Received: 23 August 2024

- - Revised: 14 January 2025

https://doi.org/10.1016/j.jtha.2025.01.009

REVIEW
Accepted: 27 January 2025

Basics of diagnosis and treatment of venous thromboembolism

Catrin Cox1 | Lara N. Roberts2,3

1
Thrombosis and Haemophilia Centre, Guy’s
& St Thomas’ NHS Foundation Trust, Abstract
London, UK
Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary
2
King’s Thrombosis Centre, Department of
embolism (PE), is common and associated with significant morbidity and mortality. The
Haematological Medicine, King’s College
Hospital NHS Foundation Trust, London, UK symptoms and signs of VTE are nonspecific. Well-established integrated diagnostic
3
Institute of Pharmaceutical Sciences, King’s strategies combining clinical probability scores and D-dimer are used to identify pa-
College London, London, UK
tients with a low probability of VTE, where the diagnosis can be safely excluded
Correspondence without imaging. In patients with confirmed VTE, anticoagulation is the mainstay of
Lara N. Roberts, King’s Thrombosis Centre,
Department of Haematological Medicine,
treatment. However, patients with high-risk features at presentation may benefit from
King’s College Hospital, Denmark Hill, advanced reperfusion therapies such as thrombolysis and/or interventional approaches
London, SE5 9RS, UK.
Email: [email protected]
to reduce early mortality and/or long-term morbidity. The advent of direct oral anti-
coagulants has greatly simplified the treatment of VTE for most patients, with a per-
sisting role for low molecular weight heparin and vitamin K antagonists in select patient
groups. Following an initial 3 to 6 months of anticoagulation, those with major transient
provoking factors can safely discontinue anticoagulation. Balancing the risk of recur-
rent VTE and bleeding risk is central to decisions regarding long-term anticoagulation,
and patients should be included in shared decision-making. Assessment and recognition
of common long-term complications such as postthrombotic syndrome and post-PE
syndrome are also essential, given they are associated with significant adverse
impact on long-term quality of life, with a significant risk of mortality associated with
the less frequent complication of chronic thromboembolic pulmonary hypertension.
This review provides a basic overview and framework for the diagnostic approach to
deep vein thrombosis and PE, risk stratification of confirmed diagnoses, and
management.

KEYWORDS
anticoagulants, pulmonary embolism, venous thrombosis, venous thromboembolism

1 | INTRODUCTION thrombosis within the deep veins and most commonly involves the
lower limb. PE occurs when some or all of the thrombosis breaks away
Venous thromboembolism (VTE) comprises deep vein thrombosis and travels to the lungs via the venous circulation to occlude the
(DVT) and pulmonary embolism (PE). DVT refers to the formation of pulmonary arterial vasculature. VTE is common, affecting an

-
Manuscript handled by: Shrey Kohli

Final decision: Shrey Kohli, 27 January 2025

© 2025 The Author(s). Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

J Thromb Haemost. 2025;▪:1–18 jthjournal.org 1

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- COX AND ROBERTS

estimated 1 in 12 adults within their lifetime, and more than 10 million TABLE 1 Risk factors for venous thromboembolism.
events are diagnosed worldwide each year [1,2]. Half of all episodes
Persistent/
are associated with recent hospitalization and/or surgery, with most
transient Inherited Acquired
events presenting following hospital discharge. Knowledge of VTE,
Persistent Antithrombin deficiency Malignancy (until remission) ±
including its diagnosis and management, is therefore relevant to all Protein C deficiency chemotherapy
clinicians, as a lack of clinical suspicion both during the index admis- Protein S deficiency Myeloproliferative disorders
sion, at outpatient follow-up, or in primary care may lead to delays in Factor V Leiden Paroxysmal nocturnal
Prothrombin gene hemoglobinuria
diagnosis and further morbidity [3].
polymorphism Antiphospholipid syndrome
In this review, we provide a basic overview and framework for the Non-O blood group Inflammatory bowel disease
diagnostic approach to DVT and PE, risk stratification of confirmed Sickle cell disease Systemic lupus
diagnoses, and management. We discuss phases of treatment including erythematosus
Nephrotic syndrome
estimating the risk of recurrent VTE and secondary prevention, along
Obesity
with a brief overview of the monitoring and management for long-term HIV infection
complications. This review does not cover the pathophysiology of VTE
Transient Major
[4], thrombosis at unusual sites [5–9], pregnancy-associated VTE [10], or Major surgery/trauma within
primary prevention of VTE [11–13], and we direct readers to the cited 3 mo
references for further information. Further topic-specific reviews and Hospitalization ≥3 d with
acute illness within 3 mo
guidance are signposted for readers wanting more detail throughout.
Heparin-induced
thrombocytopenia
Minor
2 | EPIDEMIOLOGY Combined hormonal
contraception
Oral estrogen-containing
The annual incidence of VTE in adults is estimated at 1 to 2 per 1000
HRT
per year [14]. Increasing age is associated with a significant increase in Pregnancy/puerperium
risk, with an annual incidence of 1 per 100, in those over 80 years of Immobilization, eg, in
age [15]. Females are at greater risk at younger ages owing to the use plaster cast
Long-haul travel
of combined hormonal contraception and pregnancy, with men having
a higher incidence associated with increasing age, as well as increased HRT, hormone replacement therapy.
risk of recurrent VTE [16].
Half of all VTE episodes are associated with hospitalization and/or 4 | VTE DIAGNOSIS
surgery in the preceding 3 months [17]. Where hospitalization is asso-
ciated with reduced mobility for ≥3 days, or with surgery requiring All patients with suspected DVT and PE should have a thorough his-
general anesthesia for more than 30 minutes, this is considered a major tory and examination to consider alternate diagnoses. Where PE is
provoking factor for VTE. Guidance on prevention of hospital- suspected a chest X-ray and electrocardiogram should also be per-
associated VTE is discussed elsewhere [11,12,18,19]. Other common formed to exclude alternate pathology. Where DVT and/or PE remain
risk factors are summarized in Table 1 and include cancer, obesity, and a significant concern, pretest probability should be assessed. Good
inherited thrombophilia. It is important to recognize that a third or more practice points for patients with a confirmed diagnosis are summa-
of patients with VTE may have no apparent provoking risk factor [1,17]. rized in Table 2 [18,22–27].

3 | CLINICAL PRESENTATION 4.1 | Clinical or pretest probability scores

The clinical presentation of VTE is varied and largely nonspecific. DVT As the symptoms and signs of VTE are nonspecific, pretest probability

usually presents with unilateral symptoms with leg pain the most scores (Figure 1) have been developed for use in integrated diagnostic

frequent and sometimes the only presenting symptom [20]. Other strategies. This enables VTE to be excluded without diagnostic imaging

symptoms include leg swelling, redness, and skin changes, such as using clinical criteria in conjunction with D-dimer testing [28–35]. Less

dilated superficial veins. PE can present with breathlessness, pleuritic than 5% to 20% of patients with suspected VTE are confirmed to

chest pain, cough with or without hemoptysis, dizziness, syncopal have the condition; therefore, avoiding imaging in those at very low

episodes, or when severe, cardiac arrest [3,21]. Physical examination risk improves efficiency, limits unnecessary radiation exposure for

may be unremarkable or reveal tachycardia, hypoxia, or hypotension suspected PE, and avoids unnecessary utilization of resources

in those with significant thromboembolic burden. [18,28,36].

COX AND ROBERTS
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TABLE 2 Good practice tips at diagnosis of acute venous thromboembolism (VTE).

DO Rationale
Use simple, reassuring language Word choice, incomplete transfer of information from clinician to patient, and nonverbal cues can lead to an
Examples: “You have a blood clot in your imbalance of fear over reassurance at initial encounters [23] This may contribute to ongoing stress and
leg” anxiety.
“Most patients do well when diagnosed
and treated promptly…”

Take a menstrual history from Anticoagulation commonly causes HMB. Identifying women with pre-existing HMB can influence the choice
premenopausal women of anticoagulation and also enable early intervention to mitigate against increased HMB, identify and
manage iron deficiency, and empower women to seek medical help appropriately [22]. Direct women to
available online resources, for example:
https://thrombosis.org/2023/08/bleeding-bloodthinners-hmb/
www.sciani.com/portfolio/anticoagulants-and-your-periods/

Review modifiable bleeding risk factors To reduce risk of bleeding.

[27] For example,
• discontinue antiplatelet agents unless absolute indication to continue (ie recent coronary arterial drug
eluting stent)
• counsel to avoid NSAIDs for analgesia
• reduce alcohol intake
• ensure adequate control of hypertension

Offer a single-drug approach to Apixaban and rivaroxaban offer an oral treatment approach upfront, avoiding the need for parenteral LMWH
anticoagulation when appropriate [18].
Improved patient experience, and cost-effectiveness

AVOID

Stopping combined hormonal This can precipitate withdrawal bleeding, which may be heavier in the acute phase and lead to a risk of
contraception at VTE diagnosis unwanted pregnancy. Continuing combined hormonal contraception while on anticoagulation is safe [22]

Indiscriminate testing to find a cause for Antiphospholipid antibodies should be considered in those <50 years or with other autoimmune conditions.
unprovoked VTE Lupus anticoagulant testing should be avoided at the time of acute thrombosis diagnosis as false
results can occur. MPN mutational analysis and PNH screening can be considered in those with a
suggestive FBC [24]

• Heritable thrombophilia testing Heritable thrombophilia tests do not impact acute management. There is a risk of both false negative and
positive results due to acute thrombosis±anticoagulation [24]

• Routine whole-body CT scans to look While there is a risk of occult malignancy in unprovoked VTE, studies have shown extensive screening does
for underlying malignancy not improve detection or outcomes [25] Further investigation (ie, endoscopy/imaging) should only be
ordered when indicated based on findings of a thorough history, examination, chest X-ray and basic blood
tests (FBC, calcium, renal, and liver profile) [18,26]

CT, computed tomography; FBC, full blood count; HMB, heavy menstrual bleeding; LMWH, low molecular weight heparin; MPN, myeloproliferative
neoplasm; NSAID, nonsteroidal anti-inflammatory drug; PNH, paroxysmal nocturnal hemoglobinuria; VTE, venous thromboembolism.

The most established pretest probability score for suspected DVT 4.2 | D-dimer testing
is the Wells score (Figure 1) [28,30]. DVT can be excluded in those
with an “unlikely” pretest probability and negative D-dimer, with im- D-dimers are fibrinogen degradation products, resulting from fibri-
aging required for the remainder. The diagnostic pathway for sus- nolysis of cross-linked fibrin within the thrombus. D-dimer assays are
pected DVT is illustrated in Figure 2. Alternate clinical probability widely available, cheap, and incorporated in integrated diagnostic
scores have been developed to simplify diagnosis and to reduce the pathways for VTE, where the clinical probability of DVT/PE is
proportion of patients requiring definitive imaging (Figure 1). assessed as unlikely (Figures 2 and 3) [18]. A negative D-dimer
Patients with suspected PE should also be assessed with a pretest in combination with a low pretest probability score has a high negative
probability score (Figure 1), after initial assessment to identify alter- predictive value and can safely exclude VTE without imaging [37].
nate causes including a full history, examination, and initial in- The threshold at which a D-dimer is considered “positive” varies
vestigations such as electrocardiogram and chest X-ray [18,36]. PE can by manufacturer [38]. D-dimer is a nonspecific marker and will
be excluded in those with an “unlikely” pretest probability and a be raised with increasing age, and inflammatory states including
negative D-dimer without further imaging (Figure 3). the postoperative period, concurrent infection, and malignancy.
4
- COX AND ROBERTS

F I G U R E 1 Examples of available pretest probability scores used in the assessment of suspected deep vein thrombosis (DVT) and pulmonary
embolism (PE) including simplified Wells for DVT [30,35], PE [35], revised and simplified Geneva scores [31,32], YEARS algorithm [33,34] and
pulmonary embolism rule-out criteria [34].

For this reason, raised D-dimer alone cannot be used to diagnose VTE [18,36,42]. Ultrasound can be limited to the proximal veins, or
or as a screening tool [39]. D-dimer can also be normal in those on extended to include the distal veins (whole leg scan), although this
anticoagulants and therefore should not be used to exclude VTE in practice varies between centers. If a proximal DVT is diagnosed, then
this scenario. Adapting D-dimer thresholds by age in those over 50 the more time-consuming scanning of the distal veins is not usually
(“age-adjusted” D-dimer) or by clinical probability (with incremental required. In centers without access to whole leg scanning, patients
increases in D-dimer thresholds with reducing pretest probability) with a high/likely pretest probability and positive D-dimer should have
have been investigated and are proposed as strategies to further a repeat ultrasound at 1 week (following suspension of newly
reduce the proportion of patients requiring imaging [40,41]. commenced anticoagulation), in the presence of an initially normal
proximal leg compression ultrasound. CT venography and MR
venography are rarely required for DVT diagnosis but may be
4.3 | Diagnostic imaging considered in those with inadequate views on ultrasound and a strong
clinical suspicion of iliac vein thrombosis, eg, patients presenting with
Access to imaging may be restricted out of hours or limited by ca- buttock pain and/or swelling of the upper thigh.
pacity. When DVT/PE is suspected and there is an anticipated delay in
confirmatory imaging (in England defined as >1 hour for PE, >4 hours
for DVT), interim therapeutic anticoagulation should be commenced 4.3.2 | Imaging for suspected PE
until the diagnosis is confirmed/excluded [18].
Patients with suspected PE and a high/likely clinical pretest proba-
bility, and those with low to moderate or unlikely probability and a
4.3.1 | Imaging for suspected DVT high D-dimer, require further imaging for diagnosis of PE. CT pul-
monary angiography is the predominantly used imaging modality for
The current gold standard for DVT diagnosis is compression ultra- the diagnosis of PE [18,36]. It is widely available and can be rapidly
sound of the lower limb. The inability to compress a vein indicates the performed in and out of office hours with a high sensitivity and
presence of thrombosis. Color Doppler is used to visualize blood flow specificity. Additional advantages are the identification of alternate
within the vessel and is a useful adjunct, particularly for intra- diagnoses and for confirmed PE, evaluation for radiological features of
abdominal/pelvic veins, which cannot easily be compressed right heart strain [18].
COX AND ROBERTS
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F I G U R E 2 Integrated diagnostic strategy for suspected deep vein thrombosis (DVT) using the simplified Wells score [30]. *For patients
previously on thromboprophylaxis or long-term anticoagulation, continue prior treatment. PTP, pretest probability.

Ventilation-perfusion (V/Q) scanning is a nuclear medicine imag- Other concerns include the availability of radiopharmaceuticals,
ing technique used in the diagnosis of PE, where radiopharmaceuticals interobserver variation in interpretation, and reduced sensitivity for
are given intravenously or inhaled to assess lung perfusion and subsegmental PE.
ventilation, respectively. PE is confirmed when a mismatch is identi-
fied, ie, absent perfusion with normal ventilation of 2 or more
segmental areas. The key advantage is reduced radiation exposure 5 | RISK STRATIFICATION OF CONFIRMED
and lack of need for intravenous contrast, which may be preferred in PE AND MANAGEMENT IMPLICATIONS
those with renal impairment or contrast allergy. However, it is not as
widely available and not suitable for use in patients with lung Acute PE has variable clinical severity ranging from minimal symptoms
parenchymal abnormalities where ventilation will be impaired [18]. to cardiovascular compromise, shock, and early death. PE may
6
- COX AND ROBERTS

F I G U R E 3 Integrated diagnostic strategy for suspected pulmonary embolism (PE) using the simplified Wells score for PE [35]. CTPA,
computed tomography pulmonary angiography; CXR, chest X-ray; echo, echocardiogram; ECG, electrocardiogram; VQ, ventilation/perfusion.

compromise both gas exchange and circulation with the latter comorbidities, clinical observations, and laboratory parameters can be
responsible for most mortality due to pressure overload leading to used to identify those patients at low, intermediate, and high risk of
right ventricular failure [43]. Hemodynamic instability is defined as mortality (Figure 4). Many patients with low-risk PE, including those
any of the following conditions: (1) cardiac arrest, (2) obstructive with isolated subsegmental PE, can be safely managed in the ambu-
shock (persistent hypotension, systolic blood pressure [SBP] < 90 latory setting [49].
mmHg, or need for inotropes to maintain SBP with end-organ hypo- Prognostic markers include the presence or absence of RV strain,
perfusion); or (3) persistent hypotension (SBP < 90 mmHg despite assessed radiologically via CTPA or by echocardiogram, and cardiac
adequate filling) [44]. It represents a life-threatening emergency, and biomarkers (troponin, NT-proBNP). These markers are only useful to
reperfusion therapy with thrombolysis is recommended. If a patient is predict mortality in PE when used in conjunction with clinical risk
too unstable for definitive imaging, a bedside echocardiogram can help stratification scores [43]. Patients with an intermediate high-risk score
confirm right ventricular (RV) strain suggestive of PE. In all other on PESI with evidence of RV strain on imaging (ideally echocardio-
patients, clinical risk stratification tools (PESI score [45], simplified gram) and positive troponin have higher mortality and require close
PESI score [46], HESTIA [47,48]), incorporating patient characteristics, initial monitoring due to a higher risk of clinical deterioration [43].
COX AND ROBERTS
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F I G U R E 4 Risk stratification for confirmed PE with hemodynamic stability. CCU, critical care unit; CTPA, computed tomography pulmonary
angiography; HDU, high dependency unit; PE, pulmonary embolism; PESI, pulmonary embolism severity index; [45] RV, right ventricular.

Clinical decision-making regarding treatment of intermediate-high and prevention of recurrent VTE, with assessment and management of
high-risk PE can be challenging and timely treatment decisions need to complications. Treatment considerations throughout phases of care
be made. Critical care review should be sought to consider initial are summarized in Figure 5.
observation (48-72 hours) in a high dependency/critical care unit.
Given the lack of strong evidence to inform optimal management in
this patient group, expert opinion, and experience in making these
6.1 | Available anticoagulants
clinical decisions are invaluable. Many centers now have PE response
teams enabling multispecialty discussion in real-time to optimize early
Characteristics of the available anticoagulants for VTE treatment are
decision-making, particularly with regard to reperfusion therapy [50].
summarized by class in Table 3 [52].

6 | ANTICOAGULATION MANAGEMENT 6.1.1 | Direct oral anticoagulants

The principal aim of initial and primary treatment is to prevent DOACs are preferred for the treatment of VTE in most patients. Ran-
thrombosis propagation and embolization, thereby reducing associ- domized controlled clinical trials demonstrated noninferior efficacy of
ated morbidity and mortality. Anticoagulation remains the mainstay of both direct oral activated factor X (FXa) inhibitors (apixaban, edoxaban,
treatment, with consideration of concomitant reperfusion therapy in rivaroxaban) and the oral direct thrombin inhibitor, dabigatran in the
selected high-risk patients. Direct oral anticoagulants (DOACs) are treatment of VTE in comparison to LMWH/warfarin, with a reduced risk
now the standard of care for VTE treatment, with low molecular of fatal and intracranial bleeding [53–58]. The advantages of DOACs
weight heparin (LMWH) and vitamin K antagonists (VKAs) reserved compared to VKAs include predictable pharmacokinetics allowing fixed
for selected patients. All patients should have their weight measured, dosing regimens (Table 3) without the need for therapeutic drug
along with a full blood count, creatinine, liver profile, and coagulation monitoring, rapid onset/offset of action, and fewer drug/food in-
screen, to aid in the evaluation of bleeding risk and inform the optimal teractions. Apixaban and rivaroxaban can be used as a single oral
choice and dose of anticoagulant. The vast majority of patients with drug approach in the acute phase of VTE treatment, whereas edox-
DVT can be managed in an ambulatory setting, exceptions being those aban and dabigatran require parenteral anticoagulation for at least 5
with vascular compromise or comorbidities requiring inpatient man- days prior to initiation. The short half-life of DOACs simplifies
agement [51]. In the longer term, the focus moves to secondary management in clinical scenarios such as bleeding, overdose, and
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F I G U R E 5 Approach to venous thromboembolism (VTE) management throughout phases of care Created with Biorender.com. DVT, deep
vein thrombosis; FBC, full blood count; RV, right ventricular; PE, pulmonary embolism.

perioperative management. However, this may be a disadvantage in used in patients with a creatinine clearance >15 mL/min, with dose
those with incomplete adherence. Other potential limitations of adjustments in those with a creatinine clearance of 15 to 30 mL/min.
DOACs include renal and hepatic metabolism, drug–drug in- Given the short half-life and potential for once-daily dosing, LMWH is
teractions (P-gp and CYP3A4 inducers/inhibitors), and limited scope particularly useful in those patients who have an increased risk of
for dose adjustment. While antidotes (idarucizumab and bleeding and those undergoing further invasive procedures. LMWH is
andexanet alpha) are available, there is geographic variation in access required as a bridge to VKA and should be continued until the in-
and use. There is generally insufficient data to recommend one DOAC ternational normalized ratio (INR) >2.0. It may also be used for
over another. Patient characteristics and preferences are important the initial 5 days prior to initiation of edoxaban or dabigatran in acute
factors when deciding on which anticoagulant to offer. VTE.

6.1.2 | LMWH/unfractionated heparin 6.1.3 | Fondaparinux

eparin has been extensively used in the treatment of VTE; it acts Fondaparinux is a synthetic pentasaccharide that indirectly inhibits FX
indirectly by potentiating the inhibitory action of antithrombin on FX via potentiation of antithrombin. It is as effective as LMWH/UFH in
and FII. Both unfractionated heparin (UFH) and LMWH remain the initial treatment of VTE [60,61]. It is preferred for patients
treatment options for VTE. UFH is rarely required and generally requiring parenteral anticoagulation with heparin allergy, previous
avoided due to its unfavorable safety profile with unpredictable heparin-induced thrombocytopenia, or with concerns regarding the
dose response, increased risk of bleeding, heparin-induced use of animal products (as heparin is porcine-derived).
thrombocytopenia, and mortality compared to LMWH [59]. UFH
may be preferred for patients under consideration for primary
reperfusion therapy. LMWH is administered by subcutaneous injec- 6.1.4 | VKAs
tion once or twice daily with the dose determined by body weight.
LMWH is available as prefilled syringes, and patients can be taught to VKAs were the first oral anticoagulant available to treat VTE and have
self-administer, enabling use in ambulatory settings. LMWH can be been in use for decades. VKAs inhibit vitamin K epoxide reductase
TABLE 3 Characteristics and dosing of available anticoagulants.

COX
AND
Characteristic Vitamin K antagonist LMWH Fondaparinux Dabigatran Apixaban Edoxaban Rivaroxaban

ROBERTS
Dosing Variable once daily, Weight-based, Weight-based, 150 mg twice daily Twice daily 60 mg once daily Twice daily for 3 wk
based on INR Once or twice daily 7.5 mg once daily then once daily

Initiation Overlap with LMWH Twice daily preferred Weight-based, once ≥ 5 d LMWH then 10 mg twice daily for ≥ 5 d LMWH then switch 15 mg twice daily
until INR >2 daily switch to 7d to edoxaban for 3 wk
dabigatran

Subsequent Based on INR Consider switching to No change Continue same dose 5 mg twice daily from Continue same dose 20 mg daily from
once daily if day 8. day 22.
continuing beyond Consider ↓ to 2.5 mg Consider ↓ to 10 mg
acute phase at 6 mo for after 3-6 mo for
secondary secondary VTE
prevention prevention

Dose modification Based on INR Dose reduction if CrCl <50 kg, 5 mg once Y to 110 mg twice n/a Y to 30 mg daily for n/a
<30mL/min daily daily for selected selected patientsb
>100 kg, 10 mg once patientsa
daily

Drug monitoring Y N N N N N N

Hepatobiliary and Predominant Minimal Minimal 20% 73% 50% 65%

intestinal
metabolism

Renal excretion Minimal Predominant Predominant 80% 27% 50% 66%

CKD

CrCl, 15-30 mL/min Y ↓dose Do not use Do not use Limited experience Limited experience Limited experience

<15 mL/min Y Avoid Do not use Do not use Do not use Do not use Do not use

Reversal agent Y Partial N Y Y, restricted use in N Y, restricted use in

some regions some regions

CKD, chronic kidney disease, CrCl; creatinine clearance; INR, international normalized ratio; LMWH, low molecular weight heparin; n/a, not applicable; N, no; Y, yes.
Adapted from [52] with permission from Wolters Kluwer Health, Inc.
a
Dabigatran 110 mg twice daily in patients >80 years of age and those also on verapamil. Consider dose reduction in patients aged 75-80 years, with moderate renal impairment (CrCl 30-50 mL/min), with
gastritis, esophagitis, or gastroesophageal reflux, or at increased risk of bleeding.
b
Edoxaban 30 mg once daily for patients with CrCl 15-50mL/min or <60 kg or taking concomitant PgP inhibitors.

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- COX AND ROBERTS

thereby depleting the reduced form of vitamin K required for gamma- impact on quality of life [22]. It is important to take a menstrual
carboxylation of vitamin K-dependent coagulation factors (FII, FVII, history to identify pre-existing menorrhagia when commencing
FIX, FX, protein C, and protein S). Hence, VKAs have slow onset and anticoagulation to enable preventative measures. All women should
offset of action, numerous food and drug interactions, and significant be counseled regarding the potential risk of menorrhagia. Apixaban,
intra- and interindividual variability. Therapeutic drug monitoring with dabigatran, and LMWH may be associated with a lesser risk of heavy
the INR is required to guide dosing, with a usual therapeutic range of 2.0 menstrual bleeding and may be preferred for women with pre-
to 3.0 for the treatment of VTE. Given the slow onset of action, there is existing menorrhagia [22]. Women taking hormonal contraception
the requirement to bridge patients with LMWH (or alternatives), until should not be advised to discontinue abruptly at diagnosis of VTE, as
an INR of >2.0 is achieved. Warfarin and acenocoumarin are the most this may precipitate withdrawal bleeding. Estrogen-containing
widely prescribed VKAs. As VKAs are not dependent on renal clearance, contraception should be reviewed and switched in a controlled
VKAs can be used in patients with a creatinine clearance <15 mL/min manner prior to stopping anticoagulation given the increased
and are therefore preferred in those with end-stage renal disease. recurrence risk associated with continuation. All women of child-
bearing age should be counseled regarding the limited data sup-
porting the safety of DOACs in pregnancy, the risk of embryopathy
6.2 | Assessment of bleeding risk where VKAs are continued beyond 6 weeks of pregnancy, and the
need to seek further medical advice if planning pregnancy or on
Bleeding is the most frequent side effect of anticoagulation, with an positive pregnancy test [71,72].
overall incidence of 2% to 3% in the initial 3 to 6 months, and 1% per
year in those on extended anticoagulation (with higher bleeding risk
with VKAs compared to DOAC) [62,63]. Additionally, bleeding has a 6.3.2 | Extremes of body weight
higher case fatality rate than recurrent VTE [64,65]. It is rarely
appropriate to withhold anticoagulation completely in the absence of VKAs have, until recently, remained the preferred anticoagulation for
active bleeding or very high bleeding risk in patients with acute VTE. patients with low (<50 kg) or high (>120 kg) body weight, as such
For selected patients with isolated distal DVT or subsegmental PE patients were excluded from the seminal DOAC trials. There is
(without concomitant DVT) and a lack of persisting VTE risk factors increasing evidence to support the use of apixaban and rivaroxaban in
for extension, surveillance may be appropriate. However, the optimal those with high body weight, and international guidelines now
management approach remains controversial [66–68]. The aim of recommend these agents for the treatment of VTE, without routine
assessing bleeding risk is to identify and address modifiable bleeding drug monitoring [73]. While there is no consensus guideline regarding
risk factors, such as stopping antiplatelets or NSAIDs if no longer the use of DOACs in low body weight, there is increasing use of
required, reducing alcohol intake, optimizing control of hypertension, apixaban and edoxaban in patients with low body weight <50 kg with
assessing and preventing falls, and avoiding interacting medications/ good clinical outcomes [74].
herbal remedies where suitable alternatives exist [27]. There are
validated risk assessment models to aid in evaluating bleeding risk,
however further comparative outcome studies are needed to identify 6.3.3 | Cancer
the tool with optimal prediction [27]. Patients should be counseled
regarding the risk of bleeding, symptoms, and signs to be aware of and Patients with cancer-associated thrombosis (CAT) have an increased
when to seek medical attention. risk of recurrent VTE and bleeding [75,76]. Patients with cancer
often have additional bleeding risk factors such as drug interactions
with chemotherapy, thrombocytopenia, issues with absorption (as a
6.3 | Special patient groups result of poor appetite, nausea, or vomiting), and renal impairment.
Historically, LMWH has been preferred for the treatment of CAT.
In this section, we summarize important considerations in these However, trials have more recently demonstrated that DOACs
commonly encountered patient populations [69,70]. Of note, there are are associated with a lower risk of recurrent VTE compared to
comprehensive reviews and guidelines dedicated to each of these LMWH, but with increased bleeding [77]. Bleeding risk with DOACs
special populations available, and we direct readers to these for more is at least partly influenced by site of cancer, with increased risk
detailed discussion than possible in this “basics” review. in patients with genitourinary or intraluminal gastrointestinal tu-
mors. Decisions regarding the choice of anticoagulant should be
made following consideration of bleeding risk, site of cancer,
6.3.1 | Women of childbearing age suitability of oral therapy, drug interactions, and patient preference
[78,79]. LMWH may be preferred at initiation, particularly where
Anticoagulation commonly results in or exacerbates, heavy men- a cancer diagnosis/treatment plan has not yet been confirmed
strual bleeding with consequent significant morbidity and adverse [78,79].
COX AND ROBERTS
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6.3.4 | Renal impairment Therefore VKAs remain the treatment of choice in those with
confirmed APS, particularly in those with triple-positive antibody
DOACs, LMWH, and fondaparinux are at least partially renally cleared profiles [85].
with consequent implications for patients with low or high creatinine
clearance. Patients with renal impairment were excluded from the
seminal DOAC trials, and therefore, their use is cautioned against in 7 | INTERVENTIONAL APPROACHES TO
chronic kidney disease [53–57]. Dabigatran is almost exclusively VTE MANAGEMENT
renally cleared and should not be offered to those with creatinine
clearance of < 30mL/min, with a reduced dose for moderate renal 7.1 | Catheter-directed thrombolysis for proximal
impairment (Table 3). Rivaroxaban and edoxaban are not licensed for DVT
those with creatinine clearance of < 15mL/min. In the United States,
apixaban is licensed for VTE treatment in those with renal impairment Most patients with DVT can be safely managed with anticoagulation
including those requiring dialysis but there is limited high-quality data alone. There has been significant interest in the use of catheter-
to support this and limited experience in other countries [80,81]. The directed thrombolysis (CDT) to reduce the risk of postthrombotic
seminal study of edoxaban for stroke prevention in atrial fibrillation syndrome (PTS), with conflicting findings in clinical trials [87–89]. The
suggested an increased stroke risk in patients with high creatinine use of CDT necessitates hospitalization for the duration of interven-
clearance receiving edoxaban compared to warfarin; it is therefore tion and carries a risk of bleeding. CDT has not been associated with
suggested that it should be avoided in patients with creatinine an improvement in long-term quality of life, and therefore, this should
clearance >95 mL/min [82]. only be considered for highly selected cases. It may be beneficial for
those with vascular compromise or without symptomatic improve-
ment with anticoagulation in those with recent symptom onset (<14
6.3.5 | Previous GI/bowel resection surgery/ days), iliac vein involvement, consequent significantly impaired
malabsorption mobility, and a low risk of bleeding [18]. Such patients should be
discussed with a vascular surgeon/interventional radiologist with
Absorption of DOACs occurs predominantly in the stomach and small expertise in this area.
intestine. As a result of this, there may be concern regarding the use
of DOACs in those patients who have had bariatric or major small
bowel resection surgery, percutaneous gastrostomy, or issues with 7.2 | Reperfusion therapy for PE
malabsorption [83]. LMWH/fondaparinux remain the anticoagulants
of choice in those with true malabsorption and in the acute setting, 7.2.1 | Systemic thrombolysis for PE with
following bariatric surgery [73]. There is emerging evidence of hemodynamic instability
adequate apixaban absorption following bariatric surgery and apix-
aban may be considered in selected cases [84]. Apixaban, edoxaban In this patient group, thrombolysis has been shown to significantly
and rivaroxaban are all licensed for administration via percutaneous reduce mortality and recurrent PE. There is, however, a significant risk
gastrostomy. of major bleeding and intracranial hemorrhage, particularly in those
over 65 years [44,90]. Where there is an absolute contraindication to
systemic thrombolysis or an inadequate response to treatment,
6.3.6 | Antiphospholipid syndrome catheter-directed approaches or surgical embolectomy should be
considered [44].
Antiphospholipid syndrome (APS) is an acquired autoimmune disorder
characterized by arterial and/or venous thrombosis, and/or pregnancy
morbidity alongside the presence of persistent antiphospholipid anti- 7.2.2 | Intermediate-high risk PE
bodies (one or more β2-glycoprotein, cardiolipin antibodies, and lupus
anticoagulant confirmed on repeat testing 12 weeks apart) [85]. Pa- In the absence of hemodynamic compromise, the evidence for
tients with APS have a high risk of recurrent (venous and arterial) interventional approaches to PE management is weak. A randomized
thrombosis and long-term anticoagulation is recommended. The risk controlled trial of thrombolysis for those with intermediate-risk PE
of thrombotic complications is partially mediated by antibody profile did not demonstrate a net clinical benefit due to the increased
and patients with persistent positivity of all 3 antibodies (so-called bleeding risk [91]. However, a small study suggests reduced-dose
triple positive) have the highest risk of thrombotic complications thrombolysis may be safe and beneficial [92]. A catheter-directed
including an increased risk of recurrence despite anticoagulation. approach reduces the overall dose of thrombolytic agent and is
Trials investigating rivaroxaban and apixaban in patients with APS therefore associated with a lower bleeding risk; emerging evidence
were terminated early due to safety concerns, with an increased risk suggests catheter-directed thrombectomy may be of benefit in those
of predominantly arterial thrombosis in those receiving DOAC [86]. with a high baseline bleeding risk. There is currently insufficient
12
- COX AND ROBERTS

evidence for these approaches to be considered routine care and 9 | SECONDARY VTE PREVENTION AFTER
further evidence from ongoing trials is required to guide their use. WITHDRAWAL OF ANTICOAGULATION
However, systemic thrombolysis, CDT, and/or thrombectomy should
be considered in the event of deterioration despite adequate anti- When anticoagulation is discontinued, patients should be carefully
coagulation [44]. counseled about the importance of VTE prevention in future periods
of increased VTE risk (such as surgery, hospitalization with acute
illness, lower limb immobilization, and pregnancy) and to seek medical
attention in the event of new symptoms to suggest recurrence.
7.3 | Vena cava filters
Women should also be made aware of the increased VTE risk asso-
ciated with combined hormonal contraception and oral hormone
Routine use of inferior vena cava (IVC) filters is not recommended.
replacement therapy (transdermal preparations are considered safe).
Anticoagulation is highly effective at preventing progressive
Where a decision to discontinue anticoagulation is made, combined
thrombosis and embolization [93]. IVC filters may be considered in
hormonal contraception should be switched to a progesterone-only
patients with an acute proximal DVT ± PE (within 4 weeks of diag-
form (if still required) at least 4 weeks prior to discontinuing anti-
nosis) and an absolute contraindication to anticoagulation, to reduce
coagulation. Long-haul travel is a weak risk factor for VTE, and pa-
the risk of embolization. Of note, IVC filters are associated with an
tients with major provoking factors should be reassured and advised
increased risk of DVT in the longer term [94], and early retrieval
to remain active while traveling [99]. For patients at higher risk of
should be planned at the initiation of anticoagulation when no longer
recurrence (previous unprovoked VTE, persistent risk factors, travel-
required [18].
associated VTE) who are no longer on anticoagulation, prophylactic
anticoagulation can be considered for travel >4 hours [99].

8 | DURATION OF ANTICOAGULATION

The minimum treatment duration of anticoagulation in VTE is 3

10 | LONG-TERM COMPLICATIONS
months, following which a decision is required as to whether to stop
The major complications of concern following an initial VTE are the
or continue anticoagulation [13,51,95]. Long-term anticoagulation is
risk of VTE recurrence (see above), PTS (following DVT), and chronic
effective at reducing the risk of VTE but is associated with a risk of
thromboembolic pulmonary hypertension (CTEPH) following PE.
bleeding [64]. Therefore assessment of VTE recurrence risk, risk of
bleeding, patient concerns, and preferences is required when consid-
ering extended anticoagulation. Patient characteristics such as male
sex, age, extent of thrombosis, and the presence of persistent or 10.1 | PTS
transient risk factors all influence recurrence risk [95,96]. When a
decision is made in favor of extended anticoagulation, bleeding risk PTS is common affecting up to 20% to 50% of patients following the
factors should be considered, with a focus on reducing modifiable risk first DVT [100,101]. It is thought to arise due to damage to venous
factors (see above) [27]. Of note, the risk of recurrence following a valves with consequent venous hypertension leading to increased
first isolated distal DVT is thought to be low and extended anti- capillary permeability and/or inflammation [102]. It is characterized by
coagulation is not usually required in the absence of strong persisting symptoms of pain, cramps, swelling, pruritis, and paresthesia, which
risk factors (eg, cancer) [68]. are typically exacerbated during or following activity and relieved by
Review of VTE risk factors for the acute event is the currently rest or elevation. PTS can lead to skin changes (venous ectasia, ery-
recommended strategy for determining the risk of recurrence thema, hyperpigmentation, induration) and when severe, ulceration
following proximal DVT or PE (Figure 6) [13,43,51,97]. For example, [101]. PTS remains a clinical diagnosis and further imaging is not
VTE associated with major surgery is associated with a low risk of helpful (unless there is concern for recurrent DVT). Residual vein
recurrence of <1% at 2 years, compared to VTE-associated nonsur- thrombosis is common, and while this can make diagnosing recurrent
gical, transient provoking risk factors with a recurrence risk of DVT in the ipsilateral leg difficult, it is not required for the diagnosis of
approximately 8% at 2 years, and those with unprovoked VTE a PTS. There is no specific treatment for PTS, and patients should be
recurrence rate of almost 20% at 2 years [97,98]. Patients with reassured that symptoms generally improve with time and simple
persistent provoking factors such as active autoimmune disease and measures such as exercise, elevating the leg when seated, and emol-
inflammatory disorders may benefit from extended anticoagulation lients to alleviate dry skin, may provide symptomatic benefit [102].
given the increased risk of VTE recurrence [97]. Patients with CAT Graduated compression stockings are no longer recommended for the
should continue anticoagulation for a minimum of 6 months, with prevention of PTS but may be useful to manage symptoms in selected
consideration of extension until the cancer is in remission and cancer patients, ie, with significant swelling in the absence of contraindica-
treatment is completed [18,78,79]. tions (particularly arterial disease) [100]. For selected patients with
COX AND ROBERTS
- 13

F I G U R E 6 Stratification of recurrence risk following proximal deep vein thrombosis or pulmonary embolism and recommended duration of
anticoagulation. Created with Biorender.com. VTE, venous thromboembolism. Adapted from [43] with permission from the author.

previous iliac vein thrombosis, persistent venous obstruction, and CTEPH is considered low probability in those with low or undetect-
severe symptoms, there may be a role for endovascular or surgical able tricuspid regurgitation velocity and the absence of other echo-
intervention, and referral to a vascular surgeon with a special interest cardiographic evidence of RV strain. These patients can be reassured,
in DVT is suggested [100]. Prevention of recurrent DVT is key to avoid with consideration of pulmonary rehabilitation/exercise programs to
progression of symptoms. improve exercise tolerance. Where tricuspid regurgitation velocity is
increased (>2.8 m/s) or with other echocardiographic features of RV
strain, a ventilation/perfusion scan should be performed to look for
persistent perfusion defects. Those with persistent perfusion defects
10.2 | Post-PE syndrome and CTEPH
should then be referred to a specialist pulmonary hypertension center
for further evaluation with right heart catheterization and pulmonary
CTEPH is uncommon affecting 2% to 3% of patients surviving acute
angiography. We direct readers to an excellent illustrated review and
PE [103]. Symptoms are nonspecific and most commonly comprise
the European Respiratory Society statement for further details of
persistent exertional breathlessness. Signs of RV failure (ie, RV heave,
CTEPH diagnosis and management [104,106].
raised jugular venous pressure, hepatomegaly, peripheral edema) are
only evident at a late stage [104]. Of note, up to half of patients report
persistent breathlessness up to 12 months following a PE diagnosis,
recently coined “post-PE syndrome” [105]. This is attributed to a 11 | CONCLUSION
combination of deconditioning, anxiety, and/or ventilatory or circula-
tory impairment secondary to previous PE. Post-PE syndrome has a VTE is common and associated with significant morbidity and mor-
significant adverse impact on quality of life. Evaluating which patients tality. A high degree of clinical suspicion is required to ensure early
require further investigation for CTEPH is essential as this condition is diagnosis using integrated diagnostic strategies with prompt initiation
associated with high mortality and is frequently a delayed diagnosis of anticoagulation. DOACs are the treatment of choice for the ma-
[104]. Those with significant thrombosis burden (and RV strain) at jority and have greatly simplified management. All patients should be
presentation and/or persistent symptoms of exertional breathlessness reviewed before 3 months to consider the optimal duration of anti-
should have an echocardiogram following 3 months of anticoagulation. coagulation, re-evaluate bleeding risk, and monitor for long-term
14
- COX AND ROBERTS

complications. Extended anticoagulation should be considered for thromboembolism: prophylaxis for hospitalized and nonhospital-
those at high risk of VTE recurrence. Patients should be counseled and ized medical patients. Blood Adv. 2018;2:3198–225.
[12] Anderson DR, Morgano GP, Bennett C, Dentali F, Francis CW,
involved in decision-making throughout, to minimize later anxiety and
Garcia DA, Kahn SR, Rahman M, Rajasekhar A, Rogers FB,
optimize treatment adherence. Smythe MA, Tikkinen KAO, Yates AJ, Baldeh T, Balduzzi S,
Brożek JL, Ikobaltzeta IE, Johal H, Neumann I, Wiercioch W, et al.
AUTH OR CONT RIBUTIONS American Society of Hematology 2019 guidelines for management
of venous thromboembolism: prevention of venous thromboem-
C.C. and L.N.R. cowrote the manuscript and approved the final
bolism in surgical hospitalized patients. Blood Adv. 2019;3:
submission.
3898–944.
[13] National Institute for Health and Care Excellence. Venous throm-
DECL AR ATION OF COMPETING INT ERES TS boembolism in over 16s: reducing the risk of hospital-acquired
deep vein thrombosis or pulmonary embolism. National Guidelines
C.C. has no conflicts of interest. L.N.R. has received speaker fees from
Centre. https://www.nice.org.uk/guidance/ng89/evidence; 2018.
Bayer, Chugai, and Viatris, and consultancy from Hemab. [accessed June 19, 2024].
[14] Raskob GE, Angchaisuksiri P, Blanco AN, Buller H, Gallus A,
ORCID Hunt BJ, Hylek EM, Kakkar A, Konstantinides SV, McCumber M,
Ozaki Y, Wendelboe A, Weitz JI. ISTH Steering Committee
Lara N. Roberts https://orcid.org/0000-0003-3871-8491
for World Thrombosis Day. Thrombosis: a major contributor to
global disease burden. Arterioscler Thromb Vasc Biol. 2014;34:
R EF E REN CE S 2363–71.
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