Venous thrombosis is the presence of a blood clot within a superficial or deep vein and the resultant inflammation in the blood vessel wall. Thrombosis most commonly occurs in the legs, but can also occur in the arms. Signs of thrombosis include tenderness in the involved veins, presence of a palpable “cord” in the leg, increased tissue swelling and rigidity, and distension of superficial veins. A careful history eliciting risk factors as well as a physical examination guide the clinician to a proper diagnosis, and diagnostic testing such as duplex venous ultrasonogra-phy or venography (specialized scans of the veins and venous walls) helps to confirm the diagnosis. Left untreated, patients with deep venous thrombosis (DVT) are at increased risk of pulmonary embolism (PE), a condition in which the blood clot travels through the venous system to arteries in the lungs.
Risk factors for venous thrombosis were summarized by Rudolf Virchow in 1856: (a) local trauma to the vessel wall; (b) hypercoagulability (increased tendency for clotting of blood); and (c) stasis (pooling or non-movement of the blood). Over a century later, it is still believed that these factors play a critical role in the formation of thrombus, but also that genetic abnormalities predispose individuals to develop thrombosis when exposed to particular environmental stressors. An “inherited” predisposition to hypercoagulable states can result from deficiencies in factors in the blood that prevent clotting, such as anticoagulant proteins C or S, antithrom-bin III, and plasminogen. The most frequently inherited predisposition to clot formation is due to the presence of a genetic mutation, factor V Leiden, which increases clotting. Genetic mutations are genes that differ in some individuals from those typically seen in the “normal” population. Given the important role of genetic abnormalities, a careful family history should be obtained from anyone who presents with a venous thromboembolism.
Environmental conditions that lead to venous stasis or endothelial (blood vessel wall) damage promote venous thrombosis, especially among individuals who already have clinical or subclinical tendency to form clots. Approximately 50% of thrombotic events, or clots, in patients with inherited hypercoagulable (increasing clotting) states are associated with acquired risk factors. Some of the more common conditions that can precipitate venous thrombosis are surgery, trauma, immobilization, prolonged travel (such as in cramped airplane seats), cancer, systemic arterial hypertension, indwelling venous catheters, morbid obesity, and cigarette smoking.
Moreover, patients with a history of DVT are at significantly increased risk for recurrent thrombotic events.
Conditions that uniquely place women at increased risk are the use of oral contraceptive pills (OCPs) or hormone replacement therapy (HRT), as well as pregnancy and the postpartum state. OCPs are used by over 70 million women worldwide, including 18 million Americans, making OCP use a key contributor to thrombosis in young women. While the risk of thrombosis increases within 4 months of beginning OCPs, it is unaffected by duration of therapy and returns to baseline levels within 3 months of discontinuation. Women who use OCPs suffer from venous thromboembolism about 3-4 times more than nonusers. This amounts to a total of only about one to four cases per 10,000 oral contraceptive users and should not raise alarm. Women with a genetic predisposition to clotting, such as factor V Leiden genetic mutation, are at significantly increased risk for thrombotic events. The risk of OCPs has decreased with the use of lower estrogen pills. On the other hand, third-generation OCPs containing new progestogens (desogestrel and gestodene) increase the thrombotic rate.
In postmenopausal women, HRT carries a small but significant increase in the risk of venous thrombo-embolism. In the first randomized, large-scale HRT trial, the Heart and Estrogen/Progestin Replacement Study, HRT was associated with a nearly threefold increased risk of venous thromboembolism. Similarly, the Women’s Health Initiative (WHI), which randomized over 16,000 women in an estrogen/progestin versus placebo study, found a twofold increased risk of venous thromboembolism in women treated with HRT. In summary, although these large and carefully done studies demonstrated a statistically significant increase in the rate of thrombotic events with HRT, the number of thrombotic events was still relatively small.
Pregnancy and the postpartum period are well-established risk factors for venous thromboembolism, yielding a greater than fivefold increased risk. Older age is associated with even higher risk. DVT during pregnancy occurs in the left leg more frequently than in the right leg and involves the iliofemoral (pelvic/leg vein) system. The cause of pregnancy-related thrombosis involves all three components of Virchow’s original triad: (a) stasis due to the compression of large veins by the pregnant uterus, (b) hypercoagulability due to an increase in blood clotting factors and decrease in anticlotting factors, and (c) endothelial (blood vessel lining) injury, which is worsened at the time of delivery. The risk of venous thromboembolism is further increased in women with a history of venous thrombosis or inherited thrombophilia (tendency to form clots). Thus, screening for these disorders should be provided during prenatal visits, and preventive therapy with subcutaneous low-dose heparin during pregnancy followed by warfarin for 4-6 weeks after delivery may be considered for women at increased risk. This may prevent an “at-risk” woman from developing a DVT.
Anticoagulation is the cornerstone of the treatment of venous thromboembolism. Since patients with DVT are at risk for PE, treatment should be instituted promptly with oral warfarin plus intravenous heparin. After about 5 days, the heparin can be stopped. Warfarin is usually continued for 4-6 months for DVT or at least 6 months for PE. In some patients, if the clot is recurrent or due to an irreversible cause, such as cancer, then anticoagulation may be continued indefinitely. Because warfarin is teratogenic (may cause abnormal fetal development), it is contraindicated in pregnancy. Alternative therapies are available to patients who have contraindications to anticoagulation. Awareness of risk factors and treatment options by both clinicians and patients should decrease the morbidity and mortality associated with this disorder.
- Blumenthal, R. S., & Bush, T. (1999). Hormone replacement therapy and the prevention of coronary artery disease. In P. Charney (Ed.), Coronary artery disease in women: What all physicians need to know (pp. 264-288). Philadelphia: American College of Physicians.
- Hulley, S., Furberg, C., Barrett-Connor, E., et al., for the HERS Research Group. (2002). Noncardiovascular disease outcomes during 6.8 years of hormone replacement therapy. Heart and Estrogen/progestin Replacement Study follow-up (HERS II). Journal of the American Medical Association, 288, 58-66.
- Writing Group for the Women’s Health Initiative Investigators. (2002). Risks and thromboembolic disease and combined oral contraceptives: Results of international multicentre case-control study. Lancet, 346, 1575-1582.
- Writing Group for the World Health Organization Investigators. (1995). Venous benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association, 288, 321-333.
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