Review: Laboratory markers quantifying prothrombin activation and actions of thrombin in venous and arterial thrombosis do not accurately assess disease severity or the effectiveness of treatment

Summary

Thrombin is normally produced for hemostasis and physiological wound healing. Increased thrombin production in vivo, cell activation and inflammation mediated in part by thrombin are hallmarks of both arterial and venous thrombosis. Thrombin generates (pro) coagulant, mitogenic, inflammatory and anticoagulant responses by interacting witha variety of cells in vivo.Both direct and indirect thrombin inhibitors are effective drugs for preventing and treating the consequences of arterial and venous thrombosis. For these reasons, measurements of the production and activities of thrombin in vivo have the potential for gauging the extent of thromboembolism and the responses of patients to anticoagulant, antiplatelet and anti-inflammatory drugs. How-ever, a critical review of published information suggests that measurement of thrombin production and activity in patients at risk for and in patients with significant thrombosis generally does not provide information useful for clinical decision-making. This lack of clinical utility of levels of thrombin production in vivo may arise from two causes: the inability of the measurement to differentiate between physiological (hemostatic) and disease-related (pathological) sources and/or causes of thrombin production in vivo, and the inability of antithrombotic treatment modalities to permanently eliminate the stimuli that cause increased thrombin production evident in venous and arterial thrombosis.

Keywords

Thrombin - prothrombin fragment 1 + 2 - arterial and venous thrombosis - platelets

• References

• 1 Kienast J, Thompson SG, Raskine C. et al. Prothrombin fragment 1+2 and thrombin-antithrombin III complexes in patients with angina pectoris: relation to the presence and severity of coronary atherosclerosis. Thromb Haemost 1993; 790: 550-3.
• 2 Mertini PA, Bauer KA, Oltrong L. et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-8.
• 3 Mitusch R, Siemens HJ, Garbe M. et al. Detection of a hypercoagulable state in non-valvular atrial fibrillation and the effect of anticoagulant therapy. Thromb Haemost 1992; 74: 219-23.
• 4 Corradi A, Lazzaro F, Cofrancesco E. et al. Preoperative plasma levels of prothrombin fragment 1+2 correlate with the risk of venous thrombosis after electrical hip surgery. Acta Orthop Belg 1999; 65: 39-43.
• 5 Craven SJ, Dewar L, Yang X. et al. Altered regulation of in vivo coagulation in orthopedic patients prior to knee or hip replacement surgery. Blood Coagul Fibrinolysis (In press).
• 6 Hook VM, Bjork I, Hopwood J. et al. Anticoagulant activity of heparin: separation of high-activity and lowaffinity species by affinity chromatography on immobilized antithrombin. FEBS Lett 1976; 66: 90-3.
• 7 Tollefsen DM, Petska CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 1983; 258: 6713-6.
• 8 Fernandez FA, Buchanan MR, Hirsh J. et al. Catalysis of thrombin inhibition provides an index for estimating the anti-thrombotic potential of glycosaminoglycans in rabbits. Thromb Haemost 1987; 57: 286-93.
• 9 Stone SR, Maraganore JM. Hirudin and hirudinbased peptides. Methods Enzymol 1993; 223: 312-36.
• 10 Stone SR, Hofsteenge J. Recombinant hirudin: kinetic mechanism for the inhibition of human thrombin. Protein Eng 1991; 04: 295-300.
• 11 Ofosu FA, Craven S, Dewar L. et al. Age-related changes in factor VII proteolysis in vivo . Br J Haematol 1996; 94: 407-12.
• 12 Cheras PA, Whitaker AN, Blackwell EA. et al. Hypercoagulability and hyperfibrinolysis in primary osteoarthritis. Clin Orthop 1997; 334: 57-67.
• 13 Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 2005; 94: 362-5.
• 14 Sanbrano GR, Weiss EJ, Zheng YW. et al. Role of thrombin signaling in platelets in hemostasis and thrombosis. Nature 2001; 43: 74-8.
• 15 Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 2003; 23: 2131-7.
• 16 Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131: 417-30.
• 17 Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109: 2968-704.
• 18 Blann AD, Lip GYH. Venous thromboembolism. Br Med J 2006; 332: 215-9.
• 19 Meissner MH, Chandler WL, Elliott JS. Venous thromboembolism in trauma: a local manifestation of systemic hypercoagulability?. J Trauma 2003; 54: 224-31.
• 20 Gandos Nanzakis, Kemmotsu O. Coagulofibrinolytic changes after isolated head injury are not different from those in trauma patients without head injury. J Trauma 1999; 45: 1070-6.
• 21 Nguyen NT, Owings JT, Gosselin R. et al. Systemic coagulation and fibrinolysis after laparoscopic and open gastric bypass. Arch Surg 2001; 136: 909-16.
• 22 Lowe GD, Haverkate F, Thompson SG. et al. Prediction of deep vein thrombosis after elective hip replacement surgery by preoperative clinical and haemostatic variables: The ECAT DVT Study. European Concerted Action on Thrombosis. Thromb Haemost 1999; 81: 879-86.
• 23 Freedman KB, Brookenthal KR, Fitzgerald RH. et al. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am 2000; 82: 929-38.
• 24 Ho WK, Hankey GJ, Quinlan DJ. et al. Risk of recurrent venous thromboembolism in patients with common thrombophilia. A systemic review. Arch Intern Med 2006; 166: 729-36.
• 25 Bonfils EA, Daoud-Elias M, Gauthien B. et al. Influence of long term oral anticoagulants upon prothrombin fragment 1 + 2 thrombin-antithrombin III complex and D-dimer levels in patients affected by proximal deep vein thrombosis. Thromb Haemost 1993; 69: 302-5.
• 26 Stricker H, Marchetti O, Haeberli A. et al. Hemostatic activation under anticoagulant treatment: a comparison of unfractionated heparin vs nordaparin in the treatment of proximal deep vein thrombosis. Thromb Haemost 1999; 82: 1227-31.
• 27 Schutgens RG, Esseboom EU, Snijder RJ. et al. Low molecular weight heparin (dalteparin) is equally effective as unfractionated heparin in reducing coagulation activation and perfusion abnormalities during the early treatment of pulmonary embolism. J Lab Clin Med 2004; 144: 100-7.
• 28 Prandoni P, Piccioli A, Girolami A. Cancer and venous thromboembolism: an overview. Hematologica 1999; 84: 437-45.
• 29 Donnelly R, Emslie-Smith AM, Gardner ID. et al. Vascular complications of diabetes. Br Med J 2000; 321: 1062-6.
• 30 Ludwig S, Charmalingam S, Erikson-Nesmith S. et al. Impact of simvastatin in hemostatic and fibrinolytic regulators on type 2 diabetes mellitus. Diabetes Res Clin Prac 2005; 70: 110-8.
• 31 Petrauskiene V, Falk M, Waernbaum I. et al. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologica 2005; 48: 1017-21.
• 32 Ferroni P, Basili S, Falco A. et al. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 02: 1282-91.
• 33 Heart Protection Study Group. MRC/BHF Protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003; 361: 2005-16.
• 34 Lowe GDO. Venous and arterial thrombosis: epidemiology and risk factors at various ages. Maturitas 2004; 47: 259-63.
• 35 Lowe GDO, Rumley A, Sweetman PM. et al. Fibrin D-dimer, markers of coagulation activation and the role of major ischemic heart disease in the Caephilly study. Thromb Haemost 2001; 86: 822-7.
• 36 Marcucci R, Gori AM, Giannotti F. et al. Markers of hypercoagulabillity and inflammation predict mortality in patients with heart failure. J Thromb Haemost 2006; 04: 1017-22.
• 37 Roldam V, Marin F, Blann AD. et al. Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation. Eur Heart J 2003; 24: 1373-80.
• 38 Varughese GI, Patel JV, Tomson J. et al. The prothrombotic risk of diabetes mellitus in atrial fibrillation and heart failure. J Thromb Haemost 2005; 03: 2811-3.
• 39 Falciani M, Gori AM, Fedi S. et al. Elevated tissue factor and tissue factor pathway inhibitor circulatory levels in ischemic heart disease patients. Thromb Haemost 1998; 79: 495-9.
• 40 Sechi LA, Zingaro L, Catena C. et al. Increased fibrinogen levels and hemostatic abnormalities in patients with arteriorlar nephrosclerosis: association with cardiovascular events. Thromb Haemost 2000; 84: 565-70.
• 41 MacCallum PK. Markers of hemostasis and systemic inflammation in heart disease and atherosclerosis in smokers. Proc Am Thorac Sac 2005; 02: 33-43.
• 42 Bezeaud A, Aronsen DL, Manache D. et al. Identification ofa prothrombin derivative in urine. Thromb Res 1978; 13: 551-6.
• 43 Bezeaud A, Guillin MC. Quantification of prothrombin activation products in human urine. Br J Haematol 1984; 58: 597-606.
• 44 Hemker HC, Gissen P, Al Dieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyperand hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-53.
• 45 Wieders S, Mukherjee M, Michiels J. et al. The routine determination of endogenous thrombin potential, first results in different forms of hyperand hypocoagulability. Thromb Haemost 1997; 77: 629-36.
• 46 Brummel-Zieding KE, Vossen CY, Butenas S. et al. Thrombin generation profiles in deep venous thrombosis. J Thromb Haemost 2005; 03: 2497-505.
• 47 Haidl H, Cimentil C, Leschnik B. et al. Age-dependency of thrombin generation measured by means of calibrated automated thrombography (CAT). Thromb Haemost 2006; 95: 772-5.
• 48 Hron G, Kollars M, Binder B. et al. Identification of patients at low risk for recurrent venous thromboem-bolism by measuring thrombin generation. J Am Med Assoc 2006; 296: 397-402.
• 49 Liu L, Dewar L, Song Y. et al. Inhibition of thrombin by antithrombin III and heparin cofactor II in vivo . Thromb Haemost 1995; 73: 405-12.
• 50 Liu L, Freedman J, Hornstein A. et al. Thrombin binding to platelets and their activation in plasma. Br J Haematol 1994; 72: 836-42.
• 51 Jin RC, Voetsch B, Localzo J. Endogenous mechanisms of inhibition of platelet function. Microcirculation 2005; 12: 247-58.
• 52 Marcus AJ, Broekman MJ, Drosopolilos JH. et al. The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39. J Clin Invest 1997; 99: 1351-60.
• 53 Laszik ZG, Zhou XJ, Ferrell GL. et al. Down-regulation of endothelial expression of endothelial protein C receptor and thrombomodulin in coronary atherosclerosis. Am J Path 2001; 159: 797-802.
• 54 van de Poll T, Buller Hr, ten Cate H. et al. Activation of coagulation after administration of tumor necrosis factor to normal human subjects. N Engl J Med 1990; 322: 1622-7.
• 55 Mastroroberto P, Chello M, Perticone F. Elevated circulatory levels of von Willebrand factor in heart failure and mechanical prosthesis. Scand J Thorac Cardiovascular Surg 1996; 30: 77-81.
• 56 Kosar F, Aksoy Y, Ozguntekin G. et al. Relationship between cytokines and tumour markers in patients with chronic heart failure. Eur J Heart Fail 2006; 08: 270-4.
• 57 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of antiplatelet therapy III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Br Med J 1994; 308: 235-46.
• 58 Sors H, Meyer G. Place of aspirin in prophylaxis of venous thromboembolism. Lancet 2000; 355: 1288-9.
• 59 Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295-302.
• 60 Arnesen H, Dahl OE, Aspelin T. et al. Sustained prothrombotic profile after hip replacement surgery: The influence of prolonged prophylaxis with dalteparin. J Thromb Haemost 2003; 01: 971-5.
• 61 Gonzalez Valle ADella, Serota A, Go G. et al. Venous thromboembolism is rare in a multimodel prophylaxis protocol after total hip arthroplasty. Clin Orthop Rel Res 2006; 444: 146-53.
• 62 Sharrock NE, Go G, Sculco TP. et al. Dose response of intravenous heparin on markers of thrombosis during total hip replacement. Anesthesiology 1999; 90: 981-7.
• 63 Nader HB, Walenga JM, Berkowitz SD. et al. Preclinical differentiation of low molecular weight heparins. Semin Thromb Haemost 1999; 25 (Suppl. 03) 61-71.
• 64 Eriksson BI, Ekman S, Kulebo P. et al. Prevention of deep vein thrombosis after total hip replacement: direct thrombin inhibition with hirudin, CGP 393 93. Lancet 1996; 347: 635-59.
• 65 Schiele F, Lindgaerde F, Eriksson H. et al. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial International Multicentre Hirudin Study Group. Thromb Haemost 1997; 77: 834-8.
• 66 Peternel P, Terbizan M, Trater G. et al. Markers of hemostatic system activation during treatment with subcutaneous unfractionated or low molecular weight heparin. Thromb Res 2002; 105: 241-6.
• 67 Meskers RM, Mikoteit T, Schiller M. et al. Markers of coagulation activation for evaluation of the antithrombotic efficacy of heparins: prospective study in acute deep venous thrombosis. Blood Coagul Fibrinolysis 1995; 07: 665-71.
• 68 Kyrle PA, Eichinger P, Pabinger I. et al. Prothrombin fragment 1 + 2 is not predictive for recurrent venous thromboembolism. Thromb Haemost 1997; 77: 829-33.
• 69 Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularization procedures in patients with acute myocardial ischemia without ST elevation: a randomized trial. Lancet 1999; 353: 429-38.
• 70 Eikelboom JW, Anand SS, Malonberg K. et al. Unfractionated heparin and low-molecular weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000; 355: 1936-42.
• 71 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapies for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
• 72 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomized placebo-controlled trial. Lancet 2002; 360: 7-22.
• 73 Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cardiovascular disease or other high risk conditions. Lancet 2004; 363: 757-67.
• 74 Calhoun HM, Betteridge DJ, Durrington PM. et al. on behalf of the CARD Investigators. Primary prevention of cardiovascular disease with atorvastin in type 2 diabetes in Collaborative Atorvastin Diabetes Study (CARDS): Multicenter randomized placebo-controlled trial. Lancet 2004; 364: 685-94.
• 75 Briel M, Schwartz GG, Thompson PL. et al. Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes. A meta-analysis of randomized controlled trials. J Am Med Assoc 2006; 295: 2046-56.
• 76 The Direct Thrombin Inhibitor Trialists’ Collaboration Group. Direct thrombin inhibitors in acute coronary syndromes; principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359: 294-302.
• 77 Criqui MH, Langer RD, Fronek A. et al. Mortality over a period of ten years in patients with peripheral artery disease. N Engl J Med 1992; 326: 381-6.
• 78 CAPRIE Steering Committee. A randomized, blinded trial of clopidrogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 1329-39.
• 79 Trifiletti A, Bartolne S, Scamordi R. et al. Study of thrombinic activation indexes in patients with lower critic limb ischemia before and after prostaglandin E1 therapy. Minerva Cardioangiol 1999; 47: 55-8.
• 80 Sakamaki F, Kyotami S, Nagaya N. et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertensions were improved by continuous prostacyclin therapy. Circulation 2000; 102: 2720-5.
• 81 Mozaffanan D, Minaml E, Letteren RA. et al. The effects of atorvastatin (10 mg) on systemic inflammation in heart failure. Am J Cardiol 2005; 96: 1699-704.
• 82 Sjoland JA, Pederson RS, Jespersen J. Gram J. Intraperitoneal heparin ameliorates the systemic inflammation response in PAD patients. Nephron Clin Pract 2005; 100: c105-110.
• 83 Oldgren J, Felleniuse C, Bonan K. et al. Influence of prolonged deltaparin treatment on coagulation, fibrinolysis, and inflammation in unstable coronary artery disease. J Intern Med 2005; 258: 420-7.
• 84 Breddin HK, Kadziola Z, Scully M. et al. Risk factors and coagulation parameters in relationship to phlebographic response and clinical outcome in the treatment of deep vein thrombosis. Thromb Haemost 2003; 89: 272-7.
• 85 Agnelli G, Iorio A, Renga C. et al. Prolonged antithrombin activity of low molecular weight heparins: clinical implications for the treatment of thromboembolic disease. Circulation 1995; 92: 2819-24.
• 86 Al Dieri R, Alban S, Beguin S. et al. Thrombin generation for the control of heparin treatment, comparison with the activated partial thromboplastin time. J Thromb Haemost 2004; 02: 1003-7.
• 87 Nenci GG. Dermatan sulphate as an antithrombotic drug. Pathophysiol Haemost Thromb 2002; 32: 302-7.
• 88 Tovar AMF, deMattos DA, Stelling MP. et al. Dermatan sulfate is the predominant antithrombotic glycosaminoglycan in vessel walls: Implications for a possible physiological function of heparin cofactor II. Biochim Biophys Acta 2005; 1740: 45-53.
• 89 Turpie AG, Bauer KA, Eriksson BI. et al. Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points. Chest 2004; 126: 501-8.
• 90 Yusuf S, Mehta SR, Chrolavicius S. et al. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. N Engl J Med 2006; 354: 1464-76.
• 91 Ofosu FA, Birchall KJ, Buchanan MR. Preliminary report on a new approach to laboratory monitoring of the low molecular weight heparin CY216. In: Fraxiparine. Chattier, Stuttgart-New York 1989; 35-40.
• 92 Ofosu FA, Levine M, Craven S. et al. Prophylactically equivalent doses of enoxaparin and heparin inhibit in vivo coagulation to the same extent. Br J Haematol 1992; 82: 400-9.
• 93 Ofosu FA, Leclerc J, DeLorme F. et al. The low molecular weight heparin enoxaparin inhibits the consumption of factor VII and prothrombin activation in vivo associated with elective knee replacement surgery. Br J Haematol 1992; 82: 391-9.
• 94 Dorsam RT, Kunapuli SP. The central role of the PY12 receptor in platelet activation. J Clin Invest 2004; 113: 340-5.
• 95 Undas A, Celinska-Lowenhoff M, Domagala TB. et al. Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hyper-cholesterolemia. Thromb Haemost 2005; 94: 193-9.
• 96 Negus D, Fredgood A, Cox SJ. et al. Ultra-low dose intravenous heparin in the prevention of post-operative deep-vein thrombosis. Lancet 1980; 01: 891-4.