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James E. Dalen, MD, MPH

Arch Intern Med. 2008;168(1):14-15.

As the Archives completes its first 100 years of publication, there is an opportunity to review the topic of venous thromboembolism (VTE) as represented in articles in the Archives. When the Archives began publication in 1908, venous thrombosis and its complication, pulmonary embolism (PE), had been clearly described by Virchow in 1859.¹ However, in 1908, the clinical diagnosis was elusive; there were no diagnostic tests to aid its recognition.² Most cases of VTE were discovered post mortem. The only available therapy was pulmonary embolectomy, which had just been described by Trendelenburg.³ Today, the diagnosis is greatly aided by the availability of chest x-rays (since the 1920s), electrocardiography (since the 1930s), arterial blood gases (since the 1960s), pulmonary angiography (since the 1960s), ventilation-perfusion scans (since the 1960s), computed tomographic scans (since the 1970s), Doppler ultrasonography of the legs, and D-dimer tests (since the 1990s).² Effective therapy with venous interruption (available since the 1930s), anticoagulants (since the 1940s), and thrombolytic therapy (since the 1960s) is available.³ The mortality of PE, if the diagnosis is made and therapy is initiated, is less than 5%.³

From 1908 until 2005, 3000 articles were published in the Archives that have been cited at least 50 times. Only 85 (2.8%) of these articles (with 50 citations) related to VTE. There were no articles relating to VTE published from 1908 to 1939, 3 published from 1940 to 1959, 7 published from 1960 to 1979, 49 published from 1980 to 1999, and 26 published from 2000 to 2005. Of the 85 articles, 75 have appeared since 1980 and only 10 were published from 1908 until 1980.

The first cited article, entitled "Thrombosis of the Deep Veins of the Leg: Its Clinical Significance as Exemplified in Three Hundred and Fifty-One Autopsies," by Hunter et al,⁴ was published in 1941.

The 10 most cited articles^5-14 on VTE are as follows: Harris et al,⁵ cited 506 times; Silverstein et al,⁶ cited 375 times; Lensing et al,⁷ cited 358 times; Elias and Eldor,⁸ cited 357 times; Kniffin et al,⁹ cited 213 times; Turpie et al,¹⁰ cited 209 times; Cruickshank et al,¹¹ cited 205 times; Glueck et al,¹² cited 203 times; Philbrick and Becker,¹³ cited 184 times; and Becker et al,¹⁴ cited 182 times.

Three of the 10 most cited articles, those by Elias and Eldor in 1984,⁸ Glueck et al in 1985,¹² and Harris et al in 1986,⁵ were among the first to report the high incidence of venous and arterial thrombosis and thrombocytopenia in patients with the lupus anticoagulant. The most cited article on VTE in the Archives from 1908 to 2005, by Harris et al in 1986,⁵ reported recurrent fetal loss in addition to thrombocytopenia and thrombosis in patients with anticardiolipin antibodies. Since these reports, numerous other hypercoagulable states have been described.¹⁵

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Three of the 10 most cited articles related to the pathophysiological and epidemiological features of VTE. A literature review by Philbrick and Becker in 1988¹³ demonstrated that without therapy, calf deep venous thrombosis (DVT) propagates to the thigh in 20% of cases and that embolization may occur after propagation. They recommended that calf DVT should be treated with heparin or, alternatively, clinicians may choose to observe these patients with serial testing of the legs and treatment if propagation to the thigh occurs. The 1941 Archives article by Hunter et al⁴ reported the findings at autopsy of 351 patients who had been in bed rest up until their death. Calf thrombi were present in 53% of the patients, and PE deaths was present in 15% of the patients. The authors speculated that calf thrombi may lead to PE if they extend into the thigh. Their speculation⁴ was confirmed by the report by Philbrick and Becker¹³ 47 years later!

Kniffin et al⁹ reported the incidence of DVT and PE in elderly persons in 1994. They noted a striking increase in PE and DVT with advancing age. Advanced age remains one of the most important risk factors for VTE. Silverstein et al⁶ reported trends in the incidence of DVT and PE in Olmsted County, Minnesota, from 1966 through 1990. The incidence of DVT remained constant during the 25-year period, but the incidence of PE was 45% lower in the last 15 years of the study, implying an increase in effective therapy of DVT.

Three articles were related to the therapy of VTE. Becker et al¹⁴ reviewed the indications, safety, and effectiveness of inferior vena cava filters in 1992. Their review of the literature indicated that PE is rare after inferior vena cava placement and that serious complications are uncommon. They noted the need for randomized clinical trials to assess the efficacy and safety of inferior vena cava filters (such trials have since been reported).¹⁶

Cruickshank et al¹¹ described a standard heparin nomogram for the management of continuous intravenous heparin therapy in 1991. Use of the nomogram resulted in a more rapid achievement of a therapeutic activated partial thromboplastin time and a reduction in overanticoagulation and underanticoagulation during heparin therapy. The use of nomograms for heparin therapy is nearly universal.¹⁷

Lensing et al⁷ reported a meta-analysis of the treatment of DVT with low-molecular-weight heparins in 1995. They concluded that low-molecular-weight heparins administered subcutaneously in fixed doses, adjusted for body weight and without laboratory monitoring, are more effective and safer than adjusted-dose, standard, unfractionated heparin. Low-molecular-weight heparin is the predominant therapy for VTE.

In 2002, Turpie et al¹⁰ reported the results of 4 randomized clinical trials comparing fondaparinux, a selective factor Xa inhibitor, with enoxaparin in patients undergoing major orthopedic surgery. Fondaparinux, 2.5 mg, was given subcutaneously once daily, beginning 6 hours after surgery. The incidence of postoperative VTE was decreased by 55% in patients treated with fondaparinux, but the incidence of bleeding was increased. Fondaparinux is now frequently used in patients at major risk of postoperative VTE.

What articles relating to VTE can we hope to see during the next 100 years of the Archives? I doubt that we will find articles defining more effective therapy of PE. Most patients who die of PE die because the diagnosis was not made and, therefore, therapy was not given. The key to preventing fatal PE is prevention of DVT. We can expect further studies on the prophylaxis of VTE. I would hope that we will have articles that further diagnose and define hypercoagulability so that we can determine which patients need prophylactic therapy when they are exposed to risk factors for VTE, such as surgery, pregnancy, immobility, or cancer.

I would hope that the most cited article on VTE in the next century will delineate hypercoagulable states and describe how they can be reversed.

AUTHOR INFORMATION
Correspondence: Dr Dalen, Department of Medicine, The University of Arizona, 1840 E River Rd, Ste 120, Tucson, AZ 87518 (jamesdalen{at}yahoo.com).

Financial Disclosure: None reported.

REFERENCES
1. Virchow RLK. Cellular Pathology. 1859 special ed. London, England: John Churchill; 1978:204-207. 2. Dalen JE. Pulmonary embolism: what have we learned since Virchow? natural history, pathophysiology, and diagnosis. Chest. 2002;122(4):1440-1456. FULL TEXT | ISI | PUBMED 3. Dalen JE. Pulmonary embolism: what have we learned since Virchow? treatment and prevention. Chest. 2002;122(5):1801-1817. FULL TEXT | ISI | PUBMED 4. Hunter WC, Sneeden VD, Robertson TD; et al. Thrombosis of the deep veins of the leg: its clinical significance as exemplified in three hundred and fifty-one autopsies. Arch Intern Med. 1941;68:1-17. FREE FULL TEXT 5. Harris EN, Chan JK, Asherson RA, Aber VR, Gharavi AE, Hughes GR. Thrombosis, recurrent fetal loss, and thrombocytopenia: predictive value of the anticardiolipin antibody test. Arch Intern Med. 1986;146(11):2153-2156. FREE FULL TEXT 6. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585-593. FREE FULL TEXT 7. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins: a meta-analysis. Arch Intern Med. 1995;155(6):601-607. FREE FULL TEXT 8. Elias M, Eldor A. Thromboembolism in patients with the "lupus"- type circulating anticoagulant. Arch Intern Med. 1984;144(3):510-515. FREE FULL TEXT 9. Kniffin WD Jr, Baron JA, Barrett J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med. 1994;154(8):861-866. FREE FULL TEXT 10. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833-1840. FREE FULL TEXT 11. Cruickshank MK, Levine MN, Hirsh J, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med. 1991;151(2):333-337. FREE FULL TEXT 12. Glueck HI, Kant KS, Weiss MA, Pollak VE, Miller MA, Coots M. Thrombosis in systemic lupus erythematosus: relation to the presence of circulating anticoagulants. Arch Intern Med. 1985;145(8):1389-1395. FREE FULL TEXT 13. Philbrick JT, Becker DM. Calf deep venous thrombosis: a wolf in sheep's clothing? Arch Intern Med. 1988;148(10):2131-2138. FREE FULL TEXT 14. Becker DM, Philbrick JT, Selby JB. Inferior vena cava filters: indications, safety, and effectiveness. Arch Intern Med. 1992;152(10):1985-1994. FREE FULL TEXT 15. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med. 2003;138(2):128-134. FREE FULL TEXT 16. Decousus H, Leizorovicz A, Parent F; et al, Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. 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(7):409-415. FREE FULL TEXT 17. Hirsh J, Raschke R. Heparin and low-molecular weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126(3)(suppl):188S-203S. FULL TEXT | ISI | PUBMED

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