Epidemiology,risk factors and sequelae of venous thromboembolism

Abstract

The aim of this review was to discuss the epidemiology, risk factors and sequelae of venous thromboembolism (VTE). VTE has an incidence of 1–2 per 1000 people annually. The risk of VTE increases with age and is highest in Caucasians and African Americans. Combined oral contraceptives (COC), especially the third-generation COCs, have been strongly implicated in VTE. Hospitalized patients, especially patients with underlying malignancy and undergoing surgery, have a host of risk factors for VTE. Thrombophilia can predispose an individual to VTE but indiscriminate testing for thrombophilia in patients presenting with VTE is not indicated. VTE can have serious chronic sequelae in the form of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTPH). The risk of PTS and CTPH is increased with recurrent deep vein thrombosis and pulmonary embolism, respectively. Mortality from VTE can be as high as 21.6% at one year. Patients who had an episode of VTE have a high risk of subsequent VTE and this risk is highest in patients who had a first VTE event associated with malignancy. A good understanding of the epidemiology and risk factors of VTE will enable the treating medical practitioners to identify patients at risk and administer appropriate VTE prophylaxis to prevent the longterm consequences of VTE.

Keywords

venous thromboembolism epidemiology risk factors sequelae

Introduction

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are both manifestations of the same disease process of venous thromboembolism (VTE). DVT has been reported as the most common preventable cause of hospital-related death.¹ The UK House of Commons Health Committee reported that an estimated 25,000 patients in England die each year from preventable hospital-acquired VTE,² more than the combined deaths from breast cancer, AIDS and road traffic injuries, and more than 25 times the number of deaths from methicillin-resistant Staphylococcus aureus (MRSA). In addition, VTE was found to be the immediate cause of up to 10% of hospital deaths in postmortem studies.^3,4

Epidemiology

Detailed annual incidence of VTE is hard to obtain because VTE is often clinically silent and in many cases, the first sign of the disease is a sudden fatal PE.^5,6 The overall incidence of VTE is estimated at 1–2 per 1000 annually.^7–9 About two-thirds of VTE episodes manifest as DVT and one-third as PE with or without DVT. Studies that include a large number of VTE cases diagnosed by autopsy generally report a higher proportion of cases with PE than DVT. The VTE Impact Assessment Group in Europe (VITAE) highlighted that epidemiological studies of diagnosed VTE underestimated the burden of disease as many cases are undiagnosed and studies do not include unrecognized thrombosis-related deaths.¹⁰ Based on their statistical modelling, the annual mortality due to hospital-acquired VTE is about one in 1150 of the population in six of the European countries studied. When compared with the annual incidence of VTE of 1–2 per 1000, the VITAE calculations suggest that almost as many patients die of VTE as are diagnosed, with about 85% of these deaths occurring without the diagnosis being suspected in life.¹⁰ This estimate is compatible with the finding of postmortem studies that showed that about 85% of deaths in hospital due to hospital-acquired VTE occur without a diagnosis of VTE before death (Table 1).^3–5,11,12 Studies of VTE with autopsy data have to be interpreted with caution as they often include cases with asymptomatic PE, failing to take into account other causes of death, thereby overestimating the incidence.¹³ Conversely, studies that rely on clinical diagnosis often underestimate the incidence.

Table 1

Postmortem (PM) studies recording deaths due to pulmonary embolism (PE)

Author (year)	Number of PMs (rate)	Total PE at PM	Deaths attributable to PE at PM	Proportion of fatal cases with venous thrombosis not suspected in life
Sandler(1989)³	2388(47%)	313(13%)	239(10%)	95%
Lindblad(1991)⁴	994 (77% in final year of study)	260 (26%)	93 (9.4%)	–
Stein (1995)⁵	404(–)	59(15%)	20(5.0%)	70%
Baglin (1997)¹²	400(–)	45(11.25%)	29 (7.25%)	90%
Alikhan(2004)¹¹	5107(42%)	–	265(5.2%)	–
Total	9293	–	646 7% (95% CI 6.4–7.5)

CI, confidence interval

The average annual incidence of in-hospital DVT was reported to range from 48 per 100,000 to 87 per 100,000.^8,10,14,15 In a retrospective review, the average annual age- and sex-adjusted incidence of in-hospital VTE was noted to be 100 times greater than the incidence among community residents.¹⁶ Combined with community-acquired DVT, the annual incidence of total DVT in the European Union (EU) was estimated to be 148 per 100,000 and this translates into 684,019 DVT events in the EU per annum.¹⁰ The annual in-hospital PE was reported to range between 23 per 100,000 and 69 per 100,000.^8,14,15 The VITAE study estimated that up to 434,723 PE events and up to 543,454 VTE-related deaths occur per annum. In the USA, it was estimated that more than 900,000 incident or recurrent, fatal and non-fatal VTE events occur annually, with up to a third resulting in fatality¹⁷ In the UK, this equates to approximately 59,000 new cases of DVT and 29,500 new cases of non-fatal PE per year.²

Age

The risk of VTE increases exponentially with age^14,15 and is the strongest risk factor for VTE with a thousand-fold increase in risk from the very young to the very old.^8,18–20 It is extremely uncommon in childhood (1 in 100,000 per year), increases to one per 10,000 annually before the fourth decade of life and rises to nearly 1% per year in old age.^8,9,18,19 The risk increases significantly after age 45 years and approaches 5–6 per 1000 annually by age 80.¹⁵ In fact, the eight-year rate among those aged 85 years and older at baseline was 13 times greater than in those aged 45–55.²¹

The reason for this is unclear but may be attributed to several factors such as decreased mobility, an increased presence of other illnesses predisposing to thrombosis, increase in coagulation potential or a combination of these factors.²²

Gender

Men and women are affected about equally by VTE with slightly higher rates among women in the younger age groups due to the increased thrombosis effects of oral contraceptives, pregnancy and puerperium.^8,9,15,19 The relative risks of VTE among women using oral contraceptives or hormone replacement therapy is around 2–4 compared with non-users.^23–25

Race

There are variations in the incidence of diagnosed VTE among ethnic groups. Compared with Caucasians, African Americans have an incidence of VTE approximately 25% higher,^21,26 while Asians, Native Americans, Pacific Islanders and Hispanics have an incidence almost 70% lower.^26–28 A possible explanation for the lower rates of VTE in Asian populations is due to the lower prevalence of genetic factors predisposing to VTE such as factor V Leiden or prothrombin F2G20210A mutation.^29–31 The higher incidence of VTE in African Americans could be explained by the higher levels of haemostatic markers of thrombosis risk, including factor VIII, von Willebrand factor and D-dimer.³²

Seasonal variation

Various studies and meta-analyses have demonstrated an increased incidence of VTE of 14%³³ and fatal PE during the winter months.^34,35 The mechanism is still unclear but may possibly be due to a decrease in physical activity during the winter months.

Risk factors

Virchow's triad described in the 1860s remains a valid concept in the aetiology of VTE. Any alterations in the blood flow (stasis), composition of blood (hypercoagulability) and vessel wall (venous injury) could lead to thrombosis. VTE is therefore a multifactorial disorder and could arise due to either inherited conditions or acquired predispositions (see Table 2).

Table 2

Risk factors for venous thromboembolism

Inherited	Acquired
Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden Prothrombin G20210A Elevated factor VIII levels Factor XIII 34val Fibrinogen (G) 10034T Dysfibrinogenaemia	Immobilization Surgery Trauma Acute medical illness Increasing age Pregnancy and Puerperium Oestrogen containing oral contraceptive or hormonal replacement therapy Previous VTE Malignancy Cancer therapies (hormonal, chemotherapy or radiotherapy) Antiphospholipid syndrome Myeloproliferative disorders Polycythaemia rubra vera Heart or respiratory failure Inflammatory bowel disease Stroke Nephrotic syndrome Haemoglobinopathies Paroxysmal nocturnal haemoglobinuria Paraproteinaemia Obesity Smoking Varicose veins Central venous lines

Inherited

Acquired

Antithrombin deficiency

Protein C deficiency

Protein S deficiency

Factor V Leiden

Prothrombin G20210A

Elevated factor VIII levels

Factor XIII 34val

Fibrinogen (G) 10034T

Dysfibrinogenaemia

Immobilization

Surgery

Trauma

Acute medical illness

Increasing age

Pregnancy and Puerperium

Oestrogen containing oral contraceptive or hormonal replacement therapy

Previous VTE

Malignancy

Cancer therapies (hormonal, chemotherapy or radiotherapy)

Antiphospholipid syndrome

Myeloproliferative disorders

Polycythaemia rubra vera

Heart or respiratory failure

Inflammatory bowel disease

Stroke

Nephrotic syndrome

Haemoglobinopathies

Paroxysmal nocturnal haemoglobinuria

Paraproteinaemia

Obesity

Smoking

Varicose veins

Central venous lines

VTE, venous thromboembolism

Obesity

Obesity, defined as body mass index (BMI) more than 30 kg/m² is associated with a two-to-threefold increased risk of VTE.^21,36 Severe obesity (BMI > 40 kg/m²) has an even higher associated risk of VTE.²² The mechanism of the increased risk is not well defined but may be due to impaired venous return due to the physical aspects of body size; and that biochemical parameters associated with obesity, for example, increased coagulation and inflammation, may play a role.²²

Hormone therapy

Oral contraceptives have been associated with an increased risk of VTE. In one study performed in the Netherlands, the incidence of VTE was noted to be eight per 100,000 annually.³⁷ Pregnancy, however, is associated with a higher risk of VTE with a rate of 85 per 100,000.³⁸ It is therefore vital to consider the increased risk of VTE with oral contraceptives against that related to pregnancy. Studies have shown a 3–6-fold increase in risk of VTE with third-generation combined oral contraceptives (COC) compared with a 2–3-fold increased risk in those taking second-generation COCs.^39,40 This represents a 2–3-fold increased risk with third-generation COC compared with the second generation.⁴¹ The risk of VTE is not increased with use of progestogen-only pills or hormone-releasing intrauterine devices.⁴² Users of hormone replacement therapy have been shown to have an increased risk of VTE compared with non-users.⁴³ Similarly, men receiving oestrogen therapy for prostate cancer should also be warned of the increased risks of VTE.⁴⁴

Hospitalization

Most patients admitted to hospital have risk factors for venous thrombosis such as immobility, infection, cancer and surgery. Compared with populations in the community, hospitalized patients have a more than 100-fold increase in the incidence of VTE.¹⁶ In addition, approximately half of all hospitalized patients are considered to be at risk of VTE by conventional criteria.⁴⁵ Among seven million patients discharged from nearly 1000 American acute care hospitals, postoperative VTE was the second most common complication, the second most common cause of excess length of stay and the third most common cause of excess mortality and cost. At least 50% of episodes of VTE in adults attributable to hospitalization are diagnosed following discharge from hospital and presentation may occur up to three months after discharge.^46–48 Up to 20% of patients admitted to a medical service and up to 40% admitted to a surgical service will have thrombosis.²² However, an increasing proportion of patients with hospital-acquired VTE are medical patients.^49,50 This is probably related to increasing use of thromboprophylaxis in surgical patients over the last 30 years and a relative reduction of DVT in this population of patients. Furthermore, postmortem studies indicate that the majority of patients dying due to VTE acquired during hospitalization are medical patients.^3–5,11,12 It is therefore imperative that all patients admitted to hospital be risk assessed for VTE and prophylaxis commenced balancing the benefit against the risk of bleeding.

Surgery

Immobility associated with surgery and general anaesthesia carries a significant risk of VTE due to the changes in all three elements of Virchow's triad. Surgery induces damage to vessel walls and a hypercoagulable state. Prolonged immobility during the perioperative phase results in venous stasis in the deep veins of the legs due to loss of calf muscle pump activity. In addition, general anaesthesia decreases vascular tone and distends veins resulting in more venous endothelial damage. The risk of VTE varies with the types and duration of surgery and patient characteristics.

The risk of VTE without thromboprophylaxis in patients undergoing general surgical procedures varies between 15% and 30%, while the rates of fatal PE range between 0.2% and 0.9%.^51,52 Most day case surgery patients such as hernia repairs have a low risk of VTE.⁵³

The risk of VTE appears to be lower following spinal or epidural anaesthesia.⁵⁴ Coronary artery bypass surgery, major urological surgery, surgery for gynaecological malignancies and major orthopaedics surgery are all associated with a high risk of VTE.^55–57 Orthopaedic surgery and trauma are associated with multiple pro-thrombotic processes. Bone and muscle injury causes extensive endothelial damage and thrombin generation. Furthermore, patients are exposed to vasodilatory anaesthetic agents, vessel trauma from the procedure and perioperative immobility.⁵⁸ Asymptomatic DVT is common after major orthopaedic surgery, which includes total hip, knee replacement or hip fracture surgery.⁵⁹ The rate of fatality from PE following hip and knee replacement is approximately 0.4%.² The incidence of fatal PE in trauma patients is high, accounting for 14% of deaths following hip fracture surgery.⁶⁰

Asymptomatic VTE has been reported in 15–25% of patients after vascular surgery if specific thromboprophylaxis is not used.⁶¹ Symptomatic VTE was noted in 0.9% of patients within 30 days after lower-limb bypass surgery or abdominal aortic aneurysm (AAA) repair.⁶² The incidence of symptomatic VTE within three months of major vascular surgery ranges from 1.7% to 2.8% in a population-based study of 1.6 million surgical patients, with AAA repair or aorto-femoral bypass appearing to have a higher risk of DVT than femoro-distal bypass.^63–66 Even though varicose vein surgery has a low perceived risk of DVT, the incidence of DVT following varicose vein surgery has been reported to be around 5.3%.⁶⁷ These DVTs, however, had minimal short- or longterm clinical significance. The risk of DVT following major lower-limb amputation on the other hand is substantial, and can range up to 14.3%.^64,68

Cancer

The annual incidence of VTE in a population of cancer patients is estimated at one in 200 and cancer is associated with a 4.1-fold increased risk of thrombosis.^6,69 Substances within the tumour cells such as proteases and tissue factor have pro-coagulant effects and the interaction between the tumour cells and macrophages lead to the activation of platelet and coagulation network. Chemotherapy is associated with a 6.5-fold increased risk of thrombosis, and this is thought to be due to vascular damage and release of tumour necrosis factor and interleukins.^6,70 Cancers involving the bone, ovary, brain, pancreas and lymphomas are associated with the highest incidence of thrombosis within six months of cancer diagnosis: 37.2, 32.6, 32.1, 22.7 and 17–20 per 1000, respectively.²² Cancers of the ovary, pancreas, lung, stomach and haematological malignancies have a high incidence of VTE in the year before the cancer diagnosis, suggesting the possible role of occult cancer in causing thrombosis or a commonality of risk factors for both diseases.⁷¹

Thrombophilia

Thrombophilic disorders can be classified into severe and mild. Severe thrombophilia disorders include deficiencies of the endogenous anticoagulants – antithrombin, protein C and protein S. They are less common but may be more potent risk factors for thrombosis.²² Mild thrombophilia disorders include factor V Leiden, F2G20210A variant and possibly elevation of pro-coagulant factors such as factor VIII, von Willebrand factor, and factors V, VII, IX and XI.

A high D-dimer is also a risk factor for first VTE in healthy individuals.^72,73 The relative risk of thrombosis with D-dimer in the top quarter of the normal population distribution was increased 2.5–3-fold, and the risk was even higher for idiopathic thrombosis.⁷³ While there is a causal association between heritable thrombophilia and venous thrombosis a strong gene-environment and gene-gene interaction precludes clinical utility of testing for individual thrombophilia.⁷⁴ Consequently, indiscriminate testing for heritable thrombophilias in unselected patients presenting with venous thrombosis is not indicated.⁷⁵

Travel

All modes of travelling predispose to VTE and the duration of travel is a main factor. Air, car, train or bus travel lasting for four hours or more can all increase the risk by about two-fold for several weeks after the journey.⁷⁶ Naturally, the risk of VTE is increased in the presence of other preexisting risk factors for VTE. Data on absolute rate of thrombosis with air travel suggest a rate of 1.5 per million for severe PE among those travelling more than 3000 miles and 0.39 per million for all PE.^77,78

Sequelae

DVT may lead to persistent chronic disease, which can be severely disabling due to impaired venous return in the lower limbs, termed as post-thrombotic syndrome (PTS). PTS can occur in up to 20–50% of patients.^79,81 PE on the other hand may lead to chronic thromboembolic pulmonary hypertension (CTPH). The other major outcomes of venous thrombosis are death, recurrence and major bleeding due to anticoagulation.

Recanalization occurs slowly after the development of DVT. Residual venous thrombosis is present in up to 40% of patients without cancer at 12 months and 25% at 36 months.⁸² Due to the frequent incomplete clot resolution, the diagnosis of recurrent ipsilateral DVT is often fraught with difficulty. One important tool in this regard is the demonstration that in patients with previous DVT or PE and a suspected recurrence, a negative high-sensitivity D-dimer assay result safely excludes recurrence.⁸³ Increased D-dimer levels following the completion of anticoagulant therapy after DVT is associated with residual venous thrombosis.^84,85 Both elevated D-dimer and residual venous thrombosis are associated with an increased risk of recurrent DVT, with the former factor being more pronounced.⁸⁴

Up to 85% of patients with acute symptomatic PE still have partial occlusion of the pulmonary circulation one week after thrombolysis or anticoagulation. More than 50% of patients have persistent scan defects at six months and complete resolution does not occur in the majority of patients by one year.⁸⁶ This therefore poses a diagnostic dilemma subsequently in patients who present later on and who did not have a follow-up scan at the end of the initial treatment.

Mortality

The case fatality rate of DVT, mainly due to fatal PE, ranges from 1% in young patients to 10% in older patients, and is highest in those with underlying malignancies.^7,8,14 A population-based study showed that the 30-day mortality rate after a first venous thrombosis was 6.4% with a one-year mortality of 21.6%.¹⁹ The high mortality rate in VTE is principally determined by its relationship with malignancy. However, even after exclusion of patients with malignancies, the risk of mortality from VTE remained at 3.6% after one month and 12.6% after one year.¹⁹ Up to 45% of deaths were directly attributable to PE. The one-year mortality rate is similar for both DVT and PE, indicating an effect of underlying disease, while the 30-day mortality is twice as high in PE compared with DVT (10% versus 5%) indicating an effect of the thrombosis itself. A majority of deaths (>90%) due to PE occur in untreated patients in whom the diagnosis is not made in life. Patients with symptomatic PE in the RIETE registry were five time more likely to die of fatal PE than patients with symptomatic DVT, and patients with massive PE were 17 times more likely.⁸⁷

The mortality rate for PE has been estimated to be as high as 30% in studies that included autopsy-based PE diagnosis, highlighting the fact again that many PE are not recognized clinically prior to death.⁸⁸ Mortality rates are lower among patients with idiopathic VTE and highest among those with malignancy-related VTE.

The annual in-hospital fatality rate from VTE could be as high as 12% and postmortem results have shown that up to 10% of deaths in hospitals are due to PE ^3,4,14,49 The number of VTE-related deaths in the EU was estimated at 543,454 per annum.¹⁰ European epidemiological modelling has shown that deaths from VTE could actually be as high as more than 14 times those recognized as being VTE-related, signifying a poor awareness among clinicians of the potentially fatal outcome of VTE and the importance of providing at-risk patients with VTE prophylaxis.¹⁰

Deaths due to PE result from an acute fall in cardiac output resulting in hypotension. Up to 5% of patients have massive PE with hypotension at presentation.^87,89 Right ventricular dysfunction is present in up to 40% of patients with acute PE and normal blood pressure and fatal PE is twice as likely in those with right ventricular dysfunction.^89–91 In patients without pre-existing cardiac or pulmonary disease, the haemodynamic disturbance correlates with the extent of obstruction of the pulmonary circulation.⁹²

Patients with massive PE, defined as PE with hypotension, do derive mortality benefit from thrombolysis.⁹³ The haemodynamic benefit from thrombolysis, when compared with heparin, however, dissipates after the first few days.⁹⁴

Recurrence

VTE is often a chronic condition with recurrence rates up to 5–7% annually after the first event and patients are up to 40 times more likely to suffer a further event compared with previously unaffected individuals.^9,80,95,96 The risk of recurrence is highest among those whose initial episode was associated with malignancy and lowest among those whose initial episode was associated with a temporary risk factor such as surgery.^9,80,95 Other risk factors for recurrent thrombosis include PE as the first thrombosis event and proximal versus distal limb DVT.²² Residual vein obstruction (RVO) at the time of stopping oral anticoagulant therapy following a first unprovoked episode was not associated with an increased risk of recurrent VTE.⁹⁷ In a recent meta-analysis, RVO was associated with a modestly increased risk of recurrent VTE in patients with DVT (unprovoked and provoked). However, RVO did not seem to be a predictor of recurrent VTE in patients with unprovoked DVT following anticoagulation discontinuation.⁹⁸ An abnormal D-dimer at one month following cessation of anticoagulant therapy on the other hand was found to be an independent risk factor for recurrent VTE, while RVO with or without abnormal D-dimer following withdrawal of anticoagulant therapy did not influence the risk of recurrence.

Recurrent DVT or PE is associated with a several-fold increased likelihood of PTS and CTPH. However, recurrent VTE is only prevented for as long as anticoagulation is continued.⁹⁹ Decisions regarding duration of anticoagulation should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors and risk of anticoagulant therapy-related bleeding.

Post-thrombotic syndrome

PTS presents with symptoms of swelling, pain and chronic skin changes ranging from dryness to discolouration and venous ulcers. PTS can become established after two years following acute DVT. Several studies suggested proximal DVT is associated with a higher risk of PTS compared with calf DVT.^100,101 The risk is further increased by recurrent ipsilateral DVT.¹⁰⁰ Patients with DVT with suboptimal international normalized ratio (<2.0) for more than 50% of the time were noted to be twice as likely to develop PTS.¹⁰² Anticoagulant therapy for 12 months as compared with six months does not change the risk of PTS.¹⁰¹ This suggested that early adequate treatment of DVT rather than the duration of treatment influences the development of PTS and that thrombin generation may contribute to ongoing valvular damage immediately after DVT.⁹⁹ Graduated elastic compression stockings have been proven effective in preventing PTS in those with DVT.^79,103

Chronic thromboembolic pulmonary hypertension

CTPH is defined as mean pulmonary artery pressure greater than 25 mmHg that persists six months after PE is diagnosed. It is characterized by intraluminal thrombus organization and fibrous stenosis or complete obliteration of pulmonary arteries. The consequence of CTPH is an increase in pulmonary vascular resistance resulting in pulmonary hypertension, progressive right heart failure and death. Less than 5% of patients with persistent occlusion of the pulmonary circulation after six months will develop CTPH. The incidence of CTPH ranges between 0.8% and 3.8% after a first episode of PE.^104,105 Risk factors for CTPH include recurrent PE and previous multiple PE.¹⁰⁵ On the other hand, up to two-thirds of patients with CTPH have no history of previous acute PE.¹⁰⁶ This may be due to pre-existing CTPH as a result of previous asymptomatic PE.⁹⁹

The patients often present with either of two scenarios: progressive dyspnoea on exertion, haemoptysis and/or signs of right heart dysfunction including fatigue, palpitations, syncope or oedema after a single episode, or recurrent episodes of overt PE.¹⁰⁶ Echocardiography is widely used as the initial diagnostic tool when CTPH is suspected.¹⁰⁷ Ventilation perfusion scintigraphy plays a pivotal role in determining whether pulmonary hypertension is due to thromboembolism and chest computed tomographic angiography remains the preferred initial investigation. Pulmonary angiography is often reserved for characterizing the pulmonary vasculature in planning surgical intervention.¹⁰⁸ Patients with CTPH are treated with lifelong anticoagulation to prevent recurrent thrombotic events. Pulmonary thromboendarterectomy is the only potentially curative therapy for CTPH.¹⁰⁹

Conclusion

All individuals are at varying risk of VTE. In order to prevent VTE, it is vital to understand the risk that individuals are exposed to, for example, prolonged air travel, in-hospital stay or types of surgery and their own inherent risk (for example, predisposing inherited or acquired medical conditions such as thrombophilia).

VTE is, and will remain, a major national health problem, especially among the elderly. The incidence of VTE increases markedly with advancing age. As the world population ages, the absolute number of events of VTE will likely increase. A large proportion of these events will manifest as PE with its associated poor survival rates. On the other hand, the longterm sequelae of VTE, namely PTS and CTPH, will continue to add onto the extra financial burden to healthcare costs. A good understanding of the epidemiology and risk factors of VTE will enable the treating medical practitioners to identify patients at risk and administer appropriate VTE prophylaxis to prevent the longterm consequences of VTE.

Footnotes

Conflicts of interest: None declared.

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