Thromb Haemost 1999; 82(02): 887-891
DOI: 10.1055/s-0037-1615927
Research Article
Schattauer GmbH

Initial Treatment of Venous Thromboembolism

Clive Kearon
1   Hamilton Civic Hospitals Research Centre and McMaster University, Hamilton, Ontario, CANADA
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

Introduction

Goals of the initial treatment of venous thromboembolism (VTE) include the relief of symptoms and stabilization of the patient’s acute medical condition; reversal of vascular occlusion; and the prevention of recurrent VTE, including thrombus extension. The level of priority attached to achieving each of these goals depends on the severity of the patient’s presentation. For most episodes of VTE, all three goals are adequately achieved with anticoagulant therapy alone, which prevents progression of thrombosis while the patient’s endogenous fibrinolytic system gradually reverses vascular obstruction and collateral vessels develop. In a minority of patients, usually those with massive pulmonary embolism (PE) or absolute contraindications to anticoagulant therapy, additional pharmacological or mechanical measures are required to resuscitate the patient, accelerate the reversal of thrombotic occlusion, and/or prevent emboli from reaching the lungs. Anticoagulant therapy, therefore, remains the mainstay of treatment of VTE.

The initial phase of anticoagulation with heparin or its derivatives serves two functions. First, it prevents recurrent VTE during the days that oral anticoagulation is being established. As the risk of recurrent VTE is highest acutely, a rapid onset of anticoagulation is a high priority.1-3 Second, this therapy functions to effectively “turn off” thrombosis acutely. Lack of, or inadequate, initial heparin therapy reduces the efficacy of the subsequent maintenance of anticoagulation with vitamin K antagonists.4-6

After providing a historical perspective, current approaches to the initial treatment of VTE will be reviewed, concentrating on recent developments and unresolved issues.

 
  • References

  • 1 Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, McLoughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979; 301: 855-858.
  • 2 Coon WW, Willis PW. Recurrence of venous thromboembolism. Surgery 1973; 73: 823-827.
  • 3 Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: 458-462.
  • 4 Brandjes DPM, Heijboer H, Buller HR, de Rijk M, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327: 1485-1489.
  • 5 Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997; 157: 2562-2568.
  • 6 Hull RD, Raskob G, Brant RF, Pineo GF, Valentine KA. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. Arch Intern Med 1997; 157: 2317-2321.
  • 7 Mueller RL, Scheidt S. History of drugs for thrombotic disease: discovery, development, and directions for the future. Circulation 1994; 89: 432-449.
  • 8 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1960; 1: 1309-1312.
  • 9 Gallus AS, Jackaman J, Tillett J, Mills W, Sycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; 2: 1293-1296.
  • 10 Hull RD, Raskob GE, Rosenbloom D, Panju AA, Brill-Edwards P, Ginsberg JS, Hirsh J, Martin GJ, Green D. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322: 1260-1264.
  • 11 Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-681.
  • 12 Koopman MMW, Prandoni P, Piovella F, Ockelford PA, Brandjes DPM, van der Meer J, Gallus AS, Simonneau G, Chesterman CH, Prins MH, Bossuyt PMM, de Haes H, van den Belt AGM, Sagnard L, d’Azemar P, Buller HR. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682-687.
  • 13 Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism. Is it effective? Is it safe? When is it indicated?. Arch Intern Med 1997; 157: 2550-2556.
  • 14 Blackmon JR, Sautter RD, Wagner HN. Urokinase pulmonary embolism trial: phase I results. JAMA 1970; 214: 2163-2172.
  • 15 Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Turpie AGG, Gent M. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest 1990; 98: 1473-1479.
  • 16 Dalla-Volta S, Palla A. PAIMS 2-alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism: Plasminogen Activator Italian Multicenter Study 2. J Am Coll Cardiol 1992; 20: 520-526.
  • 17 Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA. et al. Aleptase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341: 507-511.
  • 18 Bergqvist D. The role of vena caval interruption in patients with venous thromboembolism. Prog Cardiovasc Dis 1994; 37: 25-37.
  • 19 Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, Laporte S, Faivre R, Charbonnier B, Barral FG, Huet Y, Simonneau G. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 1998; 338: 409-415.
  • 20 Ginsberg J. Management of venous thromboembolism. N Engl J Med 1996; 335 (24) 1816-1828.
  • 21 Hirsh J, Warkentin TE, Raschke R, Granger CB, Ohman M, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998; 114: 489S-510S.
  • 22 Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993; 119: 874-881.
  • 23 Anand S, Ginsberg JS, Kearon C, Gent M, Hirsh J. The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin. Arch Intern Med 1996; 156: 1677-1681.
  • 24 Anand SS, Bates S, Ginsberg JS, Levine M, Buller H, Prins M. et al. Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin time results. Arch Intern Med. In press.
  • 25 Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: meta-analysis. BM J 1994; 309: 299-304.
  • 26 Lensing AWA, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. Arch Intern Med 1995; 155: 601-607.
  • 27 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis. Am J Med 1996; 100: 269-277.
  • 28 Luomanmäki K, Grankvist S, Hallert C, Jauro I, Ketola K, Kim HC, Kiviniemi H, Koskivirta H, Sorskog L, Vilkko P. A multi-centre comparison of once-daily subcutaneous dalteparin (low molecular weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Intern Med 1996; 240: 85-92.
  • 29 The Columbus Investigators. Low molecular weight heparin is an effective and safe treatment for deep-vein thrombosis and pulmonary embolism. N Engl J Med 1997; 337 (10) 657-662.
  • 30 Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, Laurent M, Hirsch JL, Ferrari E, Bosson JL, Mottier D, Beau B. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337: 663-669.
  • 31 Dolovich J, Ginsberg J. Low molecular weight heparins in the treatment of venous thromboembolism. Vessels 1997; 3: 4-11.
  • 32 Zacharski LR, Ornstein DL. Heparin and cancer. Thromb Haemost 1998; 80: 10-23.
  • 33 Wells PS, Kovacs MJ, Bormanis J, Forgie MA, Goudie D, Morrow B, Kovacs J. Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin. Arch Intern Med 1998; 158: 1809-1812.
  • 34 Harrison L, McGinnis J, Crowther M, Ginsberg J, Hirsh J. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998; 158: 2001-2003.
  • 35 Holmstrom M, Berglund S, Granquist S, Bratt G, Tornebohm E, Lockner D. Fragmin once or twice daily subcutaneously in the treatment of deep venous thrombosis of the leg. Thromb Res 1992; 67: 49-55.
  • 36 Partsch H, Kechavarz B, Mostbeck A, Köhn H, Lipp C. Frequency of pulmonary embolism in patients who have iliofemoral deep vein thrombosis and are treated with once- or twice-daily low-molecular-weight heparin. J Vasc Surg 1996; 24: 774-782.
  • 37 Charbonnier BA, Flessinger JN, Banga JD, Wenzel E, D’Azemar P, Sagnard L. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. Thromb Haemost 1998; 79: 897-901.
  • 38 Spiro TE. and the Enoxaparin Clinical Trial Group. Clinical use of low molecular weight heparins. Thromb Haemost 1997; 78 (Suppl) 373.
  • 39 Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Eliott CG, Lerner RG, Hall J, Sparling T, Brettell HR. et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-982.
  • 40 Lindmarker P, Holmstrom M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 72 (02) 186-190.
  • 41 Fiessinger JN, Lopez-Fernandez M, Gatterer E, Granqvist S, Kher A, Olsson CG, Soderberg K. Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996; 76: 195-199.
  • 42 Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127: 804-812.
  • 43 Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79: 1-7.
  • 44 Chong BH. Low molecular weight heparinoid and heparin-induced thrombocytopenia. Aust N Z J Med 1996; 26: 331.
  • 45 Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993; 70: 554-561.
  • 46 de Valk HW, Banga JD, Wester JWJ, Brouwer CB, Van Hessen MWJ, Meuwissen OJAT, Hart HC, Sixma JJ, Nieuwenhuis HK. Comparing subcutaneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A randomized controlled trial. Ann Intern Med 1995; 123: 1-9.
  • 47 Schiele F, Lindgaerde F, Eriksson H, Bassand JP, Wallmark A, Hansson PO, Grollier G, Sjo M, Moia M, Camez A, Smyth V, Walker M. 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. Thromb Haemost 1997; 77: 834-838.
  • 48 Hyers TM, Agnelli G, Hull RD, Weg JG, Morris TA, Samama M, Tapson V. Antithrombotic therapy for venous thromboembolic disease. Chest 1998; 114: 561S-578S.
  • 49 Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126: 133-136.
  • 50 Crowther MA, Ginsberg JS, Kearon C, Harrison L, Johnson J, Massicotte MP, Hirsh J. A randomized trial comparing 5 mg and 10 mg warfarin loading doses. Arch Intern Med 1999; 159: 46-48.
  • 51 Hirsh J, Lensing A. Thrombolytic therapy for deep vein thrombosis. Int Angiol 1996; 5: S22-S25.
  • 52 Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, Arriaga-Nava R, Valencia S, Rosado Buzzo A. et al. Streprokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolys 1995; 2: 227-229.
  • 53 Goldhaber SZ. Pulmonary embolism. N Engl J Med 1998; 339: 93-104.
  • 54 Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L. Echocardiography doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997; 134: 479-487.
  • 55 Goldhaber SZ, Kessler CM, Heit J, Markis J, Sharma GVRK, Dawley D, Nagel JS, Meyerovitz M, Kim D, Vaughan DE. et al. A randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2: 293-298.
  • 56 Meyer G, Sors H, Charbonnier B, Kasper W, Bassand JP, Kerr IH, Lesaffre E, Vanhove P, Verstraete M. Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a european multicenter double-blind trial. J Am Coll Cardiol 1992; 19: 239-245.
  • 57 Meneveau N, Schiele F, Vuillemenot A, Velette B, Grollier G, Bernard Y, Bassand JP. Streptokinase vs alteplase in massive pulmonary embolism: a randomized trial assessing right heart haemodynamics and pulmonary vascular obstruction. Eur Heart J 1997; 18: 1141-1148.
  • 58 Verstraete M, Miller GAH, Bounameaux H, Charbonnier B, Colle JP, Lecorf G, Marbet GA, Mombaerts P, Olsson CG. Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation 1988; 77 (02) 353-360.
  • 59 Pacouret G, Alison D, Pottier JM, Bertrand P, Charbonnier B. Free-floating thrombus and embolic risk in patients with angiographically confirmed proximal deep venous thrombosis. A prospective study. Arch Intern Med 1997; 157: 305-308.
  • 60 Gulba DC, Schmid C, Borst HG, Lichtlen P, Dietz R, Luft FC. Medical compared with surgical treatment for massive pulmonary embolism. Lancet 1994; 343: 576-577.
  • 61 Sharafuddin MJ, Hicks ME. Current status of percutaneous mechanical thrombectomy: Part I. General Principles. J Vasc Interv Radiol 1997; 8: 911-921.
  • 62 Sharafuddin MJ, Hicks ME. Current status of percutaneous mechanical thrombectomy: Part II. Devices and mechanisms of action. J Vasc Interv Radiol 1998; 9: 15-31.
  • 63 Sharafuddin MJ, Hicks ME. Current status of percutaneous mechanical thrombectomy:Part III Present and future applications. J Vasc Interv Radiol 1998; 9: 209-224.
  • 64 Schmidt-Rode T, Janssens U, Schild HH, Basche S, Hanrath P, Gunther RW. Fragmentation of massive pulmonary embolism using a pigtail rotation catheter. Chest 1998; 114: 1427-1436.