Peripheral venous disease is an important cause of morbidity and mortality. Deep venous thrombosis (DVT) may be associated with chronic pain, limb edema, and fatal pulmonary embolism. The estimated annual incidence of DVT is about 1 in 1000 persons in developed countries; the prevalence in the United States is estimated at more than 2 million.1 DVT occurs more frequently in adults older than 40 years than in younger persons; the female-to-male ratio is 1.2:1.
Venous leg ulcers develop in many patients with chronic venous insufficiency. They adversely affect quality of life and productivity; because long-term therapy is required, the condition can be costly.
In this article, I offer guidelines on the diagnosis of these venous disorders, and I discuss effective treatment strategies.
DEEP VENOUS THROMBOSIS
History. The diagnosis of DVT can be challenging. Many patients are asymptomatic, which makes clinical diagnosis unreliable.
Common presenting symptoms of DVT are unilateral leg pain and edema. However, the classic Homans sign-calf pain with dorsiflexion of the foot-lacks diagnostic accuracy.2 Other signs and symptoms-such as a palpable venous cord, warmth, redness, and fever-occur infrequently enough in patients with DVT to make them unhelpful as well.
The key to the diagnosis lies in careful identification of clinical risk factors in the history. A validated clinical model, shown in Table 1, is used as an adjunct in identifying patients who need follow-up evaluation or further testing.3
When you take the history, be sure to ask the patient about:
Trauma (especially long bone fractures).
Surgery (especially of the hip or knee).
Indwelling central venous catheter use.
Pathologic risk factors include a history of carcinoma, genetic anticoagulant deficiencies, nephritic syndrome, and polycythemia vera. Both clinical and pathologic risk factors can predispose patients to DVT. Signs and symptoms of DVT may also occur with muscle rupture, trauma to the extremity, hemorrhage, nerve compression from a variety of causes and, rarely, arthritis, fractures, and arterial occlusive disease.
Diagnostic procedures. Because physical findings are unreliable in the diagnosis of DVT, it is crucial to identify the patient's risk factors and order diagnostic tests for those at higher risk. There are no specific laboratory tests that establish the diagnosis. Evaluation consists of complete blood cell count, platelet count, and coagulation panel (prothrombin time [PT] and partial thromboplastin time). Although these studies are not diagnostic, they are necessary as baseline indicators before treatment is begun. Testing for hypercoagulable conditions is best done after the diagnosis is made and before treatment is started. Assays for protein C and protein S, antithrombin III, antiphospholipid antibodies, and factor V Leiden are recommended. The factor V Leiden defect is the most common hypercoagulable disease state.
Some experts recommend a D-dimer test to rule out DVT because in early studies it appeared to have a negative predictive value of 100%.4 Other, more recent studies done in clinical settings report a negative predictive value of 83% to 90%.5,6 A number of D-dimer assays are available; studies indicate that the rapid latex particle agglutination assays perform best.7 Although a validated algorithm does not exist, most evaluations begin with a clinical assessment followed by D-dimer and noninvasive imaging, with contrast venography reserved for only a few patients.8,9
Contrast venography has been the gold standard for the diagnosis of DVT. However, it is not ideal because it is invasive, not always technically possible, and not always available at community hospitals. It also carries a small risk of allergic reaction or venous thrombosis.
Other options include B-mode ultrasonography with Doppler flow (duplex) and impedance plethysmography. Impedance studies have been almost completely replaced by duplex scanning, which is typically the initial imaging modality used in the evaluation of a patient with suspected DVT. Duplex ultrasonography is highly sensitive and specific for the popliteal and femoral veins but is much less sensitive for the calf veins. Accurate results strongly depend on operator skill and experience. Like duplex scanning, impedance plethysmography is accurate for the popliteal and femoral veins but much less so for the calf veins. However, this test depends much less on operator skill and experience. The I-125 fibrinogen scan is useful only in cases of active thrombosis and takes 4 hours; the scan may be helpful for evaluating the calf area for ongoing thrombosis.
Treatment. Traditionally, all patients in whom DVT was diagnosed were admitted to the hospital and treated with unfractionated heparin for1 to 3weeks, followed by warfarin for 6 months. The heparin is continued until a therapeutic warfarin level is achieved. With the advent of low molecular weight heparin (LMWH), only patients who have complicated DVT need to be admitted. DVT is considered complicated if any of the conditions listed in Table 2 are present.
Patients with uncomplicated DVT are treated with LMWH delivered into the deep subcutaneous tissue-either enoxaparin, 1 mg/kg twice a day, or dalteparin, 200 IU/kg once or twice a day (depending on the specific preparation). Another alternative is tinzaparin, 175 IU/kg/d. Comparative studies of these agents have not been performed. Warfarin is started 1 to 3 days later at 5 mg/d and adjusted to achieve a PT 1.5 to 2 times baseline or an INR of 2.5 to 3. It is continued for a minimum of 6 months.
Patients with complicated DVTare treated with intravenous heparin using a dosing nomogram. The dosage is adjusted to achieve an activated partial thromboplastin time 3 times control.
Contraindications to anticoagulation therapy include active bleeding and neurosurgery within the last month; warfarin is contraindicated in pregnancy. Avoid intramuscular injections in patients receiving anticoagulation therapy, and check stool and urine for the presence of blood. Monitor inpatients for signs and symptoms of clot embolization, such as dyspnea.
CHRONIC VENOUS INSUFFICIENCY AND VENOUS ULCERS
Chronic venous disease presents as a spectrum of signs and symptoms; ulcers are the end stage. The most common cause of ulcers is venous insufficiency; others include arterial insufficiency, neuropathy (often from diabetes), pressure, and ischemia. Venous leg ulcers occur more commonly in women than men4 and develop in approximately 1 million of the nearly 7 million Americans with venous insufficiency.10
History. Patients typically complain of edema and aching of the legs that is worse at the end of the day, is aggravated by dependency, and is improved by leg elevation.10 As many as 75% of patients report pain that affects their quality of life.11 Risk factors for venous insufficiency are listed in Table 3. The typical site of ulceration is the medial malleolus (gaiter area).12
Physical examination. Venous insufficiency is characterized by dependent edema, varicose veins, and a reddish brown pigmentation and purpura attributable to extravasation of erythrocytes and subsequent hemosiderin deposition. Ulcers typically have irregular, flat or slightly elevated borders. The ulcer bed is shallow and contains granulation tissue as well as some fi-brinous material and, rarely, necrotic tissue.13
Diagnostic procedures. In most cases, the diagnosis can be made clinically. About 1 in 4 patients have ulcers with mixed features or a nontypical appearance. In these cases, noninvasive testing methods may help make the diagnosis. The ankle-brachial index or visual flush test may aid in detecting peripheral arterial obstructive disease (this test is described on page 102 of my article on peripheral arterial disease in Consultant, January 2004). Differentiation between arterial and venous disease is critical, because compression therapy-the mainstay of treatment for venous ulcers-can lead to worsening of an arterial ulcer.14 Other conditions that tend to occur concomitantly with venous diseases-including heart failure, diabetes, and neuropathy-must be ruled out through the history and physical findings.
Color duplex ultrasonography is the gold standard for evaluating venous disease. It provides anatomic and functional information about arterial and venous systems.15 If a wound is present for more than 3 months, I recommend a biopsy to rule out malignancy and evaluate for atypical infection.13
Treatment. Treatment goals for venous insufficiency and ulceration include reduction of edema, relief of pain, ulcer healing, and prevention of recurrence. The simplest method to reverse venous hypertension is bed rest with leg elevation. Elevation of the legs above the heart level for 30 minutes, 3 or 4 times daily, as well as elevation of the legs at night, allows swelling to subside and improves venous microcirculation.16
Compliance with leg elevation can be challenging for patients; therefore, graduated compression remains the cornerstone of therapy. A Cochrane review of 22 trials determined that compression increased ulcer healing rates compared with no compression. Elastic compression was more effective than nonelastic compression, and multilayered systems were more effective than single-layer systems.17 One report demonstrated that at 3 months, the use of elastic bandages resulted in better healing than nonelastic bandages and multilayer bandages were more effective than single-layer bandages.18 Another review showed that venous ulcers healed better with high-compression multilayer bandages, short-stretch bandages, Unna boots, or compression stockings compared with elevation only and no bandages.19 Compression dressings should be continued until ulcers are healed; graded compression stockings are worn to prevent recurrence. I advise my patients to replace their stockings every 6 months.
Venous ulcers commonly recur. Studies have documented recurrence rates of 4% to 79%; lower rates are linked to the use of compression stockings during therapy and after healing.20,21 The importance of adherence to the treatment regimen to prevent recurrence cannot be overemphasized.
Aspirin, 300 mg/d, improved healing in 1 small study.22,23 Further research with larger study populations is needed before this treatment can be recommended. A recent Cochrane review demonstrated that pentoxifylline, 400 mg 3 times a day, was an effective adjunct to compression bandaging.24 The effectiveness of the medication without compression dressings is difficult to determine from current studies.
Horse-chestnut seed extract is sometimes recommended for chronic venous insufficiency. A Cochrane review showed that this substance was associated with a greater overall improvement in signs and symptoms than placebo and had minimal side effects.25 However, the authors caution that more rigorous controlled clinical trials are needed to completely assess efficacy. Because horse-chestnut seed extract has minimal side effects, I often recommend a therapeutic trial for my patients. This product is sold in the nutritional supplement section of pharmacies and supermarkets. The usual dose is 300 mg bid. Because, like all supplements, it is not regulated by the FDA, batch-to-batch consistency is a concern.
Treatments shown to be ineffective for venous ulcers or chronic venous insufficiency include oral zinc sulfate, electromagnetic therapy, and laser therapy.
Clinical trials are now under way to test the effectiveness of topical or perilesional injections of granulocyte-macrophage colony-stimulating factor and keratinocyte growth factor-2. Early results are promising.
Surgery is an important option for large or slow-healing ulcers. Skin grafts may facilitate healing and can quickly relieve pain. A recent review found limited evidence that artificial skin used in conjunction with compression bandaging increased the likelihood of healing compared with compression alone.26 Further high-quality research is needed to define the role of grafting. n
1. Tovey C, Wyatt S. Diagnosis, investigation and management of deep vein thrombosis. BMJ. 2003; 326:1181-1184.
2. Ebell MH. Evaluation of the patient with suspected deep vein thrombosis. J Fam Pract. 2001;50: 167-171.
3. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pre-test probability of deep vein thrombosis in clinical management. Lancet. 1997; 350:69-74.
4. Kline JA, Johns KL, Colucciello SA, Israel EG. New diagnostic tests for pulmonary embolism. Ann Emerg Med. 2000;35:168-180.
5. Brown MD, Rowe BH, Reeves MJ, et al. The accuracy of the enzyme-linked immunosorbent assay D-dimer test in the diagnosis of pulmonary embolism: a meta-analysis. Ann Emerg Med. 2002;40: 133-144.
6. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349:1227-1235.
7. Schutgens RE, Haas RJ, Gerritsen WB, et al. The usefulness of five D-dimer assays in the exclusion of deep venous thrombosis. J Thromb Haemost. 2003;1: 976-981.
8. Anderson DR, Kovacs MJ, Kovacs G, et al. Combined use of clinical assessment and D-dimer to improve the management of patients presenting to the
emergency department with suspected deep vein
thrombosis (the EDITED study). J Thromb Haemost. 2003;1:645-651.
9. Walsh K, Kelaher N, Long K, Cervi P. An algo-
rithm for the investigation and management of patients with suspected deep venous thrombosis at a district general hospital. Postgrad Med. 2002;78: 742-745.
10. Nelzen O, Bergqvist D, Lindhagen A. Venous and non-venous leg ulcers: clinical history and appearance in a population study. Br J Surg. 1994;81: 182-187.
11. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol. 2001;44:401-421.
12. Phillips T, Stanton B, Provan A, Lew R. A study of the impact of leg ulcers on quality of life: financial, social and psychologic implications. J Am Acad Dermatol. 1994;31:49-53.
13. de Araujo T, Valencia I, Federman DG, Kirsner RS. Managing the patient with venous ulcers. Ann Intern Med. 2003;138:326-334.
14. McGuckin M, Stineman M, Goin J, Williams S. Draft guideline: diagnosis and treatment of venous leg ulcers. Ostomy Wound Manage. 1996;42:48-54.
15. Thibault PK. Duplex examination. Dermatol Surg. 1995;21:77-82.
16. Abu-Own A, Scurr JH, Coleridge Smith PD. Effect of leg elevation on the skin microcirculation in chronic venous insufficiency. J Vasc Surg. 1994;20: 705-710.
17. Cullum N, Nelson EA, Fletcher AW, Sheldon TA. Compression for venous leg ulcers. Cochrane Database Syst Rev. 2001;(2):CD000265.
18. EBM Reviews-ACP Journal Club. Review: Com-
pression treatment improves healing in venous leg ulcers. ACP J Club. 1998;129:36.
19. EBM Reviews-ACP Journal Club. Review: High-
compression bandages, stockings and Unna's boot improve healing rates in venous leg ulcers. ACP J Club. 1998;3:54.
20. Nelzen O, Bergqvist D, Lindhagen A. Long-term prognosis for patients with chronic leg ulcers: a prospective cohort study. Eur J Endovasc Surg. 1997;13:500-508.
21. Samson RH, Showalter DP. Stockings and the prevention of recurrent venous leg ulcers. Dermatol Surg. 1996;22:373-376.
22. Layton AM, Ibbotson SH, Davies JA, Goodfield MJ. Randomised trial of oral aspirin for chronic venous leg ulcers. Lancet. 1994;344:164-165.
23. Ibbotson SH, Layton AM, Davies JA, Goodfield MJ. The effect of aspirin on haemostatic activity in the treatment of chronic venous leg ulceration. Br J Dermatol. 1995;132:422-426.
24. Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2002;(1):CD001733.
25. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev. 2002;(1):CD003230.
26. Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. 2000;(1): CD001737.