CC BY 4.0 · TH Open 2018; 02(03): e291-e302
DOI: 10.1055/s-0038-1672183
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Calibrated Automated Thrombinography (CAT), a Tool to Identify Patients at Risk of Bleeding during Anticoagulant Therapy: A Systematic Review

Suzanne Zwaveling
1   Laboratory for Clinical Thrombosis and Hemostasis, Internal Medicine and Biochemistry, Maastricht University, Maastricht, The Netherlands
2   Synapse Research Institute, Maastricht, The Netherlands
,
Saartje Bloemen
2   Synapse Research Institute, Maastricht, The Netherlands
,
Bas de Laat
2   Synapse Research Institute, Maastricht, The Netherlands
,
Hugo ten Cate
1   Laboratory for Clinical Thrombosis and Hemostasis, Internal Medicine and Biochemistry, Maastricht University, Maastricht, The Netherlands
,
Arina ten Cate-Hoek
1   Laboratory for Clinical Thrombosis and Hemostasis, Internal Medicine and Biochemistry, Maastricht University, Maastricht, The Netherlands
› Author Affiliations
Further Information

Publication History

19 March 2018

01 August 2018

Publication Date:
26 September 2018 (online)

Abstract

Background Bleeding is a feared adverse event during anticoagulant treatment. In patients on vitamin K antagonists, most bleedings occur with the international normalized ratio (INR) in the therapeutic range. Currently, identification of high-risk patients via laboratory methods is not reliable. In this systematic review, we assessed the ability of calibrated automated thrombin generation (CAT-TG) to predict bleeding in patients on anticoagulant treatment.

Methods A systematic search was executed in three databases: Medline, Embase, and Cochrane.

Results Seven studies were included; two were of good methodological quality. One study showed that patients on warfarin with INRs in range (2–3) admitted for hemorrhage (n = 28), had lower CAT-TG levels (endogenous thrombin potential [ETP]: 333 ± 89 nM/min) than patients on warfarin admitted for other reasons (ETP: 436 ± 207 nM/min; p < 0.001). Another study found no difference in ETP or peak levels between bleeding and nonbleeding patients in PPP or PRP. When measured in whole blood, both levels were significantly lower in patients with bleeding compared with nonbleeding patients (median [interquartile range, IQR] ETP: 182.5 [157.2–2,847 nM/min] vs. median [IQR] ETP: 256.2 [194.9–344.2 nM/min]; p < 0.001) and median [IQR] peak: 23.9 [19.6–41.8 nM] vs. median [IQR] peak: 39.1 [24.9–53.2 nM]; p < 0.05). From the remaining studies, four suggested that CAT-TG is more sensitive in detecting hemostatic abnormalities than INR and one article found ETP and INR to be equally useful. However, insufficient data were provided to validate these conclusions.

Conclusion Studies investigating the direct association between decreased CAT-TG values and hemorrhagic events are rare. Therefore, the clinical consequences of low CAT-TG values remain to be further investigated.

Supplementary Material

 
  • References

  • 1 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 160S-198S
  • 2 Veeger NJ, Piersma-Wichers M, Tijssen JG, Hillege HL, van der Meer J. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol 2005; 128 (04) 513-519
  • 3 Palareti G, Leali N, Coccheri S. , et al; Italian Study on Complications of Oral Anticoagulant Therapy. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348 (9025): 423-428
  • 4 Jackson SL, Peterson GM, Vial JH, Daud R, Ang SY. Outcomes in the management of atrial fibrillation: clinical trial results can apply in practice. Intern Med J 2001; 31 (06) 329-336
  • 5 Abdelhafiz AH, Wheeldon NM. Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic. Clin Ther 2004; 26 (09) 1470-1478
  • 6 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
  • 7 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
  • 8 Granger CB, Alexander JH, McMurray JJ. , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
  • 9 Chee YL, Crawford JC, Watson HG, Greaves M. ; British Committee for Standards in Haematology. Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures. Br J Haematol 2008; 140 (05) 496-504
  • 10 Suchman AL, Mushlin AI. How well does the activated partial thromboplastin time predict postoperative hemorrhage?. JAMA 1986; 256 (06) 750-753
  • 11 Kitchens CS. To bleed or not to bleed? Is that the question for the PTT?. J Thromb Haemost 2005; 3 (12) 2607-2611
  • 12 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 (04) 576-582
  • 13 Gatt A, van Veen JJ, Woolley AM, Kitchen S, Cooper P, Makris M. Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro. Thromb Haemost 2008; 100 (02) 350-355
  • 14 Altman R, Scazziota A, Herrera L, González C. Relationship between thrombin generation and international normalized ratio in patients receiving oral vitamin K antagonist therapy. J Thromb Haemost 2007; 5 (07) 1552-1569
  • 15 Gerotziafas GT, Dupont C, Spyropoulos AC. , et al. Differential inhibition of thrombin generation by vitamin K antagonists alone and associated with low-molecular-weight heparin. Thromb Haemost 2009; 102 (01) 42-48
  • 16 Wells G, Shea B, O'Connel D. , et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
  • 17 Desmurs-Clavel H, Huchon C, Chatard B, Negrier C, Dargaud Y. Reversal of the inhibitory effect of fondaparinux on thrombin generation by rFVIIa, aPCC and PCC. Thromb Res 2009; 123 (05) 796-798
  • 18 Zahir H, Brown KS, Vandell AG. , et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015; 131 (01) 82-90
  • 19 Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 2014; 111 (05) 989-995
  • 20 Levi M, Moore KT, Castillejos CF. , et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014; 12 (09) 1428-1436
  • 21 Perzborn E, Heitmeier S, Laux V, Buchmüller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res 2014; 133 (04) 671-681
  • 22 Dinkelaar J, Patiwael S, Harenberg J, Leyte A, Brinkman HJ. Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate. Clin Chem Lab Med 2014; 52 (11) 1615-1623
  • 23 Dargaud Y, Desmurs-Clavel H, Marin S, Bordet JC, Poplavsky JL, Negrier C. Comparison of the capacities of two prothrombin complex concentrates to restore thrombin generation in plasma from orally anticoagulated patients: an in vitro study. J Thromb Haemost 2008; 6 (06) 962-968
  • 24 Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108 (02) 217-224
  • 25 Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 2010; 116 (05) 693-701
  • 26 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124 (14) 1573-1579
  • 27 Khoo TL, Weatherburn C, Kershaw G, Reddel CJ, Curnow J, Dunkley S. The use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol 2013; 35 (02) 222-224
  • 28 Perlstein I, Wang Z, Song Y. , et al. Reversal of apixaban anticoagulation by 4-factor prothrombin complex concentrates in healthy subjects. Blood 2014; 124 (21) 345
  • 29 Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding. Br J Haematol 2001; 115 (04) 998-1001
  • 30 Cheung KC, Rodgers S, McRae S. Local experience in reversal dabigatran using activated prothrombin complex concentrates (FEIBA). Haematologica 2012; 97: 185
  • 31 Brinkman HJM, Dinkelaar J, Patiwael S, Harenberg J, Leyte A. How should we measure the reversal of direct factor XA or thrombin inhibitors by prothrombin complex concentrate?. J Thromb Haemost 2014; 12: 16
  • 32 Reijers J, Moerland M, Frieling J. , et al. Pharmacodynamic effects of two recombinant FVIIa products in anticoagulated healthy volunteers. J Thromb Haemost 2013; 11: 1129
  • 33 Godier A, Martin AC, Samama CM, Fischer AM, Le Bonniec B. Reversal of anticoagulant effects of apixaban with non-specific prohaemostatic agents: an in vitro study. J Thromb Haemost 2013; 11: 826
  • 34 Brinkman HJA, Herpers R, Van Beem RT. , et al. Ex vivo monitoring of Fenprocoumon reversal by prothrombin complex concentrate using thrombography. J Thromb Haemost 2013; 11: 825
  • 35 Herpers R, van Rossum AP, van Beem RT. , et al. INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison. Clin Chem Lab Med 2015; 53 (08) 1227-1236
  • 36 Mullier F, Douxfils J, Chatelain C, Chatelain B, Dogne JM. Thrombin generation assay is superior to traditional coagulometric and chromogenic assays to monitor new oral anticoagulants. Blood 2012; 120 (21) 1169
  • 37 Galan AM, Arellano-Rodrigo E, Veronica Sanz V. , et al. Reversal of the antithrombotic action of rivaroxaban and dabigatran: a clinical study in healthy volunteers. Blood 2012; 120 (21) 2261
  • 38 Pillitteri D, Pilgrimm-Thorp AK, Krause M, Scholz T, Kirchmaier C. Antidotal effects of non-specific reversal agents on anticoagulant-induced inhibition of thrombin generation. J Thromb Haemost 2013; 11: 562-563
  • 39 Halim AB, Li Y, Stein E, Mendell J. Low concentrations of rhFVIIa or FEIBA significantly and rapidly reverse the anticoagulant effects of supratherapeutic edoxaban. Blood 2011; 118 (21) 1252
  • 40 Mullier F, Douxfils J, Robert S. , et al. Dabigatran: safety, usefulness and practical details of drug monitoring. J Thromb Haemost 2011; 9: 857
  • 41 Adamidou D, Riddell A, Aghighi S, Bates S, Chowdary P. PRP thrombin generation (TG) in patients on oral anticoagulation with warfarin: Influence of tissue factor (TF) concentration and corn trypsin inhibitor (CTI). J Thromb Haemost 2011; 9: 590
  • 42 Voils SA, Martin EJ, Mohammed BM, Bayrlee A, Brophy DF. Laboratory assessment of warfarin reversal with global coagulation tests versus international normalized ratio in patients with intracranial bleeding. Blood Coagul Fibrinolysis 2015; 26 (04) 443-447
  • 43 Schultz NH, Tran HTT, Bjørnsen S, Henriksson CE, Sandset PM, Holme PA. The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor. Thromb J 2017; 15: 6
  • 44 Calmette L, Martin AC, Le Bonniec B. , et al. Ticagrelor reversal: in vitro assessment of four haemostatic agents. J Clin Pathol 2017; 70 (09) 733-739
  • 45 Cheung YW, Barco S, Hutten BA, Meijers JC, Middeldorp S, Coppens M. In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers. J Thromb Haemost 2015; 13 (10) 1799-1805
  • 46 Davidson SJ, Burman JF, Philips SM. , et al. Correlation between thrombin potential and bleeding after cardiac surgery in adults. Blood Coagul Fibrinolysis 2003; 14 (02) 175-179
  • 47 Radulovic V, Hyllner M, Ternström L. , et al. Sustained heparin effect contributes to reduced plasma thrombin generation capacity early after cardiac surgery. Thromb Res 2012; 130 (05) 769-774
  • 48 Schols SE, van der Meijden PE, van Oerle R, Curvers J, Heemskerk JW, van Pampus EC. Increased thrombin generation and fibrinogen level after therapeutic plasma transfusion: relation to bleeding. Thromb Haemost 2008; 99 (01) 64-70
  • 49 Schols SE, Lancé MD, Feijge MA. , et al. Impaired thrombin generation and fibrin clot formation in patients with dilutional coagulopathy during major surgery. Thromb Haemost 2010; 103 (02) 318-328
  • 50 Coakley M, Hall JE, Evans C. , et al. Assessment of thrombin generation measured before and after cardiopulmonary bypass surgery and its association with postoperative bleeding. J Thromb Haemost 2011; 9 (02) 282-292
  • 51 Bosch YP, Al Dieri R, ten Cate H. , et al. Measurement of thrombin generation intra-operatively and its association with bleeding tendency after cardiac surgery. Thromb Res 2014; 133 (03) 488-494
  • 52 Percy CL, Jones M, Mehta D. , et al. Thrombin generation and post-operative bleeding in patients undergoing surgery requiring cardiopulmonary bypass. J Thromb Haemost 2013; 11: 578
  • 53 Feder S, Siegemund A, Correia C. , et al. Clinical application of thrombin generation: a deeper reflection of plasmatic haemostasis of ventricular assist device recipients. Thorac Cardiovasc Surg 2015; 63 (Suppl. 01) OP56
  • 54 Bloemen S, Zwaveling S, Ten Cate H, Ten Cate-Hoek A, de Laat B. Prediction of bleeding risk in patients taking vitamin K antagonists using thrombin generation testing. PLoS One 2017; 12 (05) e0176967
  • 55 Luna-Záizar H, González-Moncada AI, Padilla-López EL. , et al. Thrombin generation and international normalized ratio in inherited thrombophilia patients receiving thromboprophylactic therapy. Thromb Res 2015; 136 (06) 1291-1298
  • 56 Marchetti M, Giaccherini C, Lerede T, Maggioni A, Cefis M, Falanga A. Characterization of thrombin generation (TG) by the calibrated automated thrombography (CAT) in atrial fibrillation (AF) patients on permanent oral anticoagulation therapy (OAT) with warfarin. J Thromb Haemost 2013; 11 (Suppl. 03) 59-60
  • 57 Choi Q, Kim JE, Hyun J, Han KS, Kim HK. Contributions of procoagulants and anticoagulants to the international normalized ratio and thrombin generation assay in patients treated with warfarin: potential role of protein Z as a powerful determinant of coagulation assays. Thromb Res 2013; 132 (01) e70-e75
  • 58 Hemker HC, Giesen P, Al Dieri R. , et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (01) 4-15
  • 59 Verzeroli C, Giaccherini C, Marchetti M, Milesi V, Barcella L, Falanga A. Thrombin generation (TG) potential in patients on chronic oral anticoagulant therapy (OAT). Thromb Res 2014; 2: S98-S99
  • 60 Dargaud Y, Hoffman M, Lefrapper L. , et al. Bleeding risk in warfarinized patients with a therapeutic international normalized ratio: the effect of low factor IX levels. J Thromb Haemost 2013; 11 (06) 1043-1052
  • 61 Ninivaggi M, Apitz-Castro R, Dargaud Y, de Laat B, Hemker HC, Lindhout T. Whole-blood thrombin generation monitored with a calibrated automated thrombogram-based assay. Clin Chem 2012; 58 (08) 1252-1259
  • 62 Hemker HC, Al Dieri R, De Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost 2006; 96 (05) 553-561
  • 63 van Veen JJ, Gatt A, Makris M. Thrombin generation testing in routine clinical practice: are we there yet?. Br J Haematol 2008; 142 (06) 889-903
  • 64 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 (01) 5-11
  • 65 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 (10) 1720-1725
  • 66 Tripodi A, Legnani C, Chantarangkul V, Cosmi B, Palareti G, Mannucci PM. High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism. J Thromb Haemost 2008; 6 (08) 1327-1333
  • 67 Gatt A, van Veen JJ, 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 (06) 946-952
  • 68 Veeger NJ, Piersma-Wichers M, Meijer K, Hillege HL. Minor bleeds alert for subsequent major bleeding in patients using vitamin K antagonists. Br J Haematol 2011; 153 (04) 508-514
  • 69 van Rein N, le Cessie S, van Vliet IP. , et al. Increased risk of major bleeding after a minor bleed during treatment with vitamin K antagonists is determined by fixed common risk factors. J Thromb Haemost 2016; 14 (05) 948-952
  • 70 van der Meijden PE, Bouman AC, Feijge MA. , et al. Platelet dysfunction in thrombosis patients treated with vitamin K antagonists and recurrent bleeding. PLoS One 2013; 8 (05) e64112
  • 71 Wagenvoord RJ, Deinum J, Elg M, Hemker HC. The paradoxical stimulation by a reversible thrombin inhibitor of thrombin generation in plasma measured with thrombinography is caused by alpha-macroglobulin-thrombin. J Thromb Haemost 2010; 8 (06) 1281-1289
  • 72 Gribkova IV, Lipets EN, Rekhtina IG. , et al. The modification of the thrombin generation test for the clinical assessment of dabigatran etexilate efficiency. Sci Rep 2016; 6: 29242
  • 73 Dale B, Eikelboom JW, Weitz JI. , et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction?. J Thromb Thrombolysis 2013; 35 (02) 295-301