Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients

Summary

Hospitalized patients with acute medical conditions are at significant risk of venous thromboembolism (VTE): approximately 10–30% of general medical patients may develop deep-vein thrombosis or pulmonary embolism, and the latter is a leading contributor to deaths in hospital. Despite consensus-group recommendations that at-risk medical patients should receive thromboprophylaxis, there is currently no consensus as to which patients are at risk, and many patients may not receive appropriate thromboprophylaxis. This paper reviews evidence for the risk of VTE associated with different medical conditions and risk factors, and presents a risk-assessment model for risk stratification in medical patients. Medical conditions associated with a moderate to high risk of VTE include cardiac disease, cancer, respiratory disease, inflammatory bowel disease, and infectious diseases. Importantly, analyses of data from the MEDENOX study show that thromboprophylaxis significantly reduces the risk o f VTE in these patient subgroups. Risk factors in medical patients include a history of VTE, history of malignancy, increasing age, thrombophilia, prolonged immobility, and obesity. These medical conditions and risk factors are included in a risk-assessment model which is hoped will provide a simple means of assisting clinicians in deciding whether thromboprophylaxis should be used in an individual patient.

Keywords

Medical illness - risk-assessment model - thromboprophylaxis - venous thromboembolism

• References

• 1 Lindblad B, Sternby NH, Bergqvist D. Incidence of venous thromboembolism verified by necropsy over 30 years. BMJ 1991; 302: 709-11.
• 2 Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?. J R Soc Med 1989; 82: 203-5.
• 3 Cohen AT, Edmondson RA, Phillips M J. et al. The changing pattern of venous thromboembolic disease. Haemostasis 1996; 26: 65-71.
• 4 Sperry KL, Key CR, Anderson RE. Toward a population-based assessment of death due to pulmonary embolism in New Mexico. Hum Pathol 1990; 21: 159-65.
• 5 Samama MM, Cohen AT, Darmon J-Y. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341: 793-800.
• 6 Leizorovicz A, Cohen AT, Turpie AGG. et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110: 874-9.
• 7 Cohen AT, Davidson BL, Gallus A S. et al. Fondaparinux for the prevention of VTE in acutely ill medical patients. Blood 2003; 102: 42 (Abstract).
• 8 Geerts WH, Pineo GF, Heit J A. et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 338S-400S.
• 9 Nicolaides AN, Breddin HK, Fareed J. et al Cardiovascular Disease Educational and Research Trust and the International Union of Angiology. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001; 20: 1-37.
• 10 Second Thromboembolic Risk Factors (THRIFT II) Consensus Group.. Risk of and prophylaxis for venous thromboembolism in hospital patients. Phlebology 1998; 13: 87-97.
• 11 Scottish Intercollegiate Guidelines Network (SIGN).. Prophylaxis of Venous Thromboembolism. 2002 SIGN Publication No. 62 http://www.sign.ac.uk/pdf/sign62.pdf (accessed May 2005).
• 12 Anderson Jr FA, Wheeler HB, Goldberg R J. et al. Physician practices in the prevention of venous thromboembolism. Ann Intern Med 1991; 115: 581-5.
• 13 Ageno W, Squizzata A, Ambrosini F. et al. Thrombosis prophylaxis in medical patients: a retrospective review of clinical practice patterns. Haematologica 2002; 87: 746-50.
• 14 Ahmad HA, Geissler A, Maclellan DG. Deep venous thrombosis prophylaxis: are guidelines being followed?. ANZ J Surg 2002; 72: 331-4.
• 15 Bergmann J-F, Mouly S. Thromboprophylaxis in medical patients: focus on France. Semin Thromb Hemost 2002; 28 (Suppl. 03) 51-5.
• 16 Arcelus JI, Candocia S, Traverso C I. et al. Venous thromboembolism prophylaxis and risk assessment in medical patients. Semin Thromb Hemost 1991; 17 (Suppl. 03) 313-8.
• 17 Cohen AT, Alikhan R. Prophylaxis of venous thromboembolism in medical patients. Curr Opin Pulm Med 2001; 7: 332-7.
• 18 Thromboembolic Risk Factors (THRIFT) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. BMJ 1992; 305: 567-74.
• 19 Caprini JA, Arcelus JA, Reyna JJ. Effective risk stratification of surgical and nonsurgical patients for venous thromboembolic disease. Semin Hematol 2001; 38 (Suppl. 05) 12-9.
• 20 Haas SK. Venous thromboembolic risk and its prevention in hospitalized medical patients. Semin Thromb Hemost 2002; 28: 577-84.
• 21 Anderson Jr FA, Wheeler HB, Goldberg R J. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933-8.
• 22 Heit JA, Silverstein MD, Mohr D N. et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452-63.
• 23 Heit JA, O’Fallon WM, Petterson T M. et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism. A population-based study. Arch Intern Med 2002; 162: 1245-8.
• 24 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the SIRIUS study. Arch Intern Med 2000; 160: 3415-20.
• 25 Arcelus JI, Caprini JA, Monreal M. et al. The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients. J Vasc Surg 2003; 38: 916-22.
• 26 Belch JJ, Lowe GD, Ward A G. et al. Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J 1981; 26: 115-17.
• 27 Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med 1982; 10: 448-50.
• 28 Cade JF, Andrews JT, Stubbs AE. Comparison of sodium and calcium heparin in prevention of venous thromboembolism. Aust N Z J Med 1982; 12: 501-4.
• 29 Ibarra-Pérez C, Lau-Cortés E, Colmenero-Zubiate S. et al. Prevalence and prevention of deep vein thrombosis of the lower extremities in high-risk pulmonary patients. Angiology 1988; 39: 505-13.
• 30 Gårdlund B. Randomised, controlled trial of lowdose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet 1996; 347: 1357-61.
• 31 Dahan R, Houlbert D, Caulin C. et al. Prevention of deep vein thrombosis in elderly medical in-patients by a low molecular weight heparin: a randomized doubleblind trial. Haemostasis 1986; 16: 159-64.
• 32 Bergmann JF, Caulin C. Heparin prophylaxis in bedridden patients. Lancet 1996; 348: 205-6.
• 33 Fraisse F, Holzapfel L, Coulaud J M. et al. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. Am J Respir Crit Care Med 2000; 161: 1109-14.
• 34 Alikhan R, Cohen AT, Combe S. et al MEDENOX Study. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164: 963-8.
• 35 Alikhan R, Cohen AT, Combe S. et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX Study. Blood Coagul Fibrinolysis 2003; 14: 341-6.
• 36 Emerson PA, Marks P. Preventing thromboembolism after myocardial infarction: effect of low-dose heparin or smoking. BMJ 1977; 1: 18-20.
• 37 Handley AJ. Low-dose heparin after myocardial infarction. Lancet 1972; 2: 623-4.
• 38 Warlow C, Terry G, Kenmure A C. et al. A doubleblind trial of low doses of subcutaneous heparin in the prevention of deep-vein thrombosis after myocardial infarction. Lancet 1973; 2: 934-6.
• 39 Wray R, Maurer B, Shillingford J. Prophylactic anticoagulant therapy in the prevention of calf-vein thrombosis after myocardial infarction. N Engl J Med 1973; 288: 815-7.
• 40 Anderson GM, Hull E. The effect of dicumarol upon the mortality and incidence of thromboembolic complications in congestive heart failure. Am Heart J 1950; 39: 697-702.
• 41 Kierkegaard A, Norgren L, Olsson C G. et al. Incidence of deep vein thrombosis in bedridden non-surgical patients. Acta Med Scand 1987; 222: 409-14.
• 42 Donati MB. Cancer and thrombosis. Haemostasis 1994; 24: 128-31.
• 43 Falanga A, Donati MB. Pathogenesis of thrombosis in patients with malignancy. Int J Hematol 2001; 73: 137-44.
• 44 Sutherland DE, Weitz IC, Liebman HA. Thromboembolic complications of cancer: epidemiology, pathogenesis, diagnosis, and treatment. Am J Hematol 2003; 72: 43-52.
• 45 Otten HM, Prins MH, Smorenburg S M. et al. Risk assessment and prophylaxis of venous thromboembolism in non-surgical patients: cancer as a risk factor. Haemostasis 2000; 30 (Suppl. 02) 72-6.
• 46 Clarke-Pearson DL, Synan IS, Colemen R E. et al. The natural history of postoperative venous thromboemboli in gynaecologic oncology: a prospective study of 382 patients. Am J Obstet Gynecol 1984; 148: 1051-4.
• 47 Marras LC, Geerts WH, Perry JR. The risk of venous thromboembolism is increased throughout the course of malignant glioma. An evidence-based review. Cancer 2000; 89: 640-6.
• 48 Lip GY, Chin BS, Blann AD. Cancer and the prothrombotic state. Lancet Oncol 2002; 3: 27-34.
• 49 Halkin H, Goldberg J, Modan M. et al. Reduction of mortality in general medical in-patients by low-dose heparin prophylaxis. Ann Intern Med 1982; 96: 561-5.
• 50 Levine MN, Gent M, Hirsh J. et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988; 318: 404-7.
• 51 Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991; 9: 286-94.
• 52 Levine M, Hirsh J, Gent M. et al. Double-blind randomised trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: 886-9.
• 53 Bern MM, Lokich JJ, Wallach S R. et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Intern Med 1990; 112: 423-8.
• 54 Monreal M, Alastrue A, Rull M. et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices – prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996; 75: 251-3.
• 55 Randolph AG, Cook DJ, Gonzales C A. et al. Benefit of heparin in central venous and pulmonary artery catheters. A meta-analysis of randomized controlled trials. Chest 1998; 113: 165-71.
• 56 Joynt GM, Kew J, Gomersall C D. et al. Deep venous thrombosis caused by femoral venous catheters in critically ill adult patients. Chest 2000; 117: 178-83.
• 57 Mian NZ, Bayly R, Schreck D M. et al. Incidence of deep venous thrombosis associated with femoral venous catheterization. Acad Emerg Med 1997; 4: 1118-21.
• 58 Prescott SM, Richards KL, Tikoff G. et al. Venous thromboembolism in decompensated chronic obstructive pulmonary disease. A prospective study. Am Rev Respir Dis 1981; 123: 32-6.
• 59 Harenberg J, Kallenbach B, Martin U. et al. Randomized controlled study of heparin and low molecular weight heparin for prevention of deep-vein thrombosis in medical patients. Thromb Res 1990; 59: 639-50.
• 60 Bergmann JF, Neuhart E. A multicenter randomized double-blind study of enoxaparin compared with UFH in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. The Enoxaparin in Medicine Study Group. Thromb Haemost 1996; 76: 529-34.
• 61 Kleber F-X, Witt C, Vogel G. et al for THEPRINCE study group. A randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145: 614-21.
• 62 Motykie GD, Caprini JA, Arcelus J I. et al. Risk factor assessment in the management of patients with suspected deep vein thrombosis. Int Angiol 2000; 19: 47-51.
• 63 Miehsler W, Reinisch W, Valic E. et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism?. Gut 2004; 53: 542-8.
• 64 Bernstein CN, Blanchard JF, Houston D S. et al. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001; 85: 430-4.
• 65 Talbot RW, Heppell J, Dozois R R. et al. Vascular complications of inflammatory bowel disease. Mayo Clin Proc 1986; 61: 140-5.
• 66 Gaffney PR, Doyle CT, Gaffney A. et al. Paradoxical response to heparin in 10 patients with ulcerative colitis. Am J Gastroenterol 1995; 90: 220-3.
• 67 Vrij AA, Jansen JM, Schoon E J. et al. Low molecular weight heparin treatment in steroid refractory ulcerative colitis: clinical outcome and influence on mucosal capillary thrombi. Scand J Gastroenterol 2001; 36 (Suppl. 234) 41-7.
• 68 DeMaria AN. Relative risk of cardiovascular events in patients with rheumatoid arthritis. Am J Cardiol 2002; 89: 33D-8D.
• 69 McCarthy ST, Turner JJ, Robertson D. et al. Lowdose heparin as a prophylaxis against deep-vein thrombosis after acute stroke. Lancet 1977; 2: 800-1.
• 70 McCarthy ST, Turner J. Low-dose subcutaneous heparin in the prevention of deep-vein thrombosis and pulmonary emboli after acute stroke. Age Ageing 1986; 15: 84-8.
• 71 Prins MH, Gelsema R, Sing A K. et al. Prophylaxis of deep venous thrombosis with a low-molecularweight heparin (Kabi 2165/Fragmin®) in stroke patients. Haemostasis 1989; 19: 245-50.
• 72 Turpie AGG, Levine MN, Hirsh J. et al. Doubleblind randomised trial of ORG 10172 low-molecularweight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet 1987; 1: 523-6.
• 73 Hillbom M, Erilä T, Sotaniemi K. et al. Enoxaparin vs heparin for prevention of deep vein thrombosis in acute ischaemic stroke: a randomized, double-blind study. Acta Neurol Scand 2002; 106: 84-92.
• 74 Dumas R, Woitinas F, Kutnowski M. et al. A multicentre, double-blind, randomized study to compare the safety and efficacy of once-daily ORG 10172 and twice-daily low-dose heparin in preventing deep-vein thrombosis in patients with acute ischaemic stroke. Age Ageing 1994; 23: 512-6.
• 75 Sandset PM, Dahl T, Stiris M. et al. A double-blind and randomized placebo-controlled trial of low molecular weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke. Semin Thromb Hemost 1990; 16 (Suppl) 25-33.
• 76 Sandercock PA, van den Belt AG, Lindley R I. et al. Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials. J Neurol Neurosurg Psychiatry 1993; 56: 17-25.
• 77 Levine MN, Raskob G, Landefeld S. et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119 (Suppl. 01) 108S-21S.
• 78 Mazzone C, Chiodo Grandi F, Sandercock P. et al. Physical methods for preventing deep vein thrombosis in stroke (Cochrane Review). The Cochrane Library. 01 2003. Oxford: Update Software.;
• 79 Green D, Lee MY, Ito V Y. et al. Fixed- vs adjusteddose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA 1988; 260: 1255-8.
• 80 Green D, Lee MY, Lim A C. et al. Prevention of thromboembolism after spinal cord injury using lowmolecular-weight heparin. Ann Intern Med 1990; 113: 571-4.
• 81 Vaitkus PT, Leizorovicz A, Cohen A T. et al PREVENT Medical Thromboprophylaxis Study Group. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients. Thromb Haemost 2005; 93: 76-9.
• 82 Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001; 135: 367-73.
• 83 Laffan M, Tuddenham E. Science, medicine, and the future: assessing thrombotic risk. BMJ 1998; 317: 520-3.
• 84 Bouthier J. The venous thrombotic risk in nonsurgical patients. Drugs 1996; 52 (Suppl. 07) 16-29.
• 85 Gensini GF, Prisco D, Falciani M. et al. Identification of candidates for prevention of venous thromboembolism. Semin Thromb Hemost 1997; 23: 55-67.
• 86 Goldhaber SZ, Savage DD, Garrison R J. et al. Risk factors for pulmonary embolism. The Framingham Study. Am J Med 1983; 74: 1023-8.
• 87 Goldhaber SZ, Grodstein F, Stampfer M J. et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277: 642-5.
• 88 Hansson PO, Eriksson H, Welin L. et al. Smoking and abdominal obesity. Risk factors for venous thromboembolism among middle-aged men: “the study of men born in 1913”. Arch Intern Med 1999; 159: 1886-90.
• 89 Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003; 89: 493-8.
• 90 Leone G, Sica S, Chiusolo P. et al. Blood cell diseases and thrombosis. Haematologica 2001; 86: 1236-44.
• 91 Daly E, Vessey MP, Hawkins M M. et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977-80.
• 92 Daly E, Vessey MP, Painter R. et al. Case-control study of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 1027.
• 93 Grady D, Wenger NK, Herrington D. et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132: 689-96.
• 94 Hulley S, Furberg C, Barrett-Connor E. et al HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/ progestin Replacement Study follow-up (HERS II). JAMA 2002; 288: 58-66.
• 95 Vandenbroucke JP, Rosing J, Bloemenkamp K W. et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527-35.
• 96 Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med 1998; 338: 1202-11.
• 97 Bates SM. Treatment and prophylaxis of venous thromboembolism during pregnancy. Thromb Res 2003; 108: 97-106.
• 98 Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA 1995; 274: 335-7.
• 99 Lassen MR, Borris LC, Backs S. et al. Clinical limitations of risk assessment models. Blood Coagul Fibrinolysis 1999; 10 (Suppl. 02) S45-51.
• 100 Salzman EW, Hirsh J. Prevention of venous thromboembolism. Coleman RW, Hirsh J, Marder VJ, Salzman EW. Hemostasis and Thrombosis: Basic Principles and Clinical Practice.. Lippincott; 1982: 986.
• 101 Hirsh J, Guyatt G, Albers G W. et al. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: evidence-based guidelines. Chest 2004; 126: 172S-173S.
• 102 Mismetti P, Laporte-Simitsidis S, Tardy B. et al. Prevention of venous thromboembolism in internal medicine with unfractionated heparin or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83: 14-9.
• 103 Alikhan R, Cohen AT. A safety analysis of thromboprophylaxis in acute medical illness. Thromb Haemost 2003; 89: 590-1.
• 104 Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecularweight heparin (enoxaparin). The PRIME Study Group. Haemostasis 1996; 26 (Suppl. 02) 49-56.
• 105 Girolami B, Prandoni P, Stefani P M. et al. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 2003; 101: 2955-9.
• 106 Warkentin TE, Levine MN, Hirsh J. et al. Heparininduced thrombocytopenia in patients treated with lowmolecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-5.
• 107 Harenberg J, Roebruck P, Heene DL. Subcutaneous low-molecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. The Heparin Study in Internal Medicine Group. Haemostasis 1996; 26: 127-39.
• 108 Hull R, Schellong S, Tapson V. et al. Extended thromboprophylaxis with enoxaparin in acutely ill medical patients with prolonged periods of immobilisation: the EXCLAIM study. J Thromb Haemost 2003; 1 (Suppl. 01) OC397 (Abstract).