Seminar

Deep vein thrombosis

Paul A Kyrle, Sabine Eichinger Lancet 2005; 365: 1163–74
Medical University of Vienna,
Deep vein thrombosis and its sequelae pulmonary embolism and post-thrombotic syndrome are some of the most Department of Internal
Medicine I, Währinger Gürtel
common disorders. A thrombus either arises spontaneously or is caused by clinical conditions including surgery,
18-20, 1090 Vienna, Austria
trauma, or prolonged bed rest. In these instances, prophylaxis with low-dose anticoagulation is effective. Diagnosis (Prof P A Kyrle MD,
of deep vein thrombosis relies on imaging techniques such as ultrasonography or venography. Only about 25% of Prof S Eichinger MD)
symptomatic patients have a thrombus. Thus, clinical risk assessment and D-dimer measurement are used to rule Correspondence to:
out deep vein thrombosis. Thrombus progression and embolisation can be prevented by low-molecular-weight Prof Paul A Kyrle
[email protected]
heparin followed by vitamin K antagonists. Use of these antagonists for 3–6 months is sufficient for many patients.
Those with antithrombin deficiency, the lupus anticoagulant, homozygous or combined defects, or with previous
deep vein thrombosis can benefit from indefinite anticoagulation. In cancer patients, low-molecular-weight
heparin is more effective than and is at least as safe as vitamin K antagonists. Women seem to have a lower
thrombosis risk than men, but pregnancy or use of oral contraceptives or hormone replacement therapy represent
important risk factors.

Deep vein thrombosis is a clinical challenge for doctors Risk for first deep vein thrombosis seems to be slightly
of all disciplines. It can complicate the course of a higher in men than in women.6,9 In a population-based
disease but might also be encountered in the absence of cohort study, the age-adjusted incidence of first venous
precipitating disorders. Thrombosis can take place in thromboembolism was 1·3 per 1000 person-years in
any section of the venous system, but arises most men and 1·1 per 1000 person-years in women.2 It is
frequently in the deep veins of the leg. Long-term noteworthy that the risk for recurrence of this disorder is
morbidity due to post-thrombotic syndrome is common higher in men than in women.6,10
and can be substantial. The major concern, however, is
embolisation of the thrombus to the lung, which can be Pathophysiology
fatal. Deep vein thrombosis is highly prevalent and In 1856, Virchow postulated that damage of the vessel
poses a burden on health economy. The disorder and its wall, alterations in the flow, and hypercoagulability of
sequelae are also among the best examples of the blood are the main causes of thrombus formation.
preventable diseases. This pathophysiologic notion is still valid today.
This Seminar will focus on deep vein thrombosis of Venous thrombi are formed in the setting of low flow
the leg, with special emphasis on new diagnostic and and low shear stress and mainly consist of fibrin
therapeutic strategies. It will also discuss management strands, red blood cells, and few platelets. Usually,
of the disorder in specific groups of patients, such as thrombi form in the valve pockets of calf veins and
women and people with cancer. extend to the proximal veins.11 The raised venous and
capillary pressure after thrombus formation increases
Epidemiology the transcapillary filtration rate, resulting in oedema.
Relevant data for the frequency of deep vein thrombosis In 50% of patients, venous outflow obstruction
derive from large community-based studies because subsides within 3 months by lysis and recanalisation.12
they mainly reflect symptomatic rather than Patients with early oedema are most likely to have
asymptomatic disease. In a systematic review, the residual thrombosis, whereas late oedema is correlated
incidence of first deep vein thrombosis in the general with valvular incompetence.12
population was 0·5 per 1000 person-years.1 The
disorder is rare in children younger than 15 years,2,3 but
its frequency increases with age, with incidence per Search strategy and selection criteria
1000 person-years of 1·8 at age 65–69 years and 3·1 at
age 85–89 years.4 Two-thirds of first-time episodes of We searched the National Library of Medicine (PubMed),
deep vein thrombosis are caused by risk factors, The Cochrane Library, MEDLINE, and the AMEDEO website.
including surgery, cancer, immobilisation, or We used the search keyword “deep vein thrombosis” in
admission for other reasons.5,6 combination with the terms “prevention”, “diagnosis”,
In a retrospective hospital discharge dataset,3 the “treatment”, “pregnancy”, or “cancer”. We searched the
prevalence of deep vein thrombosis was comparable in reference lists of articles identified by this search strategy
black (0·69%) and white adults (0·84%). In a British and selected those we judged relevant. Several recently
study,7 25% of white and 22% of black people with published review articles were included because they provide
suspected thrombosis were confirmed to have the comprehensive overviews that are beyond the scope of this
disorder. The prevalence of deep vein thrombosis in Seminar.
Asian populations is low.8

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Surgery
Panel 1: Conditions associated with increased risk for deep
Thrombotic risk depends on the type of surgery and
vein thrombosis
presence of additional risk factors. Procedures with an
Advancing age especially high risk are orthopaedic surgery, major
Obesity vascular surgery, and neurosurgery.13 Advancing age,
Previous venous thromboembolism obesity, previous thrombosis, cancer, or comorbid
Surgery medical disorders increase the likelihood of
Trauma postoperative thrombosis (table 1).14–16 Risk for
thrombosis persists over several months post-surgery. In
Active cancer
a clinical outcome study of patients undergoing major
Acute medical illnesses—eg, acute myocardial infarction,
orthopaedic surgery,17 the 3-month incidence of
heart failure, respiratory failure, infection
symptomatic venous thromboembolism was 3·2% and
Inflammatory bowel disease
of fatal pulmonary embolism, 0·1%.
Antiphospholipid syndrome
Dyslipoproteinaemia
Trauma
Nephrotic syndrome
Major injury confers about a 50% risk for
Paroxysmal nocturnal haemoglobinuria
venographically proven deep vein thrombosis. Risk for
Myeloproliferative diseases
thrombosis is high in patients with spinal injuries
Behçet’s syndrome
(62%), pelvic fractures (61%), or leg fractures (80%),18
Varicose veins and it is low (19%) in people with lower limb plaster
Superficial vein thrombosis casts.19
Congenital venous malformation
Long-distance travel Acute medical disorders
Prolonged bed rest In outpatients and people admitted with acute medical
Immobilisation disorders, risk for thrombosis is comparable with that
Limb paresis for general surgery. Myocardial infarction, acute heart or
Chronic care facility stay respiratory failure, and acute infections confer the
Pregnancy/puerperium greatest risk. Risk is increased by other factors,
Oral contraceptives including advanced age, bed rest, or previous deep vein
Hormone replacement therapy thrombosis.20–23
Heparin-induced thrombocytopenia
History of deep vein thrombosis
Other drugs In patients with first spontaneous deep vein thrombosis,
Chemotherapy the annual likelihood of recurrence is 5–15%, with a
Tamoxifen cumulative recurrence rate of about 25% after 4 years.24
Thalidomide Risk is low in patients with postoperative deep vein
Antipsychotics thrombosis.24
Central venous catheter
Vena cava filter Antibodies against phospholipids
Intravenous drug abuse Antibodies against phospholipids, such as the lupus
anticoagulant or antibodies directed against cardiolipin or

2 glycoprotein I, interact with phospholipids or plasma
Risk for deep vein thrombosis proteins bound to an anionic surface. The prevalence of
Panel 1 outlines clinical factors that are associated with antibodies against phospholipids in unselected patients
increased risk for deep vein thrombosis. Some of these with deep vein thrombosis is about 5%.25 Whereas the
sources of risk are discussed below. lupus anticoagulant confers a tenfold increased risk for

Deep vein thrombosis Pulmonary embolism

Calf Proximal Clinical Fatal
Low risk (minor surgery in patients 40 years with no additional risk factors) 2% 0·4% 0·2% 0·01%
Moderate risk (minor surgery and additional risk factor; surgery in patients age 40–60 years with no additional risk factors) 10–20% 2–4% 1–2% 0·1–0·4%
High risk (surgery in patients 60 years, or age 40–60 years with additional risk factors (previous venous thromboembolism, cancer, thrombophilia) 20–40% 4–8% 2–4% 0·4–1·0%
Highest risk (surgery in patients with multiple risk factors [age 40 years, cancer, previous venous thromboembolism]; hip or knee arthroplasty, hip 40–80% 10–20% 4–10% 0·2–5%
fracture surgery; major trauma—spinal-cord surgery)

Modified from reference 16 with permission of the American College of Chest Physicians.

Table 1: Risk for venous thromboembolism in surgical patients without prophylaxis

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 Seminar

first thrombosis26,27 and is a risk factor for recurrence,26,28

the association between anticardiolipins and deep vein Panel 2: Thrombophilia
thrombosis is weak. Only high titres of the G isotype are Factor V Leiden
thrombogenic.26,27 The relevance of raised amounts of Factor II G20210A
antibodies directed against
2 glycoprotein I is Natural inhibitor deficiency
uncertain.29 High factor VIII, factor IX, or factor XI
Lupus anticoagulant
Thrombophilia High thrombin activatable fibrinolysis inhibitor
Several distinct abnormalities in the coagulation system Hyperhomocysteinaemia
are associated with increased risk for deep vein Dysfibrinogenaemia or hyperfibrinogenaemia
thrombosis (panel 2). These defects are generally Plasminogen deficiency
inherited and can be detected in about 50% of patients
with first spontaneous thrombosis. Many patients have
more than one risk factor, and combined defects further circulates as a proenzyme and, on activation by
enhance the risk. Risk for deep vein thrombosis can thrombomodulin, inhibits factors V and VIII. Protein C
increase when patients with thrombophilia are exposed deficiency arises in 1 per 200–500 people in the general
to temporal risk conditions such as surgery or trauma. population and in 3·2% of unselected patients with
Aspects on thrombophilia and women’s health issues, venous thrombolembolism.25,43 Heterozygous protein C
such as pregnancy or oral contraception, are addressed deficiency confers a sevenfold increased risk for deep
later in this Seminar. vein thrombosis.44
Protein S is a vitamin K-dependent glycoprotein and a
Factor V Leiden cofactor for protein C. The estimated prevalence of
Factor V Leiden results from a point mutation in the familial protein S deficiency is between 0·03% and
factor V gene, which renders the protein resistant to 0·13% in the general population.45 This deficiency was
degradation by activated protein C.30 The prevalence of reported in 7·3% of unselected patients with deep vein
heterozygous factor V Leiden in white populations is thrombosis, and it confers a more than eightfold lifetime
5–8%.31 Factor V Leiden is reported in 12–30% of risk for thrombosis.25,41
patients with spontaneous deep vein thrombosis,32,33 and
it confers a sevenfold risk for thrombosis in High clotting factor levels
heterozygotes and an 80-fold risk in homozygotes.34,35 Raised concentration of factor VIII (150 IU/dL), factor
Factor V Leiden is not a risk factor for recurrent deep IX (129 IU/dL), or factor XI (121 IU/dL) is an
vein thrombosis.33 independent risk factor of first spontaneous deep vein
thrombosis, with adjusted odds ratios of 4·8, 2·8, and
Factor II G20210A 2·2, respectively.46–48 The mechanisms by which
A transition at nucleotide 20210 in the 3 untranslated increased amounts of clotting factors cause thrombosis
region of the prothrombin gene increases risk for deep are unclear. Whether high clotting-factor concentrations
vein thrombosis by unknown mechanisms. Carriers of are related to a genetic background is unknown. High
the mutation have higher prothrombin concentrations factor VIII (234 IU/dL) is a potent risk factor for
than do non-carriers.36 In white populations, prevalence recurrence of thrombosis,49 whereas risk for recurrence
of the nucleotide transition is 0·7–4·0%.37 The mutation is moderately increased in patients with high amounts of
is reported in 7–18% of patients with spontaneous deep factor IX or XI.50,51
vein thrombosis, and it confers a 2·8-fold risk for the
disorder in heterozygotes.36,38 Heterozygous carriers have Mild hyperhomocysteinaemia
a moderately enhanced risk for recurrent deep vein Hyperhomocysteinaemia is caused by genetic defects,
thrombosis.10,39 most typically homozygosity for a thermolabile mutant
of methylenetetrahydrofolate reductase, nutritional
Natural inhibitor deficiencies deficiencies in vitamin cofactors (folic acid, vitamin B6,
Antithrombin is a potent inhibitor of several coagulation vitamin B12), renal function impairment, or drugs.52
proteases. The frequency of antithrombin deficiency is Mild hyperhomocysteinaemia is seen in about 25% of
rare in the general population (1 per 250–500 patients with deep vein thrombosis.53 It confers a two to
individuals)40 and is less than 1% in unselected patients threefold increased risk for first thrombosis and is a risk
with venous thromboembolism.25 Antithrombin factor for recurrence (relative risk 2·7).53,54
deficiency confers a more than eightfold risk for deep
vein thrombosis in an individual’s lifetime and Primary prevention
enhances risk for thrombosis during temporary risk Primary thromboprophylaxis is effective in reducing the
conditions (such as surgery).41,42 occurrence of symptomatic and asymptomatic deep vein
Protein C is a vitamin K-dependent glycoprotein that thrombosis in both medical and surgical patients.20,55

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Prophylaxis can be achieved by physical methods

Pretest probability
(postoperative early ambulation, graduated compression
stockings, or intermittent pneumatic compression) or
with anticoagulant drugs (unfractionated heparin, vitamin
K antagonists, low-molecular-weight heparin, or Moderate-to-high Low

fondaparinux). Whereas physical methods alone are

indicated in low-risk patients and in those with D-dimer
contraindications to anticoagulants, individuals at
moderate-to-high risk for thrombosis need anti-
coagulation. Unfractionated heparin and vitamin K High Low
antagonists are inconvenient for both patients and
medical staff because of frequent injections and laboratory
CUS Exclude DVT
monitoring. Thus, low-molecular-weight heparin is the
drug of choice.
Low-molecular-weight heparin is effective and safe in
both medical and surgical patients.16 Medical patients Positive Non-diagnostic Negative
or non-feasible
admitted for severe heart or respiratory failure, or those
bedridden with an additional risk factor such as cancer,
previous venous thromboembolism, sepsis, or acute Treat Venography Pretest probability
neurological disease, should receive low-molecular-weight
heparin at a prophylactic dose—eg, enoxaparin 40 mg
daily or dalteparin 5000 U daily.16,20,21 Surgical patients with High Low
a moderate or high thrombosis risk also need low-
molecular-weight heparin at a prophylactic dose.16 A high Venography Repeat CUS on day 8
prophylactic dose of this drug (eg, enoxaparin 40 mg daily
or dalteparin 5000 U daily) should be given to individuals
after elective spine surgery or neurosurgery and to high-
Positive Negative Positive Negative
risk patients with arthroscopy, laparoscopy, major trauma,
and before long-distance travel.16
In individuals undergoing major orthopaedic surgery, Treat Exclude DVT Treat Exclude DVT
fondaparinux (an indirect factor Xa inhibitor) 2·5 mg
daily, started 6 h after surgery, is an effective alternative to Figure 1: Procedure to safely exclude deep vein thrombosis66,67
low-molecular-weight heparin.56 In orthopaedic patients, CUS=compression ultrasonography. DVT=deep vein thrombosis.
beginning low-molecular-weight heparin 6–8 h after
surgery is as effective and at least as safe as a preoperative in fatal pulmonary embolism, whereas anticoagulation in
start.57,58 After total hip replacement, continuing low- the absence of thrombosis is irresponsible. Little
molecular-weight heparin prophylaxis for up to 35 days is consensus exists in published work about the best
recommended since it greatly reduces occurrence of diagnostic strategy. Since only a quarter of patients with
symptomatic venous thromboembolism without suspected deep vein thrombosis actually have the disease,
increasing the bleeding rate.59 In a randomised study,60 our diagnostic strategy is to safely rule out thrombosis by
fondaparinux for 28 days, compared with fondaparinux non-invasive, rapid, and cost-effective methods. To
for 7 days followed by placebo, safely reduced the rate of achieve this goal, we combine clinical assessment,
symptomatic venous thromboembolism in patients after laboratory studies, and imaging techniques (figure 1).66,67
hip fracture surgery.
Melagatran, a direct thrombin inhibitor, has been Clinical assessment
licensed in some European countries. This drug, given Assessment of the pretest probability, based on physical
subcutaneously before and after surgery followed by oral examination and medical history, is the first step when
ximelagatran, was more effective but less safe than deep vein thrombosis is suspected. Patients can be
preoperative enoxaparin.61,62 Conversely, melagatran stratified into categories of low, intermediate, or high
started postoperatively was as safe as preoperative probability either by standardised prediction rules or by
enoxaparin but less effective.63 In knee arthroplasty, empirical methods (table 2).68 Assessment of the pretest
ximelagatran is at least as effective as warfarin, with a probability is affected by many alternative diagnoses,
comparable bleeding risk.64,65 which raises concern about the reliability of the
assessment when undertaken by less experienced
Diagnosis medical staff. An extensive overview shows that the
In patients with suspected deep vein thrombosis, accurate clinical prediction rules can be accurately applied in
diagnosis is mandatory: an untreated thrombus can result inpatients and outpatients by medical staff of various

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degree of training,69 and simplified models have been Clinical feature Score
successfully validated in emergency departments.70
Active cancer (treatment ongoing or within previous 6 months or palliative) 1
Paralysis, paresis, or recent plaster immobilisation of the legs and feet 1
Laboratory studies Recently bedridden 3 days or major surgery, within 4 weeks 1
Because of its high sensitivity, measurement of D-dimer Localised tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
(a fibrin split product) has gained a prominent role as a
Calf swelling 3 cm greater than asymptomatic leg (measured 10 cm below tibial tuberosity) 1
rapid, simple, and inexpensive test for ruling out acute Pitting oedema (confined to the symptomatic leg) 1
deep vein thrombosis.71 Published work does not Collateral superficial veins (non-varicose) 1
support the use of D-dimer as a stand-alone test.72 The Alternative diagnosis as likely or greater than that of deep vein thrombosis –2
predictive value of negative D-dimer is, however, greatly For patients with symptoms in both legs, the most symptomatic leg is used. Modified from reference 68 with permission of
improved if the results are used as part of a diagnostic Schattauer Publishers.
algorithm.73 A negative D-dimer together with a low
Table 2: Standardised prediction rule for assessing pretest probability of acute deep vein thrombosis
clinical probability safely rules out acute deep vein
thrombosis. In a randomised study,66 0·4% of patients
with a low pretest probability and a negative D-dimer
had confirmed venous thromboembolism during extension of the thrombus can be detected in about 2%
3-month follow-up. The diagnostic strategy for assess- of patients.67,77,78
ment of patients with suspected deep vein thrombosis
based on pretest probability and D-dimer is safe and Recurrent deep vein thrombosis
feasible in emergency departments.74 However, D-dimer Clinical assessment of recurrent ipsilateral deep vein
concentrations can be raised in various situations, such thrombosis is hampered by the similarity between
as inflammation, surgery, or cancer, which limits its symptoms of post-thrombotic syndrome and acute deep
usefulness in inpatients. vein thrombosis. Negative D-dimer might be helpful to
rule out recurrent thrombosis, although this strategy has
Imaging techniques been assessed in only one study.79 Use of ultrasonog-
Contrast venography is the most sensitive and accurate raphy is limited because abnormalities in the proximal
test for diagnosis of deep vein thrombosis and is veins are reported in about 50% of patients 1 year after
regarded as the gold standard. Because venography is first deep vein thrombosis and because comparison with
invasive and has potential contraindications, it should be previous ultrasonography results is needed.80
reserved either for patients with negative non-invasive Diagnosis of recurrent deep vein thrombosis requires
tests and high clinical probability or for those in whom the detection of a new non-compressible segment by
non-invasive tests are equivocal or non-feasible. ultrasonography. If the result of this test is non-
Compression ultrasonography is the most useful diagnostic, or if there is high clinical probability and a
initial imaging test. Full compressibility of either of the negative finding on ultrasonography, venography should
femoral and popliteal veins excludes proximal deep vein be done. Unequivocal diagnosis of recurrent thrombosis
thrombosis. Compared with venography, ultrasonog- is not possible in many patients. Results of studies
raphy has a sensitivity of 97–100% and a specificity of assessing alternative diagnostic methods such as
98–99% for detection of proximal thrombosis.75,76 The magnetic resonance venography or CT are awaited.
rate of venous thromboembolism in patients with a
negative ultrasonography result was 0·7% during Treatment
6-month follow-up, indicating that few thromboses were Figure 2 outlines a suggested protocol for treatment of
missed and that anticoagulation can be safely withheld.77 deep vein thrombosis.
Ultrasonography is less accurate in diagnosis of distal
(calf vein) thrombosis. The lower sensitivity (about 70%) Initial treatment
carries a risk for false-negative results, whereas the low Firm evidence is available that fixed-dose, weight-
specificity (about 60%) can result in over-treatment. adjusted, subcutaneous low-molecular-weight heparin is
Non-extending distal deep vein thrombosis is rarely at least as effective and safe as unfractionated heparin
complicated by pulmonary embolism, and extension to given as an intravenous bolus followed by continuous
the proximal veins after 1 week is unusual. Hence, non- infusion at a dose that prolongs the activated partial
invasive diagnostic strategies combining clinical thromboplastin time at least 1·5 times the control
assessment, D-dimer testing, and serial ultrasonography value.81,82 Compared with unfractionated heparin, low-
can safely be applied in patients with distal thrombosis. molecular-weight heparin has a more predictable dose-
A low pretest probability together with a negative response relationship (which obviates the need for
D-dimer excludes deep vein thrombosis. If results are laboratory monitoring), has a longer half-life (which
conflicting then ultrasonography is done. If the result is allows once-daily or twice-daily administration), and
negative, anticoagulation can be withheld and confers a lower risk for immune-mediated thrombo-
ultrasonography is repeated after 1 week. At that time, cytopenia83 or osteoporosis.84 Once-daily low-molecular-

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adequate anticoagulation, or chronic thromboembolic

Confirmed diagnosis of DVT pulmonary hypertension. Concurrent anticoagulation
should be given if safe to do so. Temporary filters can be
useful to cover a surgical procedure when anticoag-
PE despite adequate Start LMWH 100 IU/kg Limb-threatening DVT ulation has to be withdrawn.
anticoagulation or twice daily or 150–200 IU/kg Consider thrombolysis
contraindications to once daily or thrombectomy
anticoagulants Long-term prevention
Insert vena cava filter and start Long-term protection from thrombus progression and
anticoagulants if it is safe to do so
recurrence can be accomplished by vitamin K
antagonists started simultaneously with heparin as soon
as the diagnosis of deep vein thrombosis has been
DVT during pregnancy Start VKA (target INR 2·0–3·0) DVT associated with cancer
Continue LMWH at full dose until together with LMWH and Continue LMWH at full dose,
confirmed.94,95 Anticoagulation is monitored by the
24 h between induction of labour discontinue LMWH after 5–7 days reduced to about 75% at 4 weeks prothrombin time, expressed in terms of the
or caesarean section and restart at a stable INR and continue for at least international normalised ratio (INR). The dose is titrated
LMWH at a reduced dose 6 months or as long as it is safe
to do so to achieve a ratio between 2·0 and 3·0, a range thought
to provide the lowest combined incidence of thrombo-
embolism and bleeding. Heparin can be discontinued
DVT caused by surgery Spontaneous DVT DVT and high occurence risk*
after 5–7 days, as long as the ratio is stable and is 2·0 or
Discontinue VKA after 3 months Discontinue VKA after Consider VKA indefinitely at an greater. Low-molecular-weight heparin followed by a
3–6 months INR of 2·0–3·0 or 1·5–2·0 3-month course of vitamin K antagonists prevents
recurrence in about 95% of patients and confers a risk
Figure 2: Suggested treatment protocol for deep vein thrombosis for severe bleeding of about 1%.96
DVT=deep vein thrombosis. PE=pulmonary embolism. LMWH=low-molecular-weight heparin. VKA=vitamin K The optimal duration of anticoagulation is ascertained
antagonist. INR=international normalised ratio. *Includes antithrombin deficiency, presence of the lupus
anticoagulant, homozygous or combined defects, more than one episode of spontaneous deep vein thrombosis.
with the risks for recurrence and for major bleeding,
both of which vary individually. Patients with deep vein
weight heparin at a dose of 150–200 U/kg antifactor Xa thrombosis caused by surgery have a low recurrence risk
is as effective and safe as twice-daily 100 U/kg antifactor and should receive vitamin K antagonists for 3 months.97
Xa.85 Monitoring antifactor Xa activity 4 h after injection Many people with spontaneous thrombosis do not
can be useful in patients with impaired renal function benefit from anticoagulation for longer than
and in severely obese individuals.86 Low-molecular- 3–6 months.98–102 Patients in whom the risk for severe
weight heparin is also safe and effective in the outpatient bleeding seems to be outweighed by the likelihood of
setting, even for patients with proximal deep vein recurrence might benefit from extended anticoagulation,
thrombosis.87,88 Treatment with this drug is cost effective but studies showing an advantage of long-term therapy
because it reduces the length of admission and in terms of reduction of mortality or morbidity are
eliminates need for laboratory monitoring.81,89,90 Because lacking. Even so, indefinite anticoagulation might be
of its shorter half-life, unfractionated heparin might be justified in patients with a high risk for recurrence,
useful in surgical patients with deep vein thrombosis in including those with the lupus anticoagulant,
whom rapid reversal of anticoagulation is necessary. antithrombin deficiency, combined or homozygous
Venous thrombi can be dissolved by thrombolytic defects, or in people with more than one spontaneous
drugs given either systemically or directly onto the episode. The decision about duration of anticoagulant
thrombus via local catheter-directed infusion. therapy is also affected by patient’s preference and risk
Thrombolytic therapy diminishes pain and swelling and for bleeding.
prevents destruction of the venous valves. Whether it In patients with mild hyperhomocysteinaemia,
can lower the incidence or severity of post-thrombotic supplementation of vitamin B6, vitamin B12, and folic
syndrome is uncertain. Compared with standard acid reduces homocysteine concentrations but does not
anticoagulation, thrombolytic therapy confers an affect recurrence risk.103
increased bleeding risk.91 It should, therefore, be
reserved for patients with limb-threatening thrombosis New treatment strategies
and possibly for young patients with major iliofemoral To reduce the recurrence risk without increasing risk for
deep vein thrombosis. bleeding, new strategies of long-term secondary
In patients with proximal deep vein thrombosis, vena thromboprophylaxis have been developed. The
cava filters are effective in preventing the short-term PREVENT investigators104 compared low-intensity
incidence of pulmonary embolism but they do not affect warfarin (INR 1·5–2·0) with placebo in patients with
mortality.92,93 Vena cava filters are thrombogenic and spontaneous venous thromboembolism who had
double the recurrence risk. They should be used received conventional-intensity anticoagulation for at
selectively in patients with contraindications to least 3 months. After 4 years, symptomatic thrombosis
anticoagulants, recurrent pulmonary embolism despite recurred in 15% of patients assigned placebo and in

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5·5% of those allocated low-intensity warfarin. Major increased risk for thrombosis in heterozygous women
haemorrhage was rare in both groups. The ELATE with factor V Leiden113 and a 16-fold enhanced risk in
investigators105 compared low-intensity warfarin (INR women with the prothrombin mutation114 have been
1·5–2·0) with conventional-intensity warfarin (INR reported during oral contraceptive intake, these
2·0–3·0). Recurrence was seen in 4·3% of the low- numbers have to be set into perspective with the very
intensity group and in 1·6% of the conventional- low absolute risk for deep vein thrombosis in young
intensity group. The rate of major bleeding was about women.1,2,6 Thus, oral contraceptives are not
2% in both groups. Thus, conventional-intensity contraindicated a priori in heterozygous women with
warfarin seems to be more effective than low-intensity factor V Leiden without a history of venous thrombo-
warfarin. However, the surprisingly low rate of major embolism.
bleeding recorded in the conventional-intensity warfarin Hormone replacement therapy during menopause is
arm might not be accomplished in day-to-day clinical associated with a two to fourfold increased risk for deep
practice. Low-intensity warfarin substantially reduces vein thrombosis, and it confers an enhanced recurrence
risk for recurrent deep vein thrombosis, confers a low risk.110,115
risk for bleeding, and might, thus, be an attractive option Pregnancy and the puerperium are associated with a
for indefinite anticoagulation. twofold and 14-fold increased risk for first deep vein
Several new anticoagulants have been evaluated in thrombosis, respectively.116 The frequency of throm-
phase III trials. In the THRIVE study,106 ximelagatran bosis is similar during the three trimesters,117 the left leg
was non-inferior to enoxaparin followed by warfarin in is more likely to be affected than the right,117 and
preventing recurrence in patients with acute venous thrombotic risk is highest after caesarean section.118 In
thromboembolism (2·0% vs 1·5% at 6 months) and was women with thrombophilia, risk for deep vein
associated with a favourable outcome with respect to thrombosis is higher than usual during pregnancy.119
major bleeding (1·3% vs 2·2%) and mortality (2·3% vs The diagnostic repertoire for deep vein thrombosis is
3·4%). In another study,107 patients with deep vein less well studied in pregnant women. Clinical
thrombosis who had completed a 6-month course of assessment is affected by common symptoms of
anticoagulation were assigned placebo or ximelagatran. pregnancy such as leg swelling and pain. The role of
At 18 months, the likelihood of recurrence was 12·6% in D-dimer is limited since—even during uncomplicated
the placebo group and 2·8% in patients allocated pregnancy—its concentrations rise with gestational
ximelagatran. Major bleeding was very rare in both age.120
groups.107 Ximelagatran can be given orally without On suspicion of deep vein thrombosis, we advise
laboratory monitoring. In 5–10% of patients, this drug is clinical assessment with emphasis on the patient’s
associated with increased concentrations of liver thrombosis and family history. A normal D-dimer in a
enzymes. The relevance of this occurrence is unclear. healthy pregnant woman with a low clinical probability
In a randomised trial,108 fondaparinux was compared might exclude thrombosis, although this approach is
with enoxaparin followed by warfarin in patients with not validated.
acute deep vein thrombosis. At 3 months, symptomatic Ultrasonography is the diagnostic method of choice.
venous thromboembolism had recurred in 3·9% of In case of a high clinical probability and non-feasibility
patients assigned fondaparinux and in 4·9% allocated of ultrasonography, or equivocal non-invasive tests,
enoxaparin and warfarin. Major bleeding was recorded venography should be done. After appropriate
in about 1% of people in both groups. precautions, the amount of radiation delivered to the
fetus is low.121 Limited ability to diagnose thrombosis in
Women and thrombosis the iliac veins by ultrasonography, insensitivity in the
Oral contraceptives, pregnancy, and menopause diagnosis of iliofemoral thrombosis by venography in
represent special challenges in assessing risk for case of lead shielding, and reluctance to use radiation or
thrombosis and in diagnosing and treating deep vein contrast might be overcome by use of MRI.
thrombosis. Overall risk for thrombosis in oral For treatment of acute deep vein thrombosis in
contraceptive users is about threefold higher than for pregnant women, fixed-dose, weight-adjusted subcuta-
non-users and is highest during the first year of use.109,110 neous low-molecular-weight heparin is to be preferred
Lowering the oestrogen dose reduces risk for over unfractionated heparin. Studies on the duration
thrombosis.111 Preparations containing third-generation and intensity of anticoagulation are lacking. We
progestogens are associated with an increased risk for recommend low-molecular-weight heparin at a
thrombosis compared with levonorgestrel.111 Oral therapeutic dose throughout pregnancy. It should be
contraceptives enhance thrombosis risk in families with discontinued 24 h before induction of labour or
a natural inhibitor deficiency.41,112 The identification of caesarean section, restarted at a reduced dose when safe
factor V Leiden and factor II G20210A led to to do so, and continued for a further 6–8 weeks. In
discussions about the use of oral contraceptives in women with a very high risk for recurrence, a temporal
carriers of these mutations. Although a 20–30-fold cava filter might be needed.

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The overall risk for recurrence in pregnant women warfarin or low-dose low-molecular-weight heparin.132,133
with a history of deep vein thrombosis is fairly low.122,123 Two larger studies than these were unable to confirm
Recurrence risk is lowest in those without these results134,135 and reported much lower overall rates
thrombophilia and deep vein thrombosis caused by of deep vein thrombosis. Currently, cancer patients with
clinical conditions such as surgery. Women with central venous catheters should not receive routine
thrombophilia and venous thromboembolism are at thromboprophylaxis.
high risk for recurrence.124 Prophylaxis with low- Treatment of acute deep vein thrombosis in cancer
molecular-weight heparin during pregnancy is safe.125 patients consists of low-molecular-weight heparin at a
Therefore, this drug at a high dose is recommended for therapeutic dose. Secondary thromboprophylaxis with
these women throughout pregnancy. Whether all vitamin K antagonists is associated with a high risk for
women with a history of deep vein thrombosis should both bleeding and recurrence.136 Findings of one study
receive thromboprophylaxis during pregnancy, show that extended anticoagulation with low-molecular-
particularly those with a thrombus caused by another weight heparin at a therapeutic dose is more effective
clinical event, is uncertain. and as safe as vitamin K antagonists at conventional
intensity.137 The optimal duration of secondary thrombo-
Cancer and thrombosis prophylaxis is less well defined. Since cancer patients
The association between cancer and thrombosis is have a high recurrence risk, we treat them with low-
twofold. First, deep vein thrombosis is sometimes the molecular-weight heparin for at least 6 months. Those
presenting symptom of cancer and, second, thrombosis who do not achieve remission could benefit from
can arise during the course of malignant disease. In two prolonged anticoagulation.
population-based case series,126,127 the standardised
incidence—ie, the ratio of the observed number of Post-thrombotic syndrome of the leg
incident cancers to those expected—at the time of Post-thrombotic syndrome of the leg arises in a third of
venous thromboembolism or in the first 6–12 months patients with first proximal deep vein thrombosis who
afterwards were 4·4 and 3·0. The risks were especially received standard treatment with anticoagulants.138,139
high for cancers of the liver, pancreas, ovary, and brain. Typical symptoms include pain, swelling, and skin
In subsequent years, a persistent increase in risk for changes. Risk factors are recurrence in the ipsilateral leg
cancer remained. The incidence of cancer is higher in and possibly proximal thrombosis.140 The incidence of
patients with spontaneous deep vein thrombosis than in post-thrombotic syndrome seems to be lower in patients
those with thrombosis caused by surgery or trauma.128 treated with thrombolytic drugs.91 In most people, the
Although extensive screening for a hidden cancer disorder arises within 2 years.24 The incidence is not
results in a high diagnostic yield,129 studies showing that affected by duration of anticoagulation. Severe post-
this approach translates into an improved clinical thrombotic syndrome is infrequent. In a prospective
outcome are lacking. Hence, a simple clinical cohort study,24 the cumulative incidence of severe
assessment, consisting of medical history, physical disorder was 8% after 5 years. Results of two prospective
examination, routine laboratory tests, and chest trials138,139 show that the incidence of post-thrombotic
radiography, seem to be sufficient. syndrome in patients with first proximal deep vein
Cancer patients have an enhanced risk for deep vein thrombosis can be reduced by a below-knee graduated
thrombosis, particularly during risk conditions elastic compression stocking (30–40 mm Hg at the
including immobilisation, infection, treatment with ankle). Since patients at risk for post-thrombotic
antineoplastic drugs, surgery, or insertion of a central syndrome cannot be identified in advance, all patients
venous catheter. Those admitted with an acute medical with deep vein thrombosis should be advised to wear
illness benefit from low-molecular-weight heparin at a such a stocking during the first 2 years.
high prophylactic dose.16 In surgical cancer patients, this
drug, at a high prophylactic dose, is as effective and safe Deep vein thrombosis of the arms
as unfractionated heparin (5000 U three times daily).130 Deep vein thrombosis of the arms arises as a
Risk for thrombosis in surgical cancer patients is complication of central venous catheters due to
persistent. In one study,131 extended thromboprophylaxis compression at the thoracic outlet between the first rib
reduced the incidence of deep vein thrombosis by two- and the clavicle, after unusual effort or without an
thirds but most events were asymptomatic or involved obvious reason (Paget-Schroetter syndrome). Although
the distal veins, and a benefit in terms of mortality was idiopathic disorder is rare (0·02 per 1000 people per
not seen. Further studies are needed before extended year), the growing use of intravenous access devices
prophylaxis can be recommended. increases the incidence of local thrombotic
Deep vein thrombosis of the arms arises in up to 30% complications.141 Risk is higher than usual in patients
of cancer patients in whom a central venous catheter has with thrombophilia.142 In a prospective registry, age
been inserted. The rate of catheter-associated younger than 67 years, a body-mass index of less than
thrombosis was substantially reduced by low-intensity 25 kg/m2, and admission were independent predictors of

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non-catheter associated deep vein thrombosis of the 9 Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based
arms.143 This disorder is complicated by symptomatic perspective of the hospital incidence and case-fatality rates of deep
vein thrombosis and pulmonary embolism: the Worcester DVT
pulmonary embolism in about 8% of patients and by Study. Arch Intern Med 1991; 151: 933–38.
asymptomatic embolism in about 35%.141,144 Within 10 Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A,
2 years, a quarter of patients develops post-thrombotic Eichinger S. The risk of recurrent venous thromboembolism in
men and women. N Engl J Med 2004; 350: 2558–63.
syndrome.145 11 Nicolaides AN, Kakkar VV, Field ES, Renney JT. The origin of deep
Symptoms of deep vein thrombosis of the arms vein thrombosis: a venographic study. Br J Radiol 1971; 44: 653–63.
include pain, oedema, and cyanosis in this area of the 12 Killewich LA, Bedford GR, Beach KW, Strandness DE Jr.
Spontaneous lysis of deep venous thrombi: rate and outcome.
body. On clinical suspicion, compression ultrasonog- J Vasc Surg 1989; 9: 89–97.
raphy is the preferred diagnostic method.146 The 13 White RH, Zhou H, Romano PS. Incidence of symptomatic venous
diagnosis is established by visualisation of a thrombus; thromboembolism after different elective or urgent surgical
non-compressibility in a segment of vein in the upper procedures. Thromb Haemost 2003; 90: 446–55.
14 Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM,
arm (eg, axillary vein, distal subclavian vein) or neck Melton LJ III. Predictors of recurrence after deep vein thrombosis
(jugular vein); or both. In case of a suspected thrombus and pulmonary embolism: a population-based cohort study.
in any other venous segment of the arms, or if Arch Intern Med 2000; 160: 761–68.
15 White RH, Gettner S, Newman JM, Trauner KB, Romano P.
ultrasonography is inconclusive or negative despite a Predictors of rehospitalization for symptomatic venous
high clinical probability, venography should be done. thromboembolism after total hip arthroplasty. N Engl J Med 2000;
Although controlled trials are lacking, low-molecular- 343: 1758–64.
16 Geerts WH, Pineo G, Heit J, et al. Prevention of venous
weight heparin at therapeutic doses (ie, antifactor Xa thromboembolism: the 7th ACCP conference on antithrombotic
150–200 U/kg once daily or 100 U/kg twice daily) is the and thrombolytic therapy. Chest 2004; 126: 338S–400S.
preferred treatment. Catheters should be removed. 17 Douketis JD, Eikelboom JW, Quinlan DJ, Willan AR,
Other treatment options, such as thrombolysis or Crowther MA. Short-duration prophylaxis against venous
thromboembolism after total hip or knee replacement: a
thrombectomy, are less well studied and should be meta-analysis of prospective studies investigating symptomatic
restricted to selected patients who might be severely outcomes. Arch Intern Med 2002; 162: 1465–71.
compromised by post-thrombotic syndrome. In patients 18 Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective
study of venous thromboembolism after major trauma.
with underlying venous compression, first rib resection N Engl J Med 1994; 331: 1601–06.
or physical therapy might be considered. In those with 19 Lassen MR, Borris LC, Nakov RL. Use of the low-molecular-weight
idiopathic deep vein thrombosis of the arms, the heparin reviparin to prevent deep-vein thrombosis after leg injury
requiring immobilization. N Engl J Med 2002; 347: 726–30.
recurrence risk is about 10% at 5 years.142,145 The optimal 20 Samama MM, Cohen AT, Darmon JY, et al. A comparison of
duration of anticoagulation has not been evaluated. We enoxaparin with placebo for the prevention of venous
discontinue vitamin K antagonists after 3 months. thromboembolism in acutely ill medical patients. N Engl J Med
1999; 341: 793–800.
Conflict of interest statement 21 Leizorovicz A, Cohen AT, Turpie AGG, Olsson CG, Vaitkus PT,
PAK is an investigator in a study supported by Bayer, is a consultant for Goldhaber SZ, for the PREVENT Medical Thromboprophylaxis
AstraZeneca (manufacturer of [xi]melagatran), and has received Study Group. Randomized, placebo-controlled trial of dalteparin
speaker’s fees from Aventis (manufacturer of enoxaparin) and Pfizer for the prevention of venous thromboembolism in acutely ill
(manufacturer of dalteparin). SE received speaker’s fees from medical patients. Circulation 2004; 110: 874–79.
SanofiSynthelabo (former manufacturer of fondaparinux). 22 Samama MM. An epidemiologic study of risk factors for deep vein
thrombosis in medical outpatients: the Sirius study. Arch Intern
Acknowledgments Med 2000; 160: 3415–20.
We thank Michaela Bronhagl for editing of the manuscript. We did not
23 Alikhan R, Cohen AT, Combe S, et al. Risk factors for venous
receive funding for writing this Seminar. thromboembolism in hospitalized patients with acute medical
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