Over the last decade we have witnessed an avalanche of newly identified risk factors for venous thrombosis. This has advanced our knowledge of its etiology, because more determinants have been described and because the underlying concepts have received a new and broader understanding.

Venous thrombosis is a common multicausal disease occurring as the result of interacting genetic, environmental and behavioral risk factors. Some of these have been known since medieval times, such as the increased risk of thrombosis during immobilization in pregnancy and after childbirth (although retained milk of the breast-feeding mother was seen as the primary cause for the latter). Pregnancy and puerperium still cause thrombosis, as do exogenous hormones in oral contraceptives and hormonal replacement therapy. Furthermore, the immobilization in the puerperium of the old days translates directly to situations of immobilization in current times, such as prolonged travel in airplanes or excessive electronic gaming.

While pedigrees with abundant thrombosis were observed in the early 1900s, the first cause of heritable thrombophilia (antithrombin deficiency) was discovered in 1965, with the subsequent identification of deficiencies of protein C and protein S in the early 1980s. These were uncommon and strong risk factors, whereas the more recently discovered genetic variants are common and weak, and cause disease only in the presence of other factors.

Thrombosis may occur in arteries and in veins. The obstructive clot formation that defines thrombosis is the end product of an imbalance of procoagulant, anticoagulant and fibrinolytic factors. Arterial thrombosis is seen predominantly as myocardial infarction and ischemic stroke, and more rarely in other locations. It is almost invariably superimposed on vessel wall disease, i.e., atherosclerosis. Although its symptoms are acute due to the blocking of the vital blood flow to an organ, arterial thrombosis could be seen as a chronic disorder related to a slowly increasing severity of atherosclerosis. Venous thrombosis contrasts with this, since the development of the clot is a relatively sudden phenomenon that does not follow a build-up of disease but often occurs in reaction to an acute and short-lasting risk. However, impeded venous blood flow from an organ or body part is much less endangering to vital function, so symptoms may sometimes be mild with an unclear time of onset, and it may even go undiagnosed. So, while arterial thrombosis is a chronic disease with acute symptoms, venous thrombosis is an acute disorder with chronic symptoms.

Due to the association of venous thrombosis to acute, transient risk factors, insight into its etiology preceded that of arterial disease. Some of the acquired causes of venous thrombosis, particularly pregnancy and the puerperium, have been known for centuries. Peripartum venous thrombosis was called ‘milk leg’ because of the sometimes shiny-white appearance of the thrombosed leg. Early physicians thought it was related to milk production, with unexpelled milk accumulating in the leg. In the late 1700s this led to the public-health advice that breast-feeding was recommended to prevent milk leg.1 

The modern era of understanding the etiology of thrombosis began with the pathologist Virchow, who in the mid-1800s postulated three major causes of thrombosis: changes in the vessel wall, changes in the blood flow, and changes in the blood composition.2 This broad classification is still valid. However, these classes of causes do not have the same role in arterial and venous thrombosis; therefore, arterial and venous thrombosis share some causes, but also each have causes that are vastly different. Arterial thrombosis is dominated by atherosclerosis (vessel wall changes) and its risk factors include hypertension, hyperlipidemia, smoking, and diabetes mellitus. Recent analyses including very large numbers of patients show that these risk factors are still the most important, with one of them present in approximately 90% of patients with myocardial infarction.3,5 Stasis does not play a role in the etiology of the arterial thrombosis because of the high blood pressure and flow through the arteries. Hypercoagulability does affect the risk of arterial thrombosis, as witnessed, for example, by the low rate of myocardial infarction in hemophilia patients and the increased rate in patients with non-O blood groups, which are associated with increased levels of von Willebrand factor and factor VIII.6,8 However, for most thrombophilic defects, their role in arterial disease is much less pronounced than in venous thrombosis. Some have even disputed the role altogether in view of the overriding effects of atherosclerosis. This is in contrast to venous thrombosis, where stasis and immobilization are equally important risk factors as prothrombotic abnormalities. However, atherogenic factors (vessel wall) such as smoking, hypertension or hyperlipidemia do not appear to affect the risk of venous thrombosis. Table 1  lists the risk factors for venous thrombosis.

The incidence of venous thrombosis is 1–3 individuals per 1000 per year.9,12 The most common forms of venous thrombosis are deep vein thrombosis of the leg and pulmonary embolism, although it also occurs in other veins (upper extremities, liver, cerebral sinus, retina, mesenteric), but rarely. Chronic sequelae can be severely debilitating due to a disabling postthrombotic syndrome, which occurs in up to 20% of patients.13 The case-fatality rate of deep-vein thrombosis, mainly due to fatal pulmonary embolism, ranges from 1% in young patients to 10% in older patients, and is highest in those with underlying malignancies.10,12 

Venous thrombosis occurs about equally often in men and women, with possibly higher rates among women in the younger age groups, and among men in the older age groups (Figure 1).11,12 The incidence of venous thrombosis is strongly age-dependent: it is extremely uncommon (1 in 100,000 per year) in childhood, and rises to nearly 1% per year in old age.11,12,14 

The causes of venous thrombosis can be divided into those that are characterized by stasis and those that are reflected in abnormalities in the blood plasma (hypercoagulability). Another common classification separates acquired and genetic risk factors; acquired (environmental) risk factors are often related to stasis (but not exclusively, for example, oral contraceptives) and genetic risk factors to hypercoagulability.

Some environmental risk factors for venous thrombosis have been known for centuries; they include bed rest, surgery, trauma, plaster casts, pregnancy, puerperium, lupus anticoagulants, cancer and female hormones.15,16 Acquired risk factors still play a major role in the burden of venous thrombosis, even though their impact has lessened because of the implementation of prophylactic anti-thrombotic strategies (Table 2 ).

A familial tendency to venous thrombosis was first described in the early 1900s, when pedigrees with a large number of individuals with venous thrombotic events suggested a heritable hypercoagulability. Egeberg described the first family with an identified hereditary tendency to thrombosis (thrombophilia), caused by antithrombin (AT) deficiency (previously known as antithrombin III), in 1965.17 Subsequently, in the 1980s, protein C deficiency and protein S deficiency were recognized as causes underlying familial thrombophilia.18,19 

Over the last 10 years, several new defects have been identified that increase the risk of venous thrombosis. Generally, these abnormalities tend to confer less increased thrombotic risk than do the deficiencies of antithrombin, protein C and protein S. However, although more mild, they are also far more common and therefore responsible for a larger proportion of all venous thrombotic events.

Age

One of the strongest risk factors for thrombosis is age, with a steep gradient of risk, in which the incidence is a thousand-fold higher in the very old than in the very young.11,14 Why age is such a strong determinant of venous thrombosis is unclear. Several explanations seem obvious, all of which probably contribute to some extent. These are decreased mobility, an increased frequency of risk-enhancing diseases, decreased muscular tone, and acquisition of other risk factors as well as aging of the veins themselves, and particularly of the valves in the veins, that are crucial for good venous flow.

Surgery and trauma

Surgical interventions carry a very high risk of thrombosis, which, dependent on the type of surgery, may occur in over 50% of the patients in the absence of antithrombotic prophylaxis. The highest risks are conferred by orthopedic surgery and neurosurgery. In hip and knee surgery, the risk of thrombosis reaches 30% to 50%.20,21 Risks that are nearly as high have been reported for abdominal surgery (up to 30%), gynecologic surgery and urologic surgery (in particular open prostatectomy).22,24 Generally, the larger the intervention, the greater the risk, but in orthopedic surgery even minor interventions, such as arthroscopy, considerably affect the risk of venous thrombosis.

The incidence of venous thrombosis is also very high in patients with multiple trauma, and thrombosis occurs in 50%–60% of patients with head trauma, spinal injury, pelvic fractures, femoral fractures and tibial fractures.25,27 Such high rates of symptomatic thrombosis are no longer observed due to anticoagulant prophylaxis that is routinely prescribed after major and orthopedic surgery. Still, even with anticoagulant treatment, high-risk surgery such as total hip or knee replacement will lead to symptomatic venous thrombosis in 1% to 3% of the patients.28 Therefore, surgery remains a major cause of venous thrombosis. In the Leiden region, where extended anticoagulant prophylaxis is routinely prescribed for most surgical interventions, we observed that 18% of patients with thrombosis had had a surgical intervention, which increased the risk of venous thrombosis 6-fold (Table 2 ).29 In a more recent analysis of over 4000 patients with a first venous thrombosis and a similar number of controls, we still noted a 4-fold increased risk of symptomatic thrombosis following orthopedic and major non-orthopedic surgery.30 

Immobilization

As stasis is the major cause of thrombosis, the risk is increased during all circumstances that are associated with immobilization of the extremities, such as paralysis, bed rest, plaster casts and prolonged travel.31,33 The common denominator is that immobilization interferes with the function of the calf musculature in pumping the blood upstream though the veins. Immobilization in a sitting position confers a higher risk than other positions. This was shown in London in World War II, where a 6-fold increased risk of pulmonary embolism was observed shortly after air raids, during which people sough shelter in the underground where they waited in deck-chairs. The risk went down after the chairs had been replaced by bunks.34 More recently, it was reported that during massive traffic jams due to public transport strikes in Paris, several cases of deep-vein thrombosis occurred.35 An even more contemporary example of thrombosis due to immobilization occurred in a young man who regularly spent 12 hours per day behind a computer screen, which was coined ‘eThrombosis.’36 

Long-distance travel

Although the first cases of venous thrombosis after air travel were reported in 1954,33 the death of a young passenger from pulmonary embolism shortly after a flight from Australia to the United Kingdom has rekindled the interest in this association. Over the years, many case reports have been published, and thrombosis following long-haul air travel became known as the ‘economy class syndrome,’ without, however, controlled studies demonstrating a truly increased risk.37,38 A very elegant study was published in 1986, in which data on sudden deaths occurring over several years at Heathrow airport in London had been collected and categorized as to where the death took place: in the arrival hall or in the departure hall.39 There were far more deaths from pulmonary embolism in the arrival than in the departure hall, yielding a relative risk of around six.39 In a similar design, severe pulmonary emboli (fatal and non-fatal) occurring in passengers shortly after their arrival at Charles de Gaulle airport in Paris were categorized according to the distance that had been travelled, and related to the distances travelled by all passengers arriving at this airport.40 There was a clear association of risk of pulmonary embolism with the duration of the flight, with a 50-fold difference in risk between flights of less than 2500 km, and those over 10,000 km.40 While these reports make it very plausible that air travel increases the risk of thrombosis, they give little information about the magnitude of the risk, since they dealt only with severe events occurring shortly after arrival. Controlled studies in which consecutive patients with venous thrombosis were included have yielded conflicting results, with some showing no risk increase at all, perhaps reflecting that the number of travellers in these studies was small.41,44 In one of the studies it was found that recent air travel doubled the risk of thrombosis, which was, however, over 14-fold increased for individuals with thrombophilia or women who used oral contraceptives.44 This was confirmed in the much larger ‘MEGA-study,’ in which we analyzed data from 1851 patients with a first deep-vein thrombosis and 1851 matched controls (SC Cannegieter et al, manuscript submitted). Travel was associated with a 3-fold increased risk of thrombosis, without much difference for the various modes of travel. The risk was particularly increased for individuals with factor V Leiden, those who were obese, and users of oral contraceptives. This analysis is part of the ‘WRIGHT’ project (WHO Research Into Global Hazards of Travel). This initiative combines several studies of the risks, mechanisms and prevention of travel-related thrombosis, in which the role of airplane cabin conditions on coagulation activation will also be studied. There are some data to suggest that mild hypoxic hypobaria, as can be found in an airplane at high altitude, leads to activation of the coagulation system.45 However, a study that was conducted as part of the WRIGHT project, in which a large number of volunteers were exposed to a test condition of hypoxic hypobaria and a control condition of normoxic normobaria in hypobaric chambers in the United Kingdom, found no evidence for a broad shift towards coagulation activation.46 In another study that was also part of the WRIGHT project, volunteers were first exposed to a real flight of 8 hours and then to 8 hours of immobilization in a cinema at ground level. Blood samples were taken before and after each exposure as well as during a day of normal daily activities.47 The study population consisted mainly of women, many of whom had factor V Leiden, used oral contraceptives, or both. In this study there were several women, mainly those with one or two risk factors, who showed pronounced coagulation activation, as evidenced by increases in thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2 (F1+2) and D-Dimers.47 In a similar study in France, no clotting activation was observed in healthy male volunteers who were flown to Réunion.48 So it seems that the conditions of air travel, e.g., hypoxic hypobaria, may lead to a hypercoagulant response in a minority of individuals, mainly those with other risk factors.

Several studies aimed at detecting asymptomatic clots after air travel have found them in several percent of travellers, with reduced rates of clots in those who used elastic stockings or antithrombotic drugs.49,52 The relevance of asymptomatic clots is unclear, although in one study, with particularly long flights, several cases of pulmonary embolism were observed.53 Asymptomatic clots also appear to occur often in daily life. This was demonstrated in a German study where extensive ultrasound scanning was performed in nearly 1000 individuals who had just flown for over 8 hours and in over 1000 controls who had not travelled.54 Asymptomatic thrombosis was found in 2.8% of the travellers, but also in 1% of the controls.54 

Cancer

Trousseau was the first, in 1865, to observe that cancer and venous thrombosis are associated.55 Recurrent thrombophlebitis at various and changing locations (saltans et migrans) suggests occult cancer, especially of the pancreas. It is not entirely clear why cancer causes thrombosis, and several factors are likely to be involved. It is very likely that the tumor itself increases the risk of thrombosis by causing a procoagulant state through release of humoral factors. In addition, large tumors may cause thrombosis due to mechanical effects and venous obstruction.56,57 Furthermore, there may be less mobility due to the illness, as well as thrombogenic effects of treatment.58,59 Central venous catheters, which are often used to administer chemotherapeutics, are the most important cause of thrombosis of the arm,60 and over 10% of patients with a central venous catheter develop symptomatic venous thrombosis of the upper extremity.61 

It is a well-known observation among clinicians that adenocarcinomas confer a higher risk of thrombosis than other types of solid tumors. However, until recently there were surprisingly few data to support this notion. We constructed a historical cohort of 537 patients with a first diagnosis of lung carcinoma, including 133 patients with an adenocarcinoma and 258 patients with squamous cell cancer.62 Thrombotic risk in lung cancer patients was 20-fold higher than in the general population (CI95 14.6–27.4). In the group of patients with adenocarcinoma the risk of venous thrombosis, after controlling for sex, age and stage of disease, was 3-fold higher than in those with squamous cell cancer, at an annualized rate of nearly 7%.62 

How many patients diagnosed with venous thrombosis have cancer? In a population-based Swedish study, 19% of patients with thrombosis had a malignancy known at the time of diagnosis, and cancer was diagnosed in the year after the thrombotic event in an additional 5%.63 In an analysis of the MEGA study, of 3220 unselected patients with deep-vein thrombosis or pulmonary embolism and 2131 controls, 389 of the patients (12.1%) had been diagnosed with cancer before the thrombotic event, and another 35 were diagnosed with cancer in the 6 months after the thrombosis.64 The presence of a malignancy increased the risk 4.3-fold compared to individuals without cancer (CI95 3.3–5.6). When information on non-participants was included in the analyses, this odds ratio became 6.7 (CI95 5.2–8.6); many of these individuals had died before the examination date for the study.64 Patients with hematological malignancies had the highest risk of venous thrombosis (OR 28.0; CI95 4.0–199.7), followed by lung cancer and gastrointestinal cancer. The risk of venous thrombosis was highest in the first few months after the diagnosis of malignancy (OR 53.5; CI95 8.6–334.3). The presence of distant metastases led to a further 20-fold increase in risk of thrombosis (OR 19.8; CI95 2.6–149.1). Carriers of the factor V Leiden mutation who also had cancer had a 12-fold increased risk versus individuals without cancer and factor V Leiden (OR 12.1; CI95 1.6–88.1), and similar results were found for the prothrombin 20210A variant.64 

Oral contraceptives

Oral contraceptives first went on the market in 1959, and the first case of pulmonary embolism was reported in 1961 in a nurse using them for treatment of endometriosis.65 Shortly after, the first cases of myocardial infarction and ischemic stroke in oral contraceptive users were reported.66,67 These early case reports have been substantiated in large controlled studies, showing that even the low-dose oral contraceptives that are used today increase the risk of arterial thrombosis and venous thrombosis 2- to 5-fold.68,75 

Combined monophasic oral contraceptives, consisting of a constant daily dose of a combination of an estrogen and a progestogen, are the most commonly prescribed form of birth control pills. The progestogen is the anti-ovulatory agent. The estrogen content in almost all cases is ethinylestradiol, while the progestogen content has changed over the years, from first generation progestogens, which are no longer used, to second generation progestogens (levonorgestrel), to third generation progestogens (desogestrel, gestodene). Two progestogens are somewhat different: the anti-androgen cyproteronacetate, which is mainly prescribed to women with acne vulgaris, seborrhoea or mild hirsutism, and drospirenone, which is an anti-mineralocorticoid with anti-aldosterone and anti-androgenic effects that inhibits ovulation.76,77 

Over the years the dose of estrogen in oral contraceptives has been substantially reduced, from 100 μg or more in the earliest preparations, to 30 μg and even lower in the currently used oral contraceptives. While there is good evidence that the reduction from the very high dose to moderate doses of 50 μg and 30 μg ethinylestradiol was accompanied by a reduction in risk of venous thrombosis, this is not clear for further dose reductions, and the latest studies still show a 4-fold increased risk in users versus non-users.73,78,83 

For women using oral contraceptives the absolute risk is more relevant than the relative risk. Oral contraceptives are used by young women, who have a low baseline risk of thrombosis. Therefore, even a quadrupled risk in oral contraceptive users confers a rate of thrombosis that is small in absolute terms. The absolute risk of venous thrombosis in women of reproductive age is less than 1 per 10,000 per year.84 In oral contraceptive users, it becomes 2 to 3 per 10,000 per year.84,85 These risks are acceptably low for many women. Nevertheless, because so many women use oral contraceptives, oral contraceptives remain the most common cause of venous thrombosis in young women. Since thrombotic events may be fatal, and when non-fatal may still be associated with postthrombotic syndrome, the search for the safest oral contraceptive remains an important goal.

The risk of venous thrombosis is highest during the first year of oral contraceptive use, reaching an absolute risk of 12 per 10,000 women per year (for second generation progestogen containing oral contraceptives).86,87 However, there is no ‘duration of use’ effect: the effect is immediate and reversible, i.e., returns to baseline shortly after discontinuation.

Both the estrogen and the progestogen content of combined oral contraceptives affect the risk of thrombosis. Starting in 1995, reports were published that users of oral contraceptives containing third generation progestogens (desogestrel and gestodene) had a 2-fold higher risk of venous thrombosis than users of other formulations, which has subsequently been confirmed by several others.73,88,90 The risk is again highest in the first year, with a risk of over 30 per 10,000 per year.86 

Estrogens markedly affect the coagulation system, with increased levels of procoagulant factors VII, IX, X, XII and XIII, and reduced concentrations of the anticoagulant factors protein S and antithrombin. The overall effect is a mild prothrombotic state. This overall effect is most clearly seen in studies of global tests of hemostasis, i.e., activated protein C (APC)-resistance and thrombin generation tests.91,95 Many of the effects on the coagulation system are more pronounced in oral contraceptives containing desogestrel or gestodene (third generation progestogens) than in those containing levonorgestrel (second generation progestogens), leading to a more pronounced prothrombotic state, as evidenced by global assays.93,97 In a crossover study in which women were exposed to a combination oral contraceptive with either levonorgestrel or desogestrel, and subsequently to only levonorgestrel or desogestrel, it appeared that the progestogens themselves did not affect the coagulation factor levels. However, the estrogenic effects were less compensated by desogestrel than by levonorgestrel in the combination preparation, leading to a prothrombotic state.98 

Oral contraceptives that contain cyproteronacetate substantially increase the risk of venous thrombosis, with a higher risk even than for third generation oral contraceptives.99 There are no clear data on the safety of oral contraceptives containing drospirenone, although cases of venous thrombosis have been reported.100 

Some women have a higher risk of venous thrombosis when using oral contraceptives than others. These are older women, obese women, and women with prothrombotic abnormalities. Obesity itself mildly affects the risk of thrombosis, with a doubling of the risk for those with a BMI over 30 kg/m2.101,102.101,102 Overweight (BMI > 25 kg/m2) and obese (BMI > 30 kg/m2) women have a 10-fold increased risk of thrombosis when they use oral contraceptives.102 Oral contraceptives also greatly increase the risk of thrombosis in familial thrombophilia caused by deficiencies of protein C, protein S or antithrombin.103,104 Heterozygous factor V Leiden carriers or prothrombin 20210A carriers have a 15- to 30-fold increased risk of thrombosis when they use oral contraceptives.84,105 High levels of several procoagulant factors (FII, FVIII, FIX, FX, FXI) confer a 2- to 3-fold increased risk when levels exceed the 90th percentile of the distribution in the population.106,110 These risks are increased when oral contraceptives are used, particularly those of high levels of factor II, factor V and factor XI.111 

Hormone replacement therapy

Postmenopausal hormone replacement therapy has been prescribed for the treatment of symptoms of menopause, to reduce the progression of osteoporosis, and to prevent ischemic heart disease. There is little doubt that estrogens relieve symptoms of menopause, although many symptoms resolve spontaneously without therapy.112 Prolonged use of estrogens reduces the progression of osteoporosis,113,115 but it is unclear whether this leads to a reduced incidence of fractures: two observational studies showed clear effects,116,117 but two recent large randomized trials yielded conflicting results. In the Women’s Health Initiative (WHI), the risk of hip fractures was reduced by one-third,118 whereas in the Heart and Estrogen/progestin Replacement Study (HERS) no effect on fractures was observed.119 These and one other randomized trial have shown that estrogens have no beneficial effect on the occurrence of arterial disease.118,120,122 

The effective content of hormonal replacement therapy is the estrogen. Since hormone replacement with only estrogens increases the risk of endometrial cancer, it is now common to combine an estrogen with a progestin, except in women without a uterus. The hormones can be administered either orally or via transdermal patches. The estrogens in most preparations are conjugated estrogens, while the progestin usually is medroxyprogesterone.82 

Several studies have demonstrated that hormone replacement therapy increases the risk of thrombosis 2- to 4-fold.123,131 It has been postulated that the absence of a first-pass effect through the liver with transdermal administration might lead to less risk, but an increased risk has been shown for patches, too.127,129 However, in one recent study, oral administration was associated with an increased risk of venous thrombosis, and transdermal administration was not.132 

Virtually all studies of oral hormone replacement therapy used a preparation containing equine conjugated estrogens. In a recent case-control study the effects of conjugated estrogens were contrasted to those of esterified estrogens among 586 postmenopausal women with venous thrombosis and 2268 control women.133 Women who used esterified estrogen had no increase in venous thrombotic risk (OR 0.9; CI95 0.7–1.2) relative to non-users, while women taking conjugated equine estrogen had an elevated risk of venous thrombosis (OR 1.7; CI95 1.2–2.2).133 

Once again, the risk of venous thrombosis is higher shortly after therapy has started.123,125,127,129,130 Women with increased risk are those who are older, are overweight or obese, have factor V Leiden or high factor IX levels.84,134,137 In women with a previous venous thrombosis, the risk of a recurrence becomes very high during use of postmenopausal hormones, as was demonstrated in a randomized trial.138 

Pregnancy and puerperium

In a large study of over 72,000 deliveries in Scotland, 62 venous thrombotic events occurred, for an incidence of deep vein thrombosis and pulmonary embolism of 0.86 per 1000 deliveries.139 About one-third of these were postpartum.139 This risk of around 1 venous thrombotic event per 1000 deliveries is at least 10-fold increased compared to non-pregnant women.139,140 Thrombophilic abnormalities affect the risk of thrombosis during pregnancy, particularly antithrombin deficiency. In the Scottish series, 12% of the patients had antithrombin deficiency.139 

Antiphospholipid antibodies

Patients with antiphospholipid antibodies, both those with systemic lupus erythematosus (half of whom have these antibodies) and those with isolated antiphospholipid antibodies, have an increased risk of thrombosis. The clinical presentation and the risk of thrombosis varies widely between patients.141,143 In the Leiden Thrombophilia Study of consecutive patients with a first deep vein thrombosis, a lupus anticoagulant was found in 3.1% of patients and 0.9% of controls, yielding a relative risk of 3.6 (CI95 1.2–10.9).144 The risk of thrombosis was only elevated when anti-beta-2 glycoprotein I antibodies could be detected, in which case the odds ratio became 10.144 

Deficiencies of natural coagulation inhibitors

Deficiencies of antithrombin, protein C, and its cofactor protein S are found in less than 1% of the population (anti-thrombin deficiency in only 1 per 5000).145,148 They increase the risk of thrombosis and therefore are found more often among patients with thrombosis. However, these deficiencies still represent only a few percent of patients with thrombosis.149,150 Population-based studies to estimate risk are scarce due to the low prevalence of these deficiencies, and most information has been garnered from family studies. However, these results should be interpreted cautiously and not be extrapolated to a patient with one of the same defects who does not come from a ‘thrombophilic family,’ i.e., a family with abundant thrombosis. It has been shown that carriers of thrombophilic defects who come from thrombophilic families have a more severe phenotype and a younger age-at-onset than individuals with the same defects who do not come from such families.151 Thrombophilic families harbor more than one genetic defect, including unknown ones that may epistatically interact with the deficiency of a coagulation inhibitor, yielding a higher risk of thrombosis.152,155 

Deficiencies of protein C, protein S and antithrombin increase the risk of thrombosis about 10-fold in heterozygotes, with the highest risk for antithrombin deficiency.150,156,157 Homozygous deficiencies are exceedingly rare and lead to a life-threatening thrombotic tendency (purpura fulminans) shortly after birth.158,159 

Factor V Leiden

First identified in 1994, factor V Leiden (factor V R506Q, G1691A) is the most common genetic prothrombotic defect, with an overall prevalence of carriers among Caucasians of around 5%, although there are regional differences due to founder effects.160,161 It is found in 20% of all patients with venous thrombosis, and in up to 50% of patients with thrombophilia.162 Factor V Leiden leads to resistance to APC-resistance as the result of the mutation of one of the cleavage sites where APC inactivates factor V.160 Because inactivation of the procoagulant mutant factor V occurs less efficiently, ‘factor Va persistence’ leads to an increased risk of thrombosis.163,164 In heterozygotes the risk of venous thrombosis is 3- to 8-fold increased, and in homozygotes, 50- to 80-fold.162,164 Although factor V Leiden is a weaker risk factor than deficiencies of other natural anticoagulants, it is also far more common. This implies that it is responsible for a substantial proportion of all thrombotic events in the population (population attributable risk [PAR] = 20%–25%). Due to the high prevalence, homozygous patients are not exceedingly rare, about 1 per 5000 in the population.

Prothrombin 20210A

Like factor V Leiden, prothrombin 20210A mutation is quite common and is seen only in Caucasians. The mutation is in the 3′-untranslated region of prothrombin at position 20210 (G to A, PT20210A) and is associated with increased levels of prothrombin.106 It is found in 2% to 3% of Caucasians, again with regional variations in the prevalence.64,106,165 Among all patients with venous thrombosis it is present in 6%.106 It increases the risk of thrombosis about 3-fold, which is mediated through elevated prothrombin levels.106,166,169 

Blood group

The association between ABO blood group and the risk of venous thrombosis has been known since the late 1960s, with a higher risk in those with non-O blood groups than those with blood group O (2- to 4-fold increased risk).170 These individuals also have higher von Willebrand factor levels and higher factor VIII levels, and in all likelihood this is the mechanism by which blood group is related to thrombotic risk.107 In the Leiden Thrombophilia Study (LETS) we observed that, with OO-genotypes as a reference group, the risk was almost 2-fold increased for all non-OO genotypes (A1A1, A1A2, A1O1/A1O2, BB/BO1/ BO2, A1B/A2B), except for A2O1/A2O2/A2A2.171 Carriers of non-OO blood group genotypes and factor V Leiden had a 23-fold (CI95 9.1–59.3) increased thrombosis risk compared to subjects with OO genotypes without factor V Leiden (separate effects of non-OO genotype: OR 1.7; CI95 1.3–2.3, and factor V Leiden: OR 4.6; CI 2.0–10.1).171 

MTHFR 677T

A variant in the gene for methylene hydrofolate reductase (MTHFR), which plays a role in homocysteine metabolism, has been shown to be associated with mildly elevated homocysteine levels.172,173 The variant (C677T) is common (about 10% of the general population are homozygous carriers), but the elevation of homocysteine levels is so small that little effect on risk can be expected.174 It has been estimated that if hyperhomocysteinemia is a true cause of thrombosis, homozygous carriers of the MTHFR 677T variant have no more than a 16% increased risk of venous thrombosis. In a recent meta-analysis of 53 studies (n = 8364 cases), the MTHFR 677TT genotype was associated with a 20% (OR 1.20, CI95 1.1–1.3) higher risk of venous thrombosis compared with the 677CC genotype.175 

Hyperhomocysteinemia

Mildly elevated levels of homocysteine (over 18 μmol/L) are associated with an increased risk of thrombosis.176,178 Such levels are found in 5%–10% of the general population and roughly double the risk of venous thrombosis. The mechanism by which hyperhomocysteinemia affects the risk of thrombosis is unknown. Hyperhomocysteinemia is usually the result of acquired causes (low intake of folate, or vitamins B6 or B12) and only rarely of heterozygous cystathionine beta-synthase (CS) deficiency, the mutation causing homocystinuria in homozygotes.

In the meta-analysis of homocysteine levels, MTHFR genotype and risk of venous thrombosis, it was observed that a 5 μmol/L higher homocysteine level was associated with a 27% (CI95 1%–59%) higher risk of venous thrombosis in prospective studies and a 60% (CI95 10%–134%) higher risk in retrospective studies.175 

Elevated clotting factor levels

When deficiencies of anticoagulant factors are risk factors for thrombosis, one would expect likewise for high levels of procoagulant factors. Indeed, elevated levels of fibrinogen, prothrombin (factor II), factor VIII, factor IX and factor XI, as well as of thrombin activatable fibrinolysis inhibitor (TAFI) are all associated with an increased risk of thrombosis.106,109,179,180 The risk of thrombosis is 2- to 3-fold increased in individuals exceeding the 90th percentile of the distribution of clotting factors in the general population. For most of these elevated levels, with the exception of prothrombin and factor VIII, it is unclear whether they are genetically determined or acquired, although a combination seems likely. For high levels of factor VIII, it has been shown that there is familial clustering of high levels, even when the blood group effect has been taken into account.181,182 

Venous thrombosis is a multicausal disease, caused by the simultaneous presence of genetic and acquired risk factors. Examples of the interactive effects of risk factors are the combination of deficiencies of natural coagulation inhibitors (protein C, protein S, antithrombin) and factor V Leiden or prothrombin 20210A;183,187 the joint effect of genetic thrombophilia due to deficiencies of protein C, of protein S, or of antithrombin, factor V Leiden or prothrombin 20210A, and pregnancy, puerperium, use of oral contraceptives, use of postmenopausal hormones;84,135,188,190 the combined effects of obesity and exogenous hormones;102,137 or the effects of factor V Leiden and travel.44 

The genetic defects that were known to cause venous thrombosis a decade ago were uncommon and strong risk factors, whereas the more recently discovered genetic variants are common and weak, and cause disease only in the presence of other factors. Black and white has become a grayscale, and no longer is thrombophilia a rare disorder: all are at risk for thrombosis, but some are more at risk than others.

Table 1.

Risk factors for venous thrombosis.

AcquiredInheritedMixed/Unknown
Abbreviations: TAFI, thrombin activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; PCI, protein C inhibitor; PAI-3, plasminogen activator inhibitor-3; APC, activated protein C 
Bed rest Antithrombin deficiency High levels of factor VIII 
Plaster cast Protein C deficiency High levels of factor IX 
Trauma Protein S deficiency High levels of factor XI 
Major surgery Factor V Leiden (FVL) High levels of fibrinogen 
Orthopedic surgery Prothrombin 20210A High levels of TAFI 
Malignancy Dysfibrinogenemia Low levels of TFPI 
Oral contraceptives Factor XIII 34val APC-resistance in the  
Hormonal replacement therapy  absence of FVL 
Antiphospholipid syndrome  Hyperhomocysteinemia 
Myeloproliferative disorders  High levels of PCI (PAI-3) 
Polycythemia vera   
Central venous catheters   
Age   
obesity   
AcquiredInheritedMixed/Unknown
Abbreviations: TAFI, thrombin activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; PCI, protein C inhibitor; PAI-3, plasminogen activator inhibitor-3; APC, activated protein C 
Bed rest Antithrombin deficiency High levels of factor VIII 
Plaster cast Protein C deficiency High levels of factor IX 
Trauma Protein S deficiency High levels of factor XI 
Major surgery Factor V Leiden (FVL) High levels of fibrinogen 
Orthopedic surgery Prothrombin 20210A High levels of TAFI 
Malignancy Dysfibrinogenemia Low levels of TFPI 
Oral contraceptives Factor XIII 34val APC-resistance in the  
Hormonal replacement therapy  absence of FVL 
Antiphospholipid syndrome  Hyperhomocysteinemia 
Myeloproliferative disorders  High levels of PCI (PAI-3) 
Polycythemia vera   
Central venous catheters   
Age   
obesity   
Table 2.

Thrombosis risk in acquired risk situations—the Leiden Thrombophilia Study.

Risk FactorPatients (n= 474)n(%)Controls (N= 474)n(%)ORCI95
Time window for surgery, hospitalization (without surgery) and bed rest (not in the hospital, > 13 days) was 1 year preceding the index date (i.e., date of thrombosis diagnosis in patients, similar date in controls), for puerperium it was delivery 30 days or less prior to the index date, and for pregnancy and oral contraceptives it was at the index date. 
Data on pregnancy, puerperium and oral contraceptive use refer to women in reproductive age. 
Surgery 85 (18) 17 (3.6) 5.9 3.4–10.1 
Hospitalization 59 (12) 6 (1.3) 11.1 4.7–25.9 
Bed rest (at home) 17 (3.6) 2 (0.4) 8.9 2.0–38.2 
Pregnancy 8 (5.0) 2 (1.3) 4.2 0.9–19.9 
Puerperium 13 (8.2) 1 (0.6) 14.1 1.8–109 
Oral contraceptives 109 (70) 65 (38) 3.8 2.4–6.0 
Risk FactorPatients (n= 474)n(%)Controls (N= 474)n(%)ORCI95
Time window for surgery, hospitalization (without surgery) and bed rest (not in the hospital, > 13 days) was 1 year preceding the index date (i.e., date of thrombosis diagnosis in patients, similar date in controls), for puerperium it was delivery 30 days or less prior to the index date, and for pregnancy and oral contraceptives it was at the index date. 
Data on pregnancy, puerperium and oral contraceptive use refer to women in reproductive age. 
Surgery 85 (18) 17 (3.6) 5.9 3.4–10.1 
Hospitalization 59 (12) 6 (1.3) 11.1 4.7–25.9 
Bed rest (at home) 17 (3.6) 2 (0.4) 8.9 2.0–38.2 
Pregnancy 8 (5.0) 2 (1.3) 4.2 0.9–19.9 
Puerperium 13 (8.2) 1 (0.6) 14.1 1.8–109 
Oral contraceptives 109 (70) 65 (38) 3.8 2.4–6.0 
Figure 1.

Incidence of first venous thrombosis (deep-vein thrombosis and pulmonary embolism, by age and sex (data from the district of Brest, France11). Rates are shown per 100,000 per year; men = filled bars, women = open bars

Figure 1.

Incidence of first venous thrombosis (deep-vein thrombosis and pulmonary embolism, by age and sex (data from the district of Brest, France11). Rates are shown per 100,000 per year; men = filled bars, women = open bars

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