Detection of procoagulant imbalance

Summary

Each individual possesses his/her own endogenous-thrombin-potential (ETP) (i. e. the ability to generate thrombin) which depends on the relative strength of the pro- and anticoagulant drivers operating in plasma. This ability depends in turn on the clinical conditions in which the balance between the two drivers is variably affected. One of the major determinants of this balance is the factor (F)VIII-protein C(PC) axis and its effect can be conveniently explored by the thrombin generation procedures with results expressed as ETP ratio with/without thrombomodulin (TM) (ETP-TM ratio). Furthermore, owing to the many feedback mechanisms mediated by thrombin (e. g. activation of PC, FXI, FV, FVIII, platelets etc.) it is also possible that any perturbation of the balance between pro- and anticoagulants that may occur in plasma even outside the FVIII-PC axis could result in an increased ETPTM ratio and therefore may suggest a procoagulant imbalance. Indeed, other non-coagulation moieties (e. g. microparticles, neutrophil extracellular traps, pro-inflammatory cytokines and others) circulating in blood of patients with various clinical conditions may also contribute to the procoagulant imbalance even when FVIII and/or PC are apparently normal. It can be postulated that dual ETP measurements performed in the presence and absence of TM with results expressed as their ratio may be the candidate procedure to detect subtle procoagulant imbalance in many clinical conditions characterised by an increased risk of thromboembolism. This article aimed at reviewing the clinical conditions in which evidence for the value of the ETP-TM ratio has been provided.

Keywords

Hypercoagulability - thrombosis - protein C/S pathway - factor VIII

• References

• 1 Mann KG. Thrombin formation. Chest 2003; 124 (03) Suppl S4-S10.
• 2 Dahlback B. Progress in the understanding of the protein C anticoagulant pathway. Int J Hematol 2004; 79: 109-116.
• 3 Huntington JA. Mechanisms of glycosaminoglycan activation of the serpins in hemostasis. J Thromb Haemost 2003; 01: 1535-1549.
• 4 Macfarlane RG, Biggs R. A thrombin generation test. J Clin Pathol 1953; 06: 3-7.
• 5 Hemker HC. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
• 6 Dargaud Y. et al. Use of calibrated automated thrombinography +/- thrombomodulin to recognise the prothrombotic phenotype. Thromb Haemost 2006; 96: 562-567.
• 7 Tripodi A. et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009; 137: 2105-2111.
• 8 Tripodi A. et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41: 553-558.
• 9 Tripodi A, Primignani M, Chantarangkul V. et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology 2006; 44: 440-445.
• 10 Chantarangkul V. et al. Thrombin generation assessed as endogenous thrombin potential in patients with hyper- or hypo-coagulability. Effects of phospholipids, tissue factor and residual platelets on the measurement performed in platelet-poor and platelet-rich plasma. Haematologica 2003; 88: 547-554.
• 11 De Smedt E, Hemker HC. Thrombin generation is extremely sensitive to preheating conditions. J Thromb Haemost 2011; 09: 233-234.
• 12 Rodgers SE. et al. Evaluation of pre-analytical variables in a commercial thrombin generation assay. Thromb Res 2014; 134: 160-164.
• 13 Esmon CT, Owen WG. The discovery of thrombomodulin. J Thromb Haemost 2004; 02: 209-213.
• 14 Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008; 112: 19-27.
• 15 Kyrle PA. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-462.
• 16 George FD. Microparticles in vascular diseases. Thromb Res 2008; 122 (Suppl. 01) S55-59.
• 17 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123: 2768-2776.
• 18 Fuchs TA. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
• 19 Semeraro F. et al. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells. J Thromb Haemost 2014; 12: 1697-1702.
• 20 Semeraro F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118: 1952-1961.
• 21 Kannemeier C. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
• 22 Ammollo CT. et al. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost 2011; 09: 1795-1803.
• 23 Diaz JA. et al. for the Michigan Research Venous Group*. Plasma DNA is Elevated in Patients with Deep Vein Thrombosis. J Vasc Surg Venous Lymphat Disord 2013; 01: 341-348.
• 24 van Montfoort ML. et al. Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis. Arterioscler Thromb Vasc Biol 2013; 33: 147-151.
• 25 Fuchs TA. et al. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 2012; 120: 1157-1164.
• 26 Borissoff JI. et al. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler Thromb Vasc Biol 2013; 33: 2032-2040.
• 27 Glaser CB. et al. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation. J Clin Invest 1992; 90: 2565-2573.
• 28 De Cristofaro R, Landolfi R. Oxidation of human alpha-thrombin by the myeloperoxidase-H2O2-chloride system: structural and functional effects. Thromb Haemost 2000; 83: 253-261.
• 29 Tripodi A. et al. Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors. Endocrine. 2016 Epub ahead of print.
• 30 Stuijver DJF. et al. Incidence of venous thromboembolism in patients with Cushing’s syndrome: a multicenter cohort study. J Clin Endocrinol Metab 2011; 96: 3525-3532.
• 31 Saibeni S. et al. Increased thrombin generation in inflammatory bowel diseases. Thromb Res 2010; 125: 278-282.
• 32 He Z. et al. Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease. Thromb Haemost 2016; 115: 738-751.
• 33 Castoldi E, Hackeng TM. Regulation of coagulation by protein S. Curr Opin Hematol 2008; 15: 529-536.
• 34 Chattopadhyay R. et al. Inhibition of intrinsic Xase by protein S: a novel regulatory role of protein S independent of activated protein C. Arterioscler Thromb Vasc Biol 2012; 32: 2387-2393.
• 35 Norris LA, Martin FA, O’Toole SA. et al. Determinants of thrombin generation in gynaecological malignancies. Thromb Res 2016; 140 (Suppl. 01) S185.
• 36 Ibbotson SH. et al. Effect of high physiological levels of factor VIII: C and factor V on rate of generation of thrombin activity in vitro. Blood Coagul Fibrinolysis 1993; 04: 415-419.
• 37 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130: 643-650.
• 38 Henkens CM. et al. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1995; 73: 402-404.
• 39 Meinardi JR. et al. Acquired APC resistance related to oral contraceptives and pregnancy and its possible implications for clinical practice. Blood Coagul Fibrinolysis 1997; 08: 152-154.
• 40 Laffan MA, Manning R. The influence of factor VIII on measurement of activated protein C resistance. Blood Coagul Fibrinolysis 1996; 07: 761-765.
• 41 Tripodi A. et al. Hyperprothrombinemia may result in acquired activated protein C resistance. Blood 2000; 96: 3295-3296.
• 42 Curvers J. et al. Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol 1999; 105: 88-94.
• 43 Kemmeren JM. et al. Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood 2004; 103: 927-933.
• 44 Johnson JV. et al. Effects of oral and transdermal hormonal contraception on vascular risk markers: a randomized controlled trial. Obstet Gynecol 2008; 111: 278-284.
• 45 Koenen RR. et al. Effect of oral contraceptives on the anticoagulant activity of protein S in plasma. Thromb Haemost 2005; 93: 853-859.
• 46 Rosing J. 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.
• 47 Tchaikovski SN. et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost 2007; 98: 1350-1356.
• 48 Gourbil M. et al. French Network of Regional Pharmacovigilance Centres. Thromboembolic events in women exposed to hormonal contraception or cyproterone acetate in 2012: a cross-sectional observational study in 30 French public hospitals. Drug Saf 2014; 37: 269-282.
• 49 Jick H. et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-1593.
• 50 van Hylckama Vlieg A. et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. Br Med J 2009; 339: b2921.
• 51 Tans G. 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.
• 52 Middeldorp S. et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost 2000; 84: 4-8.
• 53 Meijers JC. et al. Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor XI-independent down regulation of fibrinolysis: a randomized cross-over study of two low-dose oral contraceptives. Thromb Haemost 2000; 84: 9-14.
• 54 Harris GM. et al. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol 1999; 60: 175-180.
• 55 Marchetti M. et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 2008; 112: 4061-4068.
• 56 Whelihan MF. et al. Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. J Thromb Haemost 2016; 14: 1941-1952.
• 57 Tripodi A. Levels of coagulation factors and venous thromboembolism. Haematologica 2003; 88: 705-711.
• 58 Tripodi A. Hemostasis abnormalities in chronic liver failure. In: Chronic liver failure. Mechanisms and management. Human Press; London: 2011: 289-303.
• 59 Tripodi A. et al. Detection of the imbalance of pro- vs. anti-coagulant factors in cirrhosis by a simple laboratory method. Hepatology 2010; 52: 249-255.
• 60 Gatt A. et al. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost 2010; 08: 1994-2000.
• 61 Lisman T. et al. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52: 355-361.
• 62 Tripodi A. et al. Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis. J Hepatol 2013; 59: 265-270.
• 63 Tripodi A. et al. Procoagulant imbalance in patients with non-alcoholic fatty liver disease. J Hepatol 2014; 61: 148-154.
• 64 Potze W. et al. Preserved hemostatic status in patients with non-alcoholic fatty liver disease. J Hepatol 2016; 65: 980-987.
• 65 Tripodi A. et al. Procoagulant-imbalance in patients with non-alcoholic fatty liver disease. Comment. J Hepatol 2017; 66: 248-250.
• 66 Tripodi A, Chantarangkul V, Gianniello F. et al. Global coagulation in myeloproliferative neoplasms. Ann Hematol 2013; 92: 1633-1639.
• 67 Arachchillage DRJ. et al. Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome. J Thromb Haemost 2014; 12: 1801-1809.
• 68 Passamonti SM. et al. Influence of anticoagulant therapy with vitamin K antagonists on plasma levels of coagulation factor VIII. Thromb Res 2010; 126: 243-245.
• 69 Al Dieri R. et al. Procoagulant effect of vitamin K antagonists?. J Thromb Haemost 2011; 09: 2511-2512.
• 70 Hemker HC. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.