REVIEWS
`
`Epidemiology of venous thromboembolism
`
`John A. Heit
`
`Abstract | Thrombosis can affect any venous circulation. Venous thromboembolism (VTE) includes deep-vein
`thrombosis of the leg or pelvis, and its complication, pulmonary embolism. VTE is a fairly common disease,
`particularly in older age, and is associated with reduced survival, substantial health-care costs, and a high
`rate of recurrence. VTE is a complex (multifactorial) disease, involving interactions between acquired or
`inherited predispositions to thrombosis and various risk factors. Major risk factors for incident VTE include
`hospitalization for surgery or acute illness, active cancer, neurological disease with leg paresis, nursing-home
`confinement, trauma or fracture, superficial vein thrombosis, and—in women—pregnancy and puerperium, oral
`contraception, and hormone therapy. Although independent risk factors for incident VTE and predictors of VTE
`recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence
`of VTE seems to be fairly constant, or even increasing.
`
`Heit, J. A. Nat. Rev. Cardiol. 12, 464–474 (2015); published online 16 June 2015; doi:10.1038/nrcardio.2015.83
`
`Introduction
`Thrombosis can affect any branch of the venous circu-
`lation. This Review is focused on the epidemiology of
`venous thromboembolism (VTE), including deep-vein
`thrombosis (DVT) of the leg or pelvis, and its compli-
`cation, pulmonary embolism (PE). Thrombosis affect-
`ing the superficial leg veins (such as the saphenous
`vein) and other venous circulations (such as those of
`the arms, and cerebral, mesenteric, renal, hepatic, and
`portal veins) is beyond the scope of this Review. VTE is
`a multi factorial disease, involving interactions between
`clinical risk factors and predispositions to thrombo-
`sis, either acquired or inherited (thrombophilias).1–5
`Moreover, the type of VTE event (PE versus DVT)
`might also be partly heritable.6,7 In this Review, I have
`attempted to summarize and integrate the data relating
`to VTE incidence (including trends in incidence), recur-
`rence (including predictors of recurrence), attack rates,
`survival (including p redictors of s urvival), health-care
`costs, and risk factors.
`
`Scope of the Review
`This Review is focused on comprehensive studies of
`the epidemiology of objectively-diagnosed VTE, which
`reported the racial demography and included the full
`spectrum of disease occurring within a well-defined
`geographical area over time, separated by event type and
`incident versus recurrent event, as well as studies of VTE
`survival and recurrence that included a relevant dura-
`tion of follow-up. Most epidemiological studies of VTE
`have addressed populations of predominantly European
`origin, and the data discussed in this Review primarily
`relate to these populations. Where they were available,
`data from populations originating from other continents
`
`Competing interests
`The author declares no competing interests.
`
`have also been discussed. The term ‘risk factors’ relates to
`characteristics that have been shown by logistic regression
`to be associated with incident VTE, whereas ‘predictors’
`relates to characteristics associated with VTE recur-
`rence and survival via Cox proportional hazards model-
`ling. ‘Independent’ risk factors and predictors are those
`charac teristics that have been significantly associated with
`the occurrence of VTE in multivariable analyses.
`
`Incidence of VTE
`The estimated annual incidence rates of VTE among
`people of European ancestry range from 104 to 183 per
`100,000 person-years,8–18 rates that are similar to that of
`stroke.19,20 Overall VTE incidence might be higher in
`African American populations21–23 and lower in Asian,24
`Asian American,25,26 and Native American populations,27
`and might vary in the African American population
`according to US geographical location.23 Reported inci-
`dence rates for PE (with or without DVT), and for DVT
`alone (without PE), range from 29 to 78, and 45 to 117,
`per 100,000 person-years, respectively.10,12,14–18
`VTE is predominantly a disease of older age, and is rare
`prior to late adolescence.8,10–15,18 Incidence rates increase
`markedly with age for men and women (Figure 1) and for
`DVT and PE (Figure 2).10,14,15 The overall age-adjusted
`annual incidence rate is higher for men (130 per 100,000)
`than for women (110 per 100,000).10,15 Incidence rates
`are somewhat higher in women during childbearing
`years (16–44 years) compared with men of similar age,
`whereas incidence rates in individuals aged >45 years are
`generally higher in men. PE accounts for an increasing
`proportion of VTE with increasing age in both sexes.10
`In populations of European and African origins, the per-
`centage of incident VTE events that are idiopathic ranges
`from 25% to 40% (F. A. Spencer, personal communica-
`tion).26,28 In one study, 19% of incident events in a study
`www.nature.com/nrcardio
`
`Division of
`Cardiovascular
`Diseases, Mayo Clinic,
`Hematology Research-
`Stabile 660, 200 First
`Street SW, Rochester,
`MN 55905, USA.
`heit.john@mayo.edu
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`REVIEWS
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`at 180 days, 12.9% at 1 year, 16.6% at 2 years, 22.8% at
`5 years, and 30.4% at 10 years.31 The risk of first recur-
`rence varies with the time since the incident event, and
`is highest within the first 6–12 months, with rates per
`1,000 person-days of 170 at 7 days, 130 at 30 days, 30 at
`90 days, 20 at 180 days and 1 year, 10 at 2 years, 6 at 5 years
`and 5 at 10 years.31 Although secondary prophylaxis is
`effective in preventing recurrence, the duration of acute
`treatment does not affect the rate of recurrence beyond
`an initial 3 months of prophylactic anticoagulation medi-
`cation.33,34,41–45 These observations suggest that VTE is a
`chronic disease with episodic recurrence.31,32,46,47
`Independent predictors of recurrence include increas-
`ing patient age,31,32,34,35,48–53 increasing BMI,31,51,53–56 male
`sex,31,34,50,56–64 active cancer,12,30,31,48,65–70 and neurological
`disease with leg paresis.31 Additional predictors of recur-
`rence include idiopathic VTE,30,35,43,58,66,67,71–73 persistent
`lupus anticoagulant or antiphospholipid antibody,42,74–76
`deficiency of antithrombin, protein C, or protein S,77–79
`hyperhomocysteinaemia,80 persistently elevated plasma
`d-dimer in patients with idiopathic VTE,81–84 and, pos-
`sibly, residual vein thrombosis.85,86 The risk of recurrence
`is modestly increased in heterozygous carriers of the
`factor V Leiden (F5 rs6025) or prothrombin 20210G>A
`(F2 rs1799963) mutations, and in patients with blood
`types other than O.87,88 Patients with homozygous factor V
`Leiden mutations or heterozygous factor V Leiden muta-
`tions combined with deficiencies of antithrombin,
`protein S, or protein C have an increased risk of recur-
`rence. In patients with active cancer, factors associated
`with increased risk of VTE recurrence are cancer site (pan-
`creatic, brain, lung, and ovarian cancer, myelo proliferative
`or myelodysplastic disorders), stage IV cancer, cancer
`stage progression, and leg paresis.70
`Several risk factors, when present at the time of the inci-
`dent VTE event, are associated with either a reduced risk
`of recurrence, or are not predictive of recurrence.30–32,44,58,89
`In women, pregnancy or puerperium,31,38 oral contracep-
`tion,31 hormone therapy,62,90 and gynaecological surgery31
`at the incident VTE are associated with reduced risk
`of recurrence. HMG-coenzyme A reductase inhibitor
`(statin) treatment following hospital discharge after PE
`reduces the risk of recurrent PE.91 Recent surgery and
`trauma or fracture have been reported to have no predic-
`tive value,31 or to predict a reduced risk of recurrence.30,92
`Additional baseline characteristics that are not predic-
`tive of VTE recurrence include recent immobilization,
`tamoxifen therapy, and failed prophylaxis (incident VTE
`despite prophylaxis).31 For these patients, who do not
`have an increased risk of recurrence, and for patients with
`isolated calf-vein thrombosis, a shorter duration of acute
`therapy (heparin, low-molecular-weight heparin, warfarin
`or another vitamin K antagonist, or a target-specific oral
`anticoagulant) is probably adequate.44,66 Data relating to
`the use of the type of incident event as a predictor of recur-
`rence are conflicting.31,35,36,44,49,56,93–97 However, a significant
`association has been found between the type of incident
`event and the type of recurrent event.49 Patients with sub-
`segmental PE have a similar 3-month recurrence risk to
`patients with more proximal PE.98
`
`population from Asia and the Pacific Islands were found
`to be idiopathic.26
`Data relating to trends in VTE incidence are limited.
`Incidence rates for VTE, DVT, and PE either remained
`constant or increased from 1981 to 2000, with a susbstan-
`tial increase in the incidence rate of VTE occurring from
`2001 to 2009, mostly owing to an increasing incidence
`of PE (Figure 3).10,14,18,29 The rates of incident cancer-
`associated VTE, secondary VTE not associated with
`cancer, and idiopathic VTE were fairly constant from
`1999 to 2009 (F. A. Spencer, personal communication).
`The observed increases in the rates of VTE and PE could,
`at least in part, reflect increased utilization of objective
`imaging, and improved image resolution, particularly
`with CT pulmonary angiography and MRI.18
`
`Recurrence of VTE
`VTE recurs frequently, and around 30% of patients
`with VTE experience recurrence within 10 years.16,30–40
`Reported rates of recurrent VTE, DVT, and PE are 19–39,
`4–13, and 15–29 per 100,000 person-years, respectively.18
`In a study of residents of Olmsted County, MN, USA with
`incident VTE diagnosed from 1966 to 1990, the estimated
`cumulative incidence of first overall VTE recurrence was
`1.6% at 7 days, 5.2% at 30 days, 8.3% at 90 days, 10.1%
`
`NATURE REVIEWS | CARDIOLOGY
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`VOLUME 12 | AUGUST 2015 | 465
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`© 2015 Macmillan Publishers Limited. All rights reserved
`
`Key points
`■ Venous thromboembolism (VTE) occurs as often as stroke, and recurs
`frequently, with around 30% of patients with VTE experiencing recurrence
`within 10 years
`■ Occurrence of VTE, especially pulmonary embolism (PE), is associated with
`reduction in survival, and PE is an independent predictor of reduced survival
`for up to 3 months
`■ VTE is associated with high health-care costs and increased disability-adjusted
`life-years
`■ Despite identification of VTE risk factors, development of new prophylaxis
`regimens, and improved uptake of VTE prophylaxis, the occurrence of VTE
`is increasing
`
`Male
`Female
`
`1,200
`
`1,000
`
`800
`
`600
`
`400
`
`200
`
`0
`
`0–14
`
`Annual incidence per 100,000 population
`
`15–19
`
`20–24
`
`25–29
`
`30–34
`
`35–39
`
`40–44
`
`45–49
`
`50–54
`
`55–59
`
`60–64
`
`65–69
`
`70–74
`
`75–79
`
`80–84
`
`≥85
`
`Age group
`Figure 1 | Annual incidence of venous thromboembolism among residents of
`Olmsted County, MN, USA, from 1966 to 1990, by age and sex. Permission
`obtained from the American Medical Association © Silverstein, M. D. et al. Trends
`in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year
`population-based study. Arch. Intern. Med. 158, 585–593 (1998).
`
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`
`Venous thromboembolism
`Deep-vein thrombosis alone
`Pulmonary embolism
`
`1,200
`
`1,000
`
`800
`
`600
`
`400
`
`200
`
`0
`
`0–14
`
`Annual incidence per 100,000 population
`
`15–19
`
`20–24
`
`25–29
`
`30–34
`
`35–39
`
`40–44
`
`45–49
`
`50–54
`
`55–59
`
`60–64
`
`65–69
`
`70–74
`
`75–79
`
`80–84
`
`≥85
`
`Age group
`Figure 2 | Annual incidence of venous thromboembolism among residents of
`Olmsted County, MN, USA, from 1966 to 1990, by age. The overall incidence
`of venous thromboembolism is shown, along with the incidence of deep-vein
`thrombosis alone, and pulmonary embolism (with or without deep-vein thrombosis).
`Permission obtained from the American Medical Association © Silverstein, M. D.
`et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism:
`a 25-year population-based study. Arch. Intern. Med. 158, 585–593 (1998).
`
`persistently increased d-dimer level after termination of
`anticoagulation therapy, age <50 years, male sex, and—in
`women—VTE unrelated to hormonal therapy predicted
`an increased risk of recurrence after an idiopathic incident
`VTE. The only inconsistent risk factor in these models is
`patient age, given that older age is associated with a higher
`recurrence risk among women in the HERDOO2 model,99
`younger age is associated with a higher risk in men and
`women in the DASH model,101 and age is not a predic-
`tor of recurrence in the Vienna model.100 Depending on
`the model, patients with a low score have recurrence rates
`of 1.6–4.4% per year.102,103 If these recurrence rates were
`considered to be acceptable, around 50% of patients with
`idiopathic incident VTE and a low prediction score could
`avoid secondary prophylaxis, and the associated risk of
`bleeding complications.99–101 Among patients with active
`cancer and VTE, female sex, cancer site (lung) and previ-
`ous VTE are high-risk predictors of VTE recurrence, and
`cancer site (breast) and stage (stage I rather than stage II,
`III, or IV) are low-risk predictors in patients receiving
`anticoagulation therapy.69,104
`
`VTE attack rates
`Estimated VTE attack rates (including incident and
`recurrent VTE) range from 142 to >300 per 100,000
`person-years. Estimated attack rates for DVT and PE
`are 91–255 and 51–75 per 100,000 person-years, respec-
`tively.18,105 VTE attack rates related to current or recent
`hospitalization are much higher than the rates for people
`residing in the community (330 versus 8 per 100,000
`person-years, respectively).105
`Information is scarce regarding the total number of
`VTE events (incident and recurrent) occurring each year,
`and available estimates vary widely. In an incidence-based
`modelling study, the estimated total number of sympto-
`matic VTE events per year in six European Union coun-
`tries was 465,000.106 Using age-specific and sex-specific
`incidence rates for 1991–1995, projected to 2000, ≥260,000
`incident cases of VTE have been estimated to occur in
`the US white population annually.13 If incidence rates are
`similar, then around 27,000 additional incident cases will
`occur in the US African American population annually.
`In an incidence-based modelling study that included
`hospital-acquired and community-acquired, incident
`and recurrent VTE events, 600,000 nonfatal VTE events
`(370,000 DVT and 270,000 PE) were estimated to occur
`in the USA in 2005, two-thirds of which were related
`to current or recent hospitalization.13 Using 2007–2009
`National Hospital Discharge Survey diagnosis codes, an
`estimated average of 548,000 hospitalizations with VTE
`occurred each year among US residents aged ≥18 years, of
`which 349,000 were DVT and 278,000 were PE.107
`
`Costs attributable to incident VTE
`In a population-based study, adjusted mean predicted
`costs were found to be 2.5-fold higher for patients with
`VTE related to current or recent hospitalization for acute
`illness (US$62,838) than for hospitalized control patients
`matched by active cancer status ($24,464; P <0.001).108
`Costs were calculated from the VTE event date (or index
`
`Venous thromboembolism
`Deep-vein thrombosis alone
`Pulmonary embolism
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Annual incidence per 100,000 population
`
`1985/
`1986
`
`1988/
`1989
`
`1999
`
`2001
`
`2003
`
`2005
`
`2007
`
`2009
`
`Year
`Figure 3 | Trends over time in the incidence of venous thromboembolism, deep-vein
`thrombosis alone, and pulmonary embolism (with or without deep-vein thrombosis)
`among residents of Worcester, MA, USA. Permission obtained from Elsevier ©
`Huang, W. et al. Secular trends in occurrence of acute venous thromboembolism:
`the Worcester VTE study (1985–2009). Am. J. Med. 127, 829–839 (2014).
`
`Several VTE recurrence prediction algorithms have
`been derived for the stratification of recurrence risk in
`patients with incident idiopathic or cancer-associated
`VTE. In the development of the ‘Men continue and
`HERDOO2’ rule, no predictors of a reduced risk of recur-
`rence were identified in men with incident idiopathic VTE.
`By contrast, women with incident idiopathic VTE who
`had ≤1 of a set of risk factors had a significantly lower risk
`of VTE recurrence than those with >1.99 The risk factors
`were older age (≥65 years), obesity (BMI ≥30 kg/m2),
`increased d-dimer level prior to stopping warfarin therapy,
`and signs of post-thrombotic syndrome.99 In the Vienna
`prediction model,100 male sex, incident VTE type (PE and/
`or proximal DVT versus isolated calf DVT), and increas-
`ing d-dimer levels are predictors of recurrence after idio-
`pathic incident VTE. In the DASH prediction model,101
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`echocardiography, predicts poor survival among normo-
`tensive patients with PE.116 Survival over time might be
`improving for those patients with PE who are living
`sufficiently long to be diagnosed and treated.111,113,118,119
`Mortality is similar in patients with subsegmental PE and
`those with more proximal PE.98
`
`Risk factors for incident VTE
`Investigators in a case–control study identified 726
`women with incident VTE between 1988 and 2000 in
`Olmsted County, MN, USA.120 In this group, independ-
`ent risk factors for incident VTE were major surgery
`(OR 18.95), active cancer with or without concurrent
`chemotherapy (OR 14.64), neurological disease with
`leg paresis (OR 6.10), hospitalization for acute illness
`(OR 5.07), nursing-home confinement (OR 4.63),
`trauma or fracture (OR 4.56), pregnancy or puerperium
`(OR 4.24), oral contraception (OR 4.03), noncontra-
`ceptive oestrogen plus progestin (OR 2.53), oestrogen
`(OR 1.81), progestin (OR 1.20), and BMI (OR 1.08).
`Among previously identified VTE risk factors, age, vari-
`cose veins, and progestin were not significantly associ-
`ated with incident VTE in this multivariate analysis.120
`Other risk factors for incident VTE include central vein
`catheterization or transvenous pacemaker placement,
`prior superficial vein thrombosis, urinary tract infection,
`increased baseline plasma fibrin d-dimer, and family
`history of VTE, whereas patients with chronic liver
`disease have a reduced risk of VTE.121–127 Compared with
`residents in the community, hospitalized patients have
`>100-fold increased incidence of VTE.128 Hospitalization
`and nursing-home residence together account for almost
`60% of incident VTE events in the community.28,129
`Notably, hospitalization for illness and hospitalization
`for surgery account for almost equal proportions of
`VTE (22% and 24%, respectively).28,129 Nursing-home
`residence independently accounts for over one-tenth of
`all VTE disease in the community.28,129
`The risk of VTE in patients undergoing surgery can
`be stratified on the basis of patient age, type of surgery,
`smoking status, and the presence or absence of active
`cancer.130–132 The incidence of postoperative VTE is
`increased in patients who are aged ≥65 years.133 Surgical
`procedures associated with a high risk of VTE include
`neurosurgery, major orthopaedic surgery of the leg,
`renal transplantation, cardiovascular surgery, and thor-
`acic, abdominal, or pelvic surgery for cancer.124,133,134
`Obesity,135–138 and poor physical status according to
`American Society of Anesthesiology criteria,139 are risk
`factors for VTE after total hip arthroplasty.
`The risk of VTE in patients hospitalized for acute
`illness can be stratified on the basis of age, obesity,
`previous VTE, thrombophilia, cancer, recent trauma
`or surgery, tachycardia, acute myocardial infarction or
`stroke, leg paresis, congestive heart failure, prolonged
`immobilization (bed rest), acute infection or rheumato-
`logical disorder, hormone therapy, central venous cathe-
`ter, admission to an intensive or coronary care unit, white
`blood cell count, and platelet count.140–146 Although risk-
`assessment models have been derived for prediction of
`
`Deep-vein thrombosis alone
`Pulmonary embolism
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Survivial (%)
`
`0
`
`1
`
`2
`
`3
`
`4
`Years
`Figure 4 | Kaplan–Meier estimates of survival among residents of Olmsted County,
`MN, USA with incident venous thromboembolism diagnosed 1966–1990.111
`Pulmonary embolism includes cases with or without deep-vein thrombosis,
`where pulmonary embolism was the cause of death.
`
`5
`
`6
`
`7
`
`8
`
`date for controls) to 5 years post-index, and cost differ-
`ences between cases and controls were greatest ($16,897)
`within the first 3 months.108 Similarly, the 5-year costs
`were predicted to be 1.5-fold higher for patients with
`VTE related to current or recent hospitalization for major
`surgery ($55,956) than for hospitalized control patients
`matched by the type of surgery and active cancer status
`($32,718; P <0.001).109 Again, cost differences between
`cases and controls were greatest ($12,381) in the first
`3 months after the index date. Predicted costs over 5 years
`were also nearly twofold higher for patients with VTE
`and active cancer ($49,351) than for patients with active
`cancer but no VTE ($26,529; P <0.001; J. A. Heit, unpub-
`lished work). VTE associated with hospitalization was
`the leading cause of disability-adjusted life-years in low-
`income and middle-income countries, and the second
`most common cause in high-income countries.110
`
`Predictors of survival after incident VTE
`Overall, survival after VTE is worse than the expected
`survival in a population of similar age, sex, and ethnic
`distribution, and survival after PE is much worse than
`after DVT alone (Figure 4).36,111–115 The risk of early
`death in patients experiencing PE is 18-fold higher than
`in patients with DVT but not PE.111 PE is an independent
`predictor of reduced survival (compared with patients
`with incident DVT alone) for up to 3 months after the
`event, although beyond 3 months, survival after PE is
`similar to expected survival.15,111,112 For almost one-
`quarte r of patients experiencing PE, the initial clinical
`presentation is sudden death.103 Independent predic-
`tors of reduced early survival after VTE include older
`age, male sex, lower BMI, confinement to a hospital
`or nursing home at the onset of VTE, congestive heart
`failure, chronic lung disease, serious neurological disease,
`and active cancer.40,111,112,116 Additional clinical predictors
`of poor early survival after PE include syncope and arter-
`ial hypotension.116,117 Evidence of right heart failure, on
`the basis of clinical examination, plasma markers (such
`as cardiac troponin T and B-type natriuretic peptide), or
`
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`VTE in hospitalized, nonsurgical patients, these models
`are highly variable in terms of the number and type of
`predictors, and the strengths of associations with VTE,
`and lack generalizability and adequate validation.147,148
`Active cancer accounts for almost 20% of all incident
`VTE occurring in the community.28,129 The risk of VTE
`is higher in patients with cancers of the brain, pancreas,
`ovaries, colon, stomach, lungs, kidneys, or bones, com-
`pared with other locations,149,150 and in patients with
`metastases.150 Patients with cancer who are receiving
`immunosuppressive or cytotoxic chemotherapy, including
`l-aspariginase,151,152 thalidomide153 or lenalidomide,154 or
`tamoxifen,155 are at even higher risk of VTE.121,150 Routine
`screening for occult (undiagnosed) cancer is controver-
`sial and probably not warranted.156,157 However, if clinical
`features suggest a possible occult cancer (such as idio-
`pathic VTE, especially among patients with abdominal-
`vein or bilateral leg-vein thrombosis,158 or in whom VTE
`recurs159), then the only imaging study shown to be useful
`is a CT scan of the abdomen and pelvis.159 Among patients
`with cancer, the risk of chemotherapy-associated VTE is
`increased in patients with pancreatic or gastric cancer,
`platelet count ≥350 × 109/l, haemoglobin <100 g/l or use
`of red cell growth factors, leukocyte count ≥11 × 109/l, or
`BMI ≥35 kg/m2;160 biomarkers (plasma soluble P-selectin
`and d-dimer) add further predictive value.161
`A central venous catheter or transvenous pacemaker
`accounts for 9% of all incident VTE occurring in the
`community.28 Central venous access via femoral vein
`catheters is associated with a higher incidence of VTE
`compared with subclavian vein catheterization.162 Prior
`superficial vein thrombosis is an independent risk factor
`for subsequent DVT or PE, remote from the episode of
`superficial thrombophlebitis.121,163 The risk of DVT associ-
`ated with varicose veins is uncertain, and seems to vary
`with patient age.121,164,165 Long haul (>4–6 h) air travel is
`associated with a slightly increased risk of VTE (1 VTE
`event per 4,656 flights166–168), which is preventable by the
`use of elastic compression stockings.169 Statin therapy
`can result in a 20–50% reduction in the risk of VTE.170–172
`Hypertriglyceridaemia doubles the risk of VTE in post-
`menopausal women.173 However, the risk associated with
`atherosclerosis, or other risk factors for atherosclerosis,
`remains uncertain.126,174–178 Diabetes mellitus,120 myo-
`cardial infarction,179 current or past tobacco smoking,
`HDL-cholesterol level, lipoprotein(a) level, and chronic
`obstructive pulmonary disease are not independent risk
`factors for VTE.121,180,181 The risk associated with congestive
`heart failure, independent of hospitalization, is low.121,130
`In women, additional risk factors for VTE include
`oral contraception,120,130,182–184 hormone therapy,120,185,186
`pregnancy and puerperium,130,183,187 and therapy with
`the selective oestrogen-receptor modulator, raloxifene.188
`First-generation and third-generation oral contraceptives
`convey higher risks than second-generation oral contra-
`ceptives.184 Injectable depot medroxyprogesterone acetate
`contraception is associated with a threefold increased
`risk of VTE, whereas a levonorgestrel intra uterine device
`imparts no risk.189 Hormone therapy is associated with a
`twofold to fourfold increased risk of VTE,120,185 depending
`
`on the type of oestrogen and the mode of delivery, with
`evidence suggesting possibly no risk with trans dermal
`oestro gen.190 The overall incidence of p regnancy-
`associate d VTE is around 200 events per 100,000 women-
`years, a fourfold relative risk compared with nonpregnant
`women of childbearing age.187,191 The risk of VTE during
`the postpartum period is around fivefold higher than the
`risk during pregnancy.187 Prior superficial vein thrombosis
`is an independent risk factor for VTE during pregnancy or
`puerperium.192,193 Additional risk factors for incident VTE
`associated with pregnancy include varicose veins, urinary
`tract infection, pre-existing diabetes mellitus, stillbirth,
`obesity, obstetric haemorrhage, preterm delivery, and
`delivery by Caesarean section.194
`Other conditions associated with VTE include auto-
`immune disorders,178 Behçet’s disease, coeliac disease,195
`heparin-induced thrombocytopenia,196 homocystinuria
`and hyperhomocysteinaemia,197,198 hyperthyroidism,199
`immune thrombocytopenia,200,201 infection,123 inflam-
`matory bowel disease,202 intravascular coagulation and
`fibrinolysis/disseminated intravascular coagulation
`(ICF/DIC), myeloproliferative neoplasms (especially
`polycythaemia rubra vera and essential thrombocythae-
`mia),203,204 chronic kidney disease with severely reduced
`glomerular filtration rate,205 nephrotic syndrome,206
`paroxys mal nocturnal haemoglobinuria,207 rheumatoid
`arthritis,208,209 obstructive sleep apnoea,210,211 thromboangi-
`itis obliterans (Buerger disease), thrombotic thrombo-
`cytopenic purpura, sickle-cell disease,212 systemic lupus
`erythematosus, and granulomatosis with polyangiitis
`(Wegener’s granulomatosis).213
`Studies of twins and families show that VTE is highly
`heritable and follows a complex mode of inheritance,
`involving interaction with clinical risk factors.1,3,4,7
`Inherited reductions in plasma levels of natural anti-
`coagulants, such as antithrombin, protein C, or protein S,
`have long been recognized as uncommon, but potent,
`risk factors for VTE.214–217 More recent discoveries of
`additional reduced natural anticoagulants218–223 or anti-
`coagulant cofactors,224 impaired downregulation of the
`procoagulant system (for example, activated protein C
`resistance, factor V Leiden [F5 rs6025]),29,225–227 increased
`plasma concentrations of procoagulant factors (such as
`factor I [fibrinogen], factor II [prothrombin; prothrom-
`bin 20210G>A [F2 rs1799963], factors VIII, IX, and
`XI, von Willebrand factor [ABO rs8176719]),56,215,228–245
`increased basal procoagulant activity,122,246,247 impaired
`fibrinolysis,248 and increased basal innate immunity activ-
`ity and reactivity,249,250 have added new paradigms to the
`list of inherited or acquired disorders predisposing to
`thrombosis (thrombophilias). These plasma h aemostasis-
`related factors, or markers of coagulation activation,
`correlate with increased thrombotic risk and are highly
`heritable.2,251–255 Inherited thrombophilias interact with
`obesity and tobacco smoking,254,256,257 and clinical risk
`factors such as oral contraception,258–261 pregnancy,262,263
`hormone therapy,264–266 minor trauma,267 surgery,268,269
`and cancer,270 to compound the risk of incident VTE.
`Similarly, interactions between genetic risk factors further
`increase the risk of incident VTE.271
`
`468 | AUGUST 2015 | VOLUME 12
`
`© 2015 Macmillan Publishers Limited. All rights reserved
`
`www.nature.com/nrcardio
`
`

`

`REVIEWS
`
`Conclusions
`VTE is a fairly common disease that recurs frequently, and
`is associated with reduced survival and substantial health-
`care costs. Although independent risk factors for VTE and
`predictors of VTE recurrence have been identified,
`and effective primary and secondary prophylaxis is avail-
`able, the occurrence of VTE is generally constant or even
`increasing. Future research should be directed towards
`identification of the optimal targets for VTE prophylaxis.
`
`Groups currently considered to be at high risk of VTE,
`such as all patients undergoing hip or knee replacement
`surgery, include few individuals who would experience
`VTE in the absence of prophylaxis. The requirement is
`to identify the individuals within these groups who are at
`high risk of incident or recurrent VTE, who would benefit
`most from primary or secondary prophylaxis, thereby
`minimizing the risk of bleeding complications incurred
`by treatment of those at low risk.
`
`3.
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`2. Ariëns, R. A. et al. Activation markers of
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