Risk factors in venous thromboembolism

Risk factors for thrombosis are usually divided into genetic and acquired. Mechanistically, they fall into three groups of causes, according to Virchow: reduced blood flow, changes in the vessel wall, and changes in the composition of the blood.31,32 For venous thrombosis, the first (stasis) and the third group (changes in blood coagulability) appear most prominent. For arterial disease, factors that affect the vessel wall, i.e., promote atherosclerosis are most relevant. The genetic risk factors for venous thrombosis are all associated with changes in the blood composition. Acquired causes are either associated with decreased flow, i.e., immobilisation, paralysis, surgery, or plaster casts or related to hypercoagulability, such as in, the anti-phospholipid antibody syndrome, pregnancy, oral contraception, or cancer. Table 3 lists the main risk factors for venous thrombosis.

Table 3. Risk Factors in VTE

Acquired

Inherited

Mixed/Unknown

Malignancy Previous VTE Immobilisation Orthopaedic surgery Oral contraceptives Hormonal replacement therapy Anti-phospholipid syndrome Myeloproliferative disorders

Factor V Leiden mutation Prothrombin 20210A Protein S deficiency AT deficiency Protein C deficiency Dysfibrinogenaemia

Hyperhomocysteinaemia Elevated factor VIII Non-Leiden APC-resistance Elevated factor IX Elevated factor XI Elevated levels of TAFI

The term "thrombophilia" defines situations associated with an increased risk of VTE characterised by hypercoagulability. Inherited coagulation abnormalities predisposing to VTE, such as, deficiencies of the naturally occurring anti-coagulants anti-thrombin, protein C, and protein S and genetic mutations in coagulation factor V (factor V Leiden) and prothrombin33--35 define inherited thrombophilia. These two mutations in coagulation factors, together with high factor VIII levels have been identified as risk factors only in the last decade, and their identification has greatly improved our understanding of the aetiology of VTE. Today, inherited thrombophilia may explain more than 50% of cases of VTE.33--35 On the other hand, individuals with thrombophilia, particularly with the more common factor V Leiden or prothrombin mutations, frequently remain asymptomatic. This suggests that risk factors for inherited thrombophilia require interactions with other factors to elicit thrombosis. Situations of acquired throm-bophilia associated with an increased risk of VTE, i.e., the presence of anti-phospholipid antibodies, cancer, surgery, trauma, prolonged immobilisation, pregnancy/puerperium, and oral contraceptive use have been known for many decades. Some of these acquired conditions, such as, surgery or pregnancy are transient, but others, such as, anti-phospholipid antibodies or cancer may persist over time.

The presence and the interactions of transient or persistent risk factors for VTE, as well as their different strengths in triggering thrombosis must be taken into account for making decisions on primary and secondary prophylaxis of VTE with anti-thrombotic drugs. While awaiting specially designed controlled clinical trials, decisions concerning anti-thrombotic prophylaxis, particularly secondary prophylaxis, should be based on the identification of different risk profiles of individual cases.

Acquired risk factors for venous thromboembolism

VTE rarely manifests before puberty, after which the annual incidence progressively increases. The estimated annual incidence of VTE is 1 per 10,000 in the young (before age 40) and 1 per 1000 among the elderly (after age 75).22--26 Higher incidence of malignancy and frequent orthopaedic surgery in the elderly population may partially explain the high incidence. The thrombotic risk associated with age may be further excerabated by thrombophilic abnormalities as it has been shown that men heterozygous for factor V Leiden have an age-related increased risk for VTE.34,35 Furthermore, three other studies on very elderly people (above 85 years of age and centenarians) have shown a similar prevalence of the factor V Leiden mutations among young people, with no selection effect.34,35 In addition, there is no association between age and the plasma levels of anti-thrombin, protein C, protein S, and TFPI as observed in a study of patients over 65 years of age.33

Malignancy

The procoagulant activity of tumour cells or their products and the administration of chemotherapeutic drugs36--40 account for the associated increased risk of thrombosis in cancer patients. VTE is more common with certain types of cancer, such as, pancreatic, gastrointestinal, ovarian, prostatic, or pulmonary neoplasms.38,39 VTE usually complicates advanced malignant disease. It may also, however, be the first sign of an underlying cancer that may herald the diagnosis of cancer by several years.41 In individuals with a first episode of idiopathic VTE, there is a 10 to 20% probability of having cancer at diagnosis or within the following 24 months.38

Therefore, a physical examination together with routine laboratory testing, chest radiograph, and abdominal ultrasonography should be performed in all patients aged over 40 years, presenting with idiopathic VTE. The initiation of more aggressive investigations is controversial, in the absence of any evidence of improved survival or cost effectiveness. Further investigations, such as, CT-scan of the pelvis, abdomen, and chest, however, should be performed routinely in patients aged over 25 years, presenting with idiopathic VTE. These investigations may identify an occult cancer in its early stage in approximately 10% of cases.38,40 In addition, a thorough search for occult cancer should be carried out in patients with recurrent thrombosis involving superficial or deep veins, especially if anti-coagulant therapy has been given.

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