Inhibition of clot formation process by treatment with the lowmolecular-weight heparin nadroparin in patients with carotid artery disease undergoing angioplasty and stenting - A thromboelastography study on whole blood

Summary

Low-molecular-weight heparins (LMWHs) have become the corner stone of antithrombotic treatment but their administration protocol needs to be optimized for certain groups of patients. In this paper, we studied the influence of nadroparin treatment on clot formation process assessed by thromboelastography in patients with carotid artery disease undergoing angioplasty and stenting. Standard thromboelastography assays (in-TEM^® and ex-TEM^® ) and minimal TF-triggered thromboelastography assay in citrated whole blood were performed in normal volunteers (n=20), in patients with carotid artery disease receiving only antiplatelet treatment (n=30), and in patients undergoing angioplasty receiving nadroparin 5750 anti-Xa IU s.c. twice daily (n=60). Blood samples were collected four hours after a second injection of nadroparin. In a subgroup of LMWH-patients (n=18) blood samples were also obtained prior to first injection of LMWH. Antiplatelet treatment had no effect on any parameter of the thromboelastographic pattern. Nadroparin treatment resulted in significant prolongation of clotting time (CT) and clot formation time (CFT) and significantly reduced α-angle in minimal TF-triggered thromboelastography and 30–38% of nadroparin treated patients had thromboelastographic parameters beyond the normal maximum limit. In-TEM test revealed a significant prolongation of clotting time while ex-TEM was not modified, and 20 to 30% of the patients had thromboelastographic parameters beyond the normal maximum limit. Anti factor-Xa activity in platelet-poor plasma (PPP) was also measured, and statistical analysis showed that prolongation of CFT of minimal TF-triggered TEM was significantly correlated to the levels of anti-Xa activity in patients’ plasma (p=0.04; r² =0.7). There was no statistical correlation for any other parameter in all tests. In conclusion, the present study shows that nadroparin treatment in patients with carotid artery disease undergoing endovascular procedures induces significant modification of the thrombus kinetics assessed by minimal TF-triggered whole blood thromboelastography. The clinical relevance of these findings has to be evaluated in future studies.

Keywords

Tissue factor (TF) - thromboelastography - LMWH - nadroparin - carotid artery disease - angioplasty - antithrombotic treatment

• References

• 1 Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688-98.
• 2 Samama MM, Gerotziafas GT. Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost 2000; 26: 31-8.
• 3 Hirsh J, Raschke R. Heparin and low-molecularweight Heparin. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 188S-203S.
• 4 Thorevska N, Amoateng-Adjepong Y, Sabahi R. et al Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin. Chest 2004; 125: 856-63.
• 5 Fuin-Thibault I, Pautas E, Siguret V. Safety profile of different low-molecular weight heparins used at therapeutic dose. Drug Saf 2005; 28: 333-49.
• 6 Wholey MH, Al-Mubarek N, Wholey M. Updated review of the global carotid artery stent registry. Catheter Cardiovasc Interv 2003; 60: 259-66.
• 7 Biasi GM, Froio A, Diethrich EB. et al Carotid plaque echolucency increases the risk of stroke in carotid stenting: the imaging in carotid angioplasty and risk of stroke (ICAROS study). Circulation 2004; 110: 756-62.
• 8 Gray WA. Endovascular treatment of extra-cranial carotid artery bifurcation disease. Minerva Cardioangiol 2005; 53: 69-77.
• 9 Dorffler-Melly J, Koopman M, Prins M. et al Antiplatelet and anticoagulant drugs for prevention of restenosis/ reocclusion following peripheral endovascular treatment. Cochrane Database Syst Rev 2005; Jan 25 CD002071.
• 10 Elliott M, Antman MD, Cohen M. et al for the TIMI 11B (Thrombolysis In Myocardial Infarction) and ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events) Investigators. Assessment of the Treatment Effect of Enoxaparin for Unstable Angina/Non–Q-Wave Myocardial Infarction TIMI 11B–ESSENCE Meta-Analysis. Circulation 1999; 100: 1602-8.
• 11 Wong GC, Giugliano RP, Antman EM. Use of lowmolecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. J Am Med Assoc 2003; 289: 331-42.
• 12 Deutsch E. The emerging role of low-molecularweight heparin and antiplatelet therapies in the cardiac catheterization laboratory. Am Heart J 1999; 138: S577-S585.
• 13 Young J, Kereiakes D. Low-molecular-weight heparin in percutaneous intervention: ready for prime time?. ACC Curr J Rev 2002; 11: 59-64.
• 14 Faxon DP, Spiro TE, Minor S. et al Low molecular weight heparin in prevention of restenosis after angioplasty. Results of Enoxaparin Restenosis (ERA) trial. Circulation 1994; 90: 908-14.
• 15 Cairns JA, Gill J, Morton B. et al Fish oils and lowmolecular-weight-heparin for the reduction of restenosis after percutaneous Transluminal coronary angioplasty. The EMPAR Study. Circulation 1996; 94: 1553-60.
• 16 Grassman ED, Leya F, Fareed J. et al A randomized trial of the low-molecular-weight-heparin certoparin to prevent restenosis following coronary angioplasty. J Invas Cardiol 2001; 13: 723-8.
• 17 Karsch KR, Preisack MB, Baildon R. et al Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation. J Am Coll Cardiol 1996; 28: 1437-43.
• 18 Kastrup A, Groschel K, Krapf H. et al Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke 2003; 34: 813-9.
• 19 Kadakia RA, Baimeedi SR, Ferguson JJ. Low-molecular-weight Heparins in the cardiac catheterization laboratory. Tex Heart Inst J 2004; 31: 72-83.
• 20 Bara L, Planes A, Samama MM. Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol 1999; 104: 230-40.
• 21 Antman EM, McCabe CH, Gurfinkel EP. et al for the TIMI (Thrombolysis In Myocardial Infarction) 11B Investigators. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B Trial. Circulation 1999; 100: 1593-601.
• 22 Ma MJ, Jackevicius CA, Yeo E. Anti-Xa monitoring of enoxaparin for acute coronary syndromes in patients with renal disease. Ann Pharmacother 2004; 38: 1576-81.
• 23 Schoen P, Lindhout T, Franssen J. et al Low molecular weight heparin-catalyzed inactivation of factor Xa and thrombin by antithrombin III--effect of platelet factor 4. Thromb Haemost 1991; 66: 435-41.
• 24 Bendetowicz AV, Kai H, Knebel R. et al The effect of subcutaneous injection of unfractionated and low molecular weight heparin on thrombin generation in platelet rich plasma--a study in human volunteers. Thromb Haemost 1994; 72: 705-12.
• 25 Hartert H. Blutgerinnungessstudien mit der thrombelastographie, einem neuen Unter suchungsverfahern. Klin Wochenchr 1948; 26: 577-83.
• 26 Marchal G, Leroux ME, Samama MM. Interêt de thrombodynamographie (Thromboelastographie) dans l‘étude des syndromes hémorragiques. Pat Biol 1958; 951-53.
• 27 Kang YG, Martin DJ, Marquez J. Intraoperative changes in blood coagulation and thromboelastographic monitoring in liver transplantation. Anesth Analg 1985; 64: 888-96.
• 28 Tuman KJ, McCarthy RJ, Djuric M. Evaluation of coagulation during cardiopulmonary bypass with heparinase-modified thromboelastographic assay. J Cardiothorac Vasc Anesth 1994; 8: 144-9.
• 29 Shore Lesserson, Manspeizer HE, DePerio M. Thromboelastography-guided transfusion algorithm reduces transfusion in complex cardiac surgery. Anesth Analg 1999; 88: 312-9.
• 30 Savry C, Quinio P, Lefevre F. et al Manageability and potential for haemostasis monitoring by near-patient modified thromboelastometer (Rotem) in intensive care unit. Ann Fr Anesth Reanim 2005; 24: 589-90.
• 31 Gerotziafas GT, Chakroun T, Samama MM. et al In vitro comparison of the effect of fondaparinux and enoxaparin on whole blood thromboelastography profile employing minimal tissue factor pathway activation. Thromb Haemost 2004; 92: 1296-302.
• 32 Gerotziafas GT, Vasilopulos D., Vemmos K. et al Evidence based guidelines for the antiplatelet tratment in patients with atherothrombosis. Guidelines on antiplatelet treatment in patients with atherothrombosis. 1st Hellenic Consnensus Statement. Hellenic J Cardiol 2006; 47 (Suppl A) 1-48.
• 33 Parhami-Seren B, Butenas S, Krudysz-Amblo J. et al Immunologic quantitation of tissue factors. J Thromb Haemost 2006; 4: 1747-55.
• 34 Lang T, Bauters A, Braun SL. et al Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis 2005; 16: 301-10.
• 35 Gerotziafas GT, Depasse F, Busson J. et al Towards a standardization of thrombin generation assessment: The influence of tissue factor, platelets and phospholipids concentration on the normal values of Thrombogram-Thrombinoscope assay. Thromb J 2005; 3: 16
• 36 Chantarangkul V, Clerici M, Bressi C. et al Standardisation of the endogenous thrombin potential measurement : how to minimise the effect of residual platelets in stored plasma. Br J Haematol 2004; 124: 355-7.
• 37 Vanschoonbeek K, Feijge MA, Van Kampen RJ. et al Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogram characteristics. J Thromb Haemost 2004; 2: 476-84.
• 38 Butenas S, van’t Veer C, Mann KG. ’Normal’ thrombin Generation. Blood 1999; 94: 2169-78.
• 39 Rand MD, Lock JB, van’tVeer C. et al Blood clotting in minimally altered whole blood. Blood 1996; 88: 3432-45.
• 40 Holmes MB, Schneider DJ, Hayes MG. et al Novel, bedside, tissue factor-dependent clotting assay permits improved assessment of combination antithrombotic and antiplatelet therapy. Circulation 2000; 24 (102) 2051-7.
• 41 Rivard GE, Brummel K, Mann KG. et al Evaluation of thrombin generation during the process of whole blood clotting as assessed by thromboelastography. J Thromb Haemost 2005; 3: 2039-43.
• 42 Lehmann KG, Gonzales E, Tri BD. et al Systemic and translesional activation of coagulation, fibrinolytic, and inhibitory systems in candidates for coronary angioplasty: basal state and effect of successful dilation. Am Heart J 1999; 137: 274-83.
• 43 Al Dieri R, Alban S, Béguin S. et al Fixed dosage of low-molecular-weight heparins causes large individual variation in coagulability, only party correlated to body weight. J Thromb Haemost 2006; 4: 83-9.
• 44 Khurana S, Mattson JC, Westley S. Monitoring platelet glycoprotein IIb/IIIa-fibrin interaction with tisuue factor-activated thromboelastography. J Lab Clin Med 1997; 130: 401-11.
• 45 Gerotziafas GT, Chakroun T, Depasse F. et al The role of platelets and recombinant factor VIIa on thrombin generation, platelet activation and clot formation. Thromb Haemost 2004; 91: 977-85.
• 46 Chakroun T, Gerotziafas GT, Seghatchian J. et al The influence of fibrin polymerization and plateletmediated contractile forces on citrated whole blood thromboelastography profile. Thromb Haemost 2006; 95: 822-8.
• 47 Nielsen VG, Cohen BM, Cohen E. Effects of coagulation factor deficiency on plasma coagulation kinetics determined via thromboelastography ? : critical roles of fibrinogen and factors II, VII, X and XII. Acta Anaesthesiol Scand 2005; 49: 222-31.
• 48 Sørensen B, Johansen P, Christiansen K. et al Whole blood coagulation thromboelastographic profiles employing minimal tissue factor activation. Thromb Haemost 2003; 1: 551-8.
• 49 Gerotziafas GT, 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: 149-56.
• 50 Petros S, Siegemund T, Siegemund A. et al The effect of different anticoagulants on thrombin generation. Blood Coagul Fibrinolysis 2006; 17: 131-7.
• 51 Gerotziafas GT, Petropoulou A, Hatmi M. et al Inhibition of In Vitro Thrombin Generation: Another Parameter Reinforcing the LMWH Heterogeneity. 47^th American Society of Hematology Annual Meeting, Atlanta 10 –13/12/2005. Poster Session 70-I, Abstract 912.
• 52 Craft RM, Chavez JJ, Bresee SJ. et al A novel modification of the Thrombelastograph assay, isolating platelet function, correlates with optical platelet aggregation. J Lab Clin Med 2004; 143: 301-9.
• 53 Craft RM, Chavez JJ, Snider CC. et al Comparison of modified Thrombelastograph and Plateletworks whole blood assays to optical platelet aggregation for monitoring reversal of clopidogrel inhibition in elective surgery patients. J Lab Clin Med 2005; 145: 309-15.
• 54 Carroll RC, Craft RM, Chavez JJ. et al Thrombelastograph whole blood assay for clinical monitoring of NSAID-insensitive transcellular platelet activation by arachidonic acid. J Lab Clin Med 2005; 146: 30-5.