History of venous thromboembolism

The history of previous VTE is an independent risk factor for further thrombotic events. Patients who have had VTE have an increased frequency of new episodes.30 The malfunctioning of venous valves, which follows thrombosis of deep veins in the leg, is an important factor contributing to stasis. This, in turn, increases the risk of recurrence.30 As the increased risk does not seem to be attributable to known thrombophilic factors, a history of previous VTE remains an independent risk factor for recurrence.

Transient risk factors for venous thromboembolism

Surgery and major trauma

Together with malignancy, surgery is a common (and likely to be the strongest) risk factor for VTE. Orthopaedic surgery and neurosurgery are among the most thrombogenic.45--47 The risk of deep vein thrombosis after total knee or hip replacement carried out without prophylaxis, ranges from 45 to 70%, with fatal pulmonary embolism complicating up to 3%.48 A high risk of thrombosis is also associated with abdominal surgery, urological surgery (particularly open operations of the prostate), and gynaecological surgery.49 The risk of thrombosis is not confined to the immediate postoperative period, but continues for several weeks.46 Similar to surgery, major traumas, such as, head trauma, spinal injury, and pelvic fracture are frequently complicated by VTE. Nearly 60% of individuals with major trauma had deep vein thrombosis of the legs. This, in most cases, was asymptomatic.50 Pulmonary embolism is the third most common cause of death in individuals with trauma, occurring in 2 to 22% of those who survive the first 24 hours.50

Pregnancy and the puerperium

Assuming that the incidence of VTE in women of fertile age is 1 per 10,000, pregnancy enhances the risk by 10-fold to up to 1.3 per 1000.51,53 The relative risk of VTE during the puerperium, defined as the 6 weeks after delivery, is 10- to 15-fold higher than that during pregnancy.51,52 Assuming that the duration of pregnancy is 280 days (40 weeks) and the puerperium is 42 days (6 weeks), the relative distribution of 100 venous thrombotic episodes would be 0.23 and 0.82 per day, respectively.51 In women heterozygous for the factor VLeiden the risk of pregnancy-related VTE is 1 per 100 pregnancies and in heterozygous women with the prothrombin mutation it is 1 per 500.52 The same risk becomes 1 per 25 pregnancies in women with homozygous factor V Leiden.52 The reasons for increased thrombogenicity are multifactorial, including hypercoagulability and hypofibrinolysis due to changes in blood constituents during pregnancy. Obesity and high parity are also contributory factors. The further increase of the risk during the puerperium is only explained partially by caesarean section at delivery and by procoagulant changes. Inherited throm-bophilic factors are associated with an increased risk of thrombosis during pregnancy and the puerperium.52

Oral contraceptives and hormone replacement therapy

The increased risk of VTE associated with the use of oral contraceptives has been known since the early 1960s. In women of child-bearing age, oral contraceptives are the most common transient risk factor associated with VTE. The risk of thrombosis is primarily attributed to the oestrogen dose,53 but the type of progestogen is also an important determinant of the risk.54 Third generation oral contraceptives, i.e., those containing desogestrel or gestodene as pro-gestogens, are more thrombogenic than the second-generation pill, containing levonorgestrel53,54 and are associated with 2- to 3-fold higher risk than that induced by the third generation variety. Initially, these studies attracted a lot of controversy and criticism due to referral bias, diagnostic suspicion bias, recall bias, and reporting bias.53,54 Subsequently, it was demonstrated that all these possible biases did not influence the risks and, therefore, the estimated risks were realistic.53 A more pronounced APC resistance has been found with the use of third generation rather than second generation oral contraceptives.54 The synerigistic effect of oral contraceptive use in association with thrombophilia has been well-recognised, with the risk of thrombosis being increased 20-fold in women with factor V Leiden and 16-fold in those with the prothrombin gene mutation.54 Furthermore, a more striking risk amplification between thrombophilia and oral contraceptive use (150-fold increased risk) has been observed for cerebral vein thrombosis.55

Compared with oral contraceptives, there have been fewer studies on the relationship between the use of post-menopausal hormone replacement therapy and VTE. The doses of oestrogen used for post-menopausal replacement are much lower than those used for contraception, and the route of administration is sometimes different

(transdermal vs. oral). Yet, several studies have shown a 2- to 4-fold increased risk of thrombosis associated with hormone replacement therapy.56,57 Perhaps the lower risk associated with the low oestrogen dose of hormone replacement therapy is neutralised by the higher baseline risk of post-menopausal women due to their older age, in comparison with women of child-bearing age who use oral contraceptives.

Prolonged immobilisation

This refers to any circumstance that contributes to the malfunction of the leg musculature in pumping the blood upstream in the veins. Impaired blood flow is associated with an increased risk of thrombosis. Plaster casts, bed rest, limb paralysis, and prolonged air travel are examples in which stasis plays a major role in the formation of venous thrombi.58 Studies on autopsy series of patients confined to bed for longer periods found a prevalence of VTE ranging from 15 to 80%.47,59 Although the relative risk of thrombosis during immobilisation is difficult to calculate because of the variety of definitions of immobilisation, it is well established as an independent risk factor for thrombosis.

Inherited risk factors for venous thromboembolism

Deficiencies of naturally occurring anti-coagulant proteins

The role of naturally occurring anti-coagulants in the prevention of VTE was discovered when the association between inherited deficiencies of anti-thrombin, protein C, or protein S33--35 and VTE was made between the 1960s and the 1980s. Homozygous deficiencies of protein C or protein S may cause extensive VTE manifestations, such as, neonatal purpura fulminans or warfarin-induced skin necrosis.33--35 VTE may manifest at a young age (less than 40 to 45 years) in individuals with heterozygous deficiency of these anticoagulants, often without environmental triggers and, sometimes, at unusual sites. These sites include cerebral sinuses, abdominal veins, and deep veins of the arms. Tendency to recurrent VTE and positive family history34,35 is very common. Among the general population the prevalence of these conditions is low at less than 1%,33--35 but accounts for about 5 to 10% of patients with VTE.33--35 The mode of inheritance is autosomal dominant. The reported prevalence of the defects varies significantly among different studies due to the selection criteria (lower in unselected patients and higher in patients referred to specialised centres for thrombophilia screening).35 AT deficiency is the most thrombogenic of these conditions as shown in large family studies, while protein C or protein S deficiency33 has significantly lower risk.

Factor V Leiden

Dahlb├Ąck et al. in 1993 found that the plasma from members of a thrombophilic family failed to prolong the activated partial thromboplastin time after adding APC.60 This condition was later called resistance to APC. This was subsequently attributed to the presence of a single amino acid substitution in one of the three cleavage sites of factor V by APC, an Arg instead of Gln at position 506, now best known as factor V Leiden.60 This corresponds to a G to A substitution at nucleotide 1691 of the factor V gene. This is the most common cause of genetic thrombophilia, and its discovery has dramatically increased the understanding of the aetiology of VTE. The frequency of factor V Leiden is relatively high among Caucasians ranging between 2 and 15% in the general population33--35 and up to 50% in selected patients with VTE.33--35 Various studies have confirmed an increased risk of VTE for carriers.61,62 The risk for a first episode of VTE as estimated in a large case control study is 7-fold and 80-fold for heterozygous and homozygous factor V Leiden carriers, respectively.33--35 Carriers of factor V Leiden often have a mild thrombotic manifestation, such as, superficial vein thrombosis.33--35 They rarely develop pulmonary embolism,33--35 and may develop the first thrombotic symptoms at a relatively advanced age.35

Prothrombin G20210A mutation

This mutation was discovered in 1996, when candidate genes for thrombosis were investigated in patients with family clustering of VTE.61 As for factor V Leiden and in contrast with the deficiencies of the naturally occurring anti-coagulants, this mutation causes a "gain of function'' in the coagulation system. Carriers of the mutation have about 30% higher plasma prothrombin levels than non-carriers,61 associated with an increased potential for thrombin generation.61 The mutation is present in 2 to 4% of the Caucasian population, and its prevalence in Southern Europe is twice higher than in Northern Europe.34,35 This prevalence is the opposite of the geographical prevalence observed for factor V Leiden. In selected patients with VTE the prevalence of the mutation is up to 20%, and the relative risk in carriers is 2 to 4 times higher than in non-carriers.34,35,62 Due to the relatively high frequency of the prothrombin mutation and the factor V Leiden in the general Caucasian population, their combined presence is not so rare. Not surprisingly, individuals who carry both mutations have a higher risk of developing a first35 or recurrent62 venous thrombotic episode than those with either mutation alone.

Other risk factors for venous thromboembolism

The following factors are of "mixed" inherited and acquired, and their role in determining VTE is usually less well-established.

Hyperhomocysteinaemia

Genetic defects cause an approximately 50% reduction in the activities of the corresponding enzymes, e.g., methylenetetrahydrofo-late reductase (MTHFR). Acquired conditions include deficiencies of folate, cobalamine, and pyridoxine deficiencies, which are cofactors for homocysteine metabolism and chronic renal insufficiency. The association between moderate hyperhomocysteinaemia and VTE was made due to the high prevalence of this metabolic abnormality in a series of young patients with VTE in whom other causes of thrombophilia were excluded.63 Since then several case-control studies have consistently demonstrated an increased thrombotic risk among indi-vidualswith hyperhomocysteinaemia. Other prospective studies, however, have found no association. Therefore, the causal relationship between hyperhomocysteinaemia and VTE is still unclear. There are also conflicting results on the role of the common homozygous mutation of MTHFR (cytosine to thymine at nucleotide 677), as a risk factor for VTE. Although the homozygous variant is often associated with mild hyperhomocystaeinaemia (mainly in the presence of low folate concentration), many studies have failed to demonstrate a clear

association.64

When associated with factor V Leiden, hyperhomocystaeinaemia or homozygosity for MTHFR increases the risk of VTE.34,35 Therefore, the inclusion of this in the screening of thrombophilia is doubful. Hyperhomocystaeinaemia is corrected by vitamin supplementation, a treatment that is effective in the large majority of cases.

High levels of factor VIII

Elevated factor VIII is a riskfactor for VTE.65 Agradual dose-response relationship between risk of VTE and factor VIII levels has been observed.34,35,65 The risk of thrombosis is independent of two major determinants of factor VIII levels, blood group and von Willebrand's factor levels.65 The prevalence of high factor VIII levels among patients with thrombosis, taking as a cut-off value the 90th percentile of the distribution of values in a control population, varies from 19 to 25%.65 Elevated factor VIII levels persist over time65 and confer a high risk of recurrent VTE.65 The latter finding may have important implications for the duration of treatment after the first episode of thrombosis.

High levels of factor IX, factor XI, and thrombin activatable fibrinolysis inhibitor (TAFI)

High plasma levels of factor IX or factor XI are associated with an increased risk of VTE.34,35 The prevalence of patients with high levels of factor IX or factor XI was 20% and 19%, respectively, with an increased risk of VTE of 2-fold for both factors. A lower prevalence (14%) and increased thrombotic risk (odds ratio 1.7) has been found in association with high TAFI antigen.35 As all of these findings derive from the same population-based case-control study of patients with a first episode of VTE (the Leiden Thrombophilia Study), further investigations are needed to confirm the causal relationship of these abnormalities with the occurrence of thrombosis.

Activated protein C resistance (without factor V Leiden)

Activated protein C (APC) resistance not caused by factor V Leiden may be of genetic or acquired origin. The former has been based on the description of families with APC resistance in the absence of factor V Leiden,66 but other mutations are perhaps implicated, such as, the HR2 haplotype of factor V.67 Among acquired causes of APC resistance the most common and well-established are pregnancy and the use of oral contraceptives.67 A population-based study covering more than 15,000 individuals showed that the risk of thrombosis in the presence of APC resistance (in the absence of factor V Leiden) was nearly doubled.67 In the Leiden Thrombophilia Study, a dose-response relationship between the degree of APC resistance and the risk of VTE was observed, with a 4-fold increased risk of VTE.67 This study showed that the overall prevalence of APC resistance in patients with thrombosis was 36%, being 24% after the exclusion of factor V Leiden carriers. Therefore, the finding of APC resistance without factor V Leiden is to be expected in one in every 10 unselected patients with VTE, and the functional APC resistance assay should be a part of thrombophilia screening.

Risk stratification in venous thromboembolism

The high-risk (Table 4) category includes patients with the most severe forms of thrombophilia, including anti-thrombin deficiency, homozygous protein C or protein S deficiency, homozygous factor V Leiden, anti-phospholipid syndrome, combined thrombophilic defects, malignancy, and recurrent VTE. The low-risk category (Table 4) includes patients with only one episode of VTE that occurred in the presence of one or more transient risk factors, such as, surgery, immobilisation, pregnancy, oral contraceptive use, or hormone replacement therapy. Generally, patients in the high-risk category should be managed with indefinite anti-coagulant therapy (in case of malignancy, as long as the cancer is active), while short-term prophylaxis (up to 6 months) is an acceptable practice in patients belonging to the low-risk group. Patients who fall in other categories (Table 4), for example, those with mild thrombophilia (such as, heterozygous deficiencies of protein C or protein S, heterozygous factor

Table 4. Risk Stratification of Patients with Venous Thromboembolism

Risk Stratification Patient Categories

Duration of Anti-coagulant Therapy

Transient risk factors*

Short-term, usually

3 months

Intermediate

Mild thrombophilia*

Not well-established, but 6 to 24 months

Thrombosis in life-threatening sites (portal vein, mesenteric vein, cerebral vein), massive pulmonary embolism

High

Severe thrombophilia' Malignancy Recurrent VTE

Indefinite

"Includes AT deficiency, homozygous protein C, protein S, and F V Leiden, anti-phospholipid syndrome, and combined thrombophilic defects. ^Includes heterozygous protein C, protein S, F V Leiden, and P 20210A.

* Includes immobilisation, surgery, pregnancy/puerperium, oral contraceptive use, and hormone replacement therapy.

V Leiden, or prothrombin mutations) and those with no obvious risk factors who had venous thrombosis in a life-endangering location (for example, portal vein, mesenteric veins, or cerebral veins) or had massive pulmonary embolism, can be grouped in an intermediate-risk category. For this group, there is no consensus about the duration of anti-coagulant therapy.

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