hemker H. Thrombin generation for the control of heparin treatment: comparison to the activated partial thromboplastin time. J Thromb Haemost 2003;2:yy. In 12 volunteers, 9000 IU of four heparins of different molecular weight distribution was injected. The aPTT showed the effect of heparin in 34[ref] of the samples; the ETP in 80[ref]. Relative to the baseline value of the individual, the heparin effect was recognized by the aPTT in 55[ref] of the cases and by the ETP in 98[ref]. There were no large differences between the different types of heparin.
55. Herault JP, Dol F, Gaich C, et al.: Effect of clopidogrel on thrombin generation in platelet-rich plasma in the rat. Thromb Haemost 1999, 81:957-960.
56. Kessels H, Béguin S, Andree H, Hemker HC: Measurement of thrombin generation in whole blood: the effect of heparin and aspirin. Thromb Haemost 1994, 72:78-83.