**7. Hormonal replacement therapy**

There is a 2- to 3-fold increased risk of VTE with the use of hormone replacement therapy in postmenopausal women.75,76 Among postmenopausal women who had coronary artery disease and received estrogen plus progestin, the relative hazard of VTE was 2.7 compared with nonusers.77 Review showed that the risk of VTE is highest in the first year of hormone replacement therapy.78 The risk of VTE is increased for oral estrogen alone, oral estrogen combined with progestin, and probably for transdermal hormone replacement therapy.78

#### **8. Congenital hypercoagulable disorders**

#### **8.1 Antithrombin deficiency**

Antithrombin is a serine protease inhibitor of thrombin and also inhibits factors IXa, Xa, XIa, and XIIa. Thrombin is irreversibly bound by antithrombin and prevents thrombin's action on fi brinogen, on factors V, VIII, and XIII, and on platelets.79 This anticoagulant is synthesized in the liver and endothelial cells, and has a half-life of 2.8 days.80 Antithrombin deficiency has a prevalence of 1 : 5000 with more than 100 genetic mutations and an autosomal dominant inheritance pattern.81 Homozygotes typically die *in utero* whereas heterozygotes typically have an antithrombin level that is 40 to 70% of normal.

Risk Factors of Deep Vein Thrombosis 9

Homocysteine is an amino acid formed during the metabolism of methionine and may be elevated secondary to inherited defects in two enzymes that are part of the conversion of homocysteine to cysteine. The two enzymes involved are N5,N10–methylene tetrahydrofolate reductase (MTHFR) or cystathionine beta-synthase. Hyperhomocysteinemia has been shown to increase the risk of atherosclerosis, atherothrombosis, and venous thrombosis. Elevated plasma homocysteine levels cause

Hypercoagulable syndromes include inherited and acquired thrombophilias. The former is discussed in detail in the article by Weitz in this issue. The latter includes the antiphospholipid syndrome, heparin-induced thrombocytopenia, acquired dysfibrinogenemia, myeloproliferative disorders, and malignancy. Myeloproliferative disorders and malignancy are described elsewhere in this article. Regarding the antiphospholipid syndrome, antiphospholipid antibodies are associated with both arterial and venous thrombosis.89 The most commonly detected subgroups of antiphospholipid antibodies are lupus anticoagulant antibodies, anticardiolipin antibodies and anti-b2 glycoprotein I antibodies.90 DVT, the most common manifestation of the antiphospholipid syndrome, occurs in 29% to 55% of patients with the syndrome, and about half of these patients have pulmonary emboli.91,92 The risk of heparin-associated thrombocytopenia is more duration related than dose related. Heparin-associated thrombocytopenia occurs more frequently with unfractionated heparin when used for an extended duration than with LMWH used for an extended duration.93 When used for prophylaxis, there was a higher prevalence of heparin-associated thrombocytopenia inthose receiving unfractionated heparin (1.6%, 57 of 3463) than in those receiving LMWH (0.6%, 23 of 3714).93 However, treatment resulted in only a small difference in the prevalence of heparinassociated thrombocytopenia comparing unfractionated heparin (0.9%, 22 of 2321) with LMWH (0.6%, 18 of 3126).93 Acquired dysfibrinogenemia occurs most often in patients with severe liver disease.94 The impairment of the fibrinogen is a structural defect caused by an increased carbohydrate content impairing the polymerization of the fibrin, depending on the degree of

Congestive heart failure (CHF) is considered amajor risk factor for VTE.13,41,61,95,96 Among patients with established CHF, those with lower ejection fractions had a higher risk of thromboembolic event.97,98 However, some investigators did not evaluate CHF among the risk factors for VTE.99 The reported frequency of PE in patients with heart failure has ranged widely from 0.9% to 39% of patients. 13,97,98,100,101 The reported frequency of DVT in patients with CHF also ranged widely from 10% to 59%.13,41,61 The largest investigation was from the National Hospital Discharge Survey.102 Among 58,873,000 patients hospitalized with heart failure in short-stay hospitals from 1979 to 2003, 1.63% had VTE (relative risk 5 1.47).102 The relative risk for VTE was highest in patients less than 40 years old (relative risk 5 6.91). Some showed the lower the ejection fraction, the greater the risk of VTE.103 Among 755,807 adults older than 20 years with heart failure who died from 1980 to 1998, PE was listed as the cause of death in 20,387 (2.7%).104 Assuming that the accuracy of death certificates was only 26.7%,105 the rate of death from PE in these patients may have been as high as 10.1%.

various dysfunctions of endothelial cells leading to a prothrombotic state.

**8.5 Hyperhomocysteinemia** 

abnormality of the fibrinogen molecule.94

**9. Heart failure** 

Antithrombin deficiency is associated with lower extremity venous thrombosis as well as mesenteric venous thrombosis. The most common presentation in those with antithrombin deficiency is deep venous thrombosis with or without pulmonary embolism.82
