Thrombo-embolic venous disease: diagnosis and management

Venous thrombo-embolic disease (VTE) is an important part of vascular medicine, and has 2 aspects: Venous thrombosis, commonly known as "phlebitis", which corresponds to the obstruction of a vein by a clot, and the migration of this clot into the pulmonary circulation, which represents the serious complication of pulmonary embolism.

1 - Venous thromboembolic disease: diagnosis

Venous thromboembolic disease (VTE) is a major public health issue, since it represents the third most frequent acute cardiovascular syndrome after myocardial infarction and stroke.
VTE is a frequent disease (1.57/1000 inhabitants in 2013), with an increase over the last 2 years in connection with the worldwide pandemic of Covid 19 infection, particularly during the 1st wave, reaching over 20% in patients hospitalized in intensive care or critical care, with a clear excess of mortality.
It takes two main forms: deep vein thrombosis (DVT) or superficial vein thrombosis (SVT), and pulmonary embolism (PE).

Clinical probability assessment -> a diagnostic approach now well codified

1. pulmonary embolism (PE)

Symptoms that should raise the suspicion of PE are mainly unusual shortness of breath and/or sudden-onset chest pain. As these symptoms are inconstant and unspecific, many other diagnoses may be evoked, such as myocardial infarction, pericarditis, pneumothorax, pneumopathy, especially in cases of fever, or aortic dissection.
When faced with this list of diagnoses, a clinical context must be systematically sought, in particular factors favoring VTE such as a personal or family history of VTE, the presence of an active cancer, estrogen-progestin treatment, an active pregnancy, a progressive inflammatory disease or prolonged immobilization in the last 3 months (surgery, travel).
The diagnostic approach has been detailed in the latest recommendations of the European Society of Cardiology in 2019.

If the hypothesis of PE is suspected, it is recommended to assess its level of probability with a validated score that classifies clinical probability into 2 categories: probable or improbable.

2 Deep vein thrombosis

As with PE, it is recommended that clinical probability be estimated using a validated score that can be used to conclude whether clinical probability is high or low and guide further investigations.

Which paraclinical examinations and when?

1. pulmonary embolism

In case of unlikely PE, it is recommended to assay a substance found elevated during activation of coagulation: the D-dimers in order to exclude the hypothesis of PE.
It should be noted that there are many causes of elevated D-dimer levels, such as age, pregnancy, post-partum, infections, cancer, inflammatory diseases or surgery and other traumas.
Consequently, an elevated level is not decisive for the diagnosis, whereas a normal level excludes the diagnosis (negative predictive value).
In the event of probable PE, or when D-dimer levels are above the threshold value, it is recommended that a thoracic angioscan be performed as the reference examination.
In the event of a "doubtful" angioscan, it is recommended to continue investigations with a venous ultrasound scan of the lower limbs or a lung scan, or to repeat the examination.

If venous ultrasound is positive in a patient with thoracic symptoms, we recommend retaining the diagnosis of PE. If venous ultrasonography is performed before thoracic angioscanning, it is suggested that no further investigations be carried out.

The latest recommendations from the European Society of Cardiology on the management and diagnosis of PE in 2019 call for assessment of the right ventricle (which may undergo sudden hyperpressure, making the pathology severe) by cardiac ultrasound or the measurement of biomarkers of heart function.

In the event of hemodynamic instability (shock, arterial hypotension), a thoracic angioscan should be performed immediately if the patient can be transported, and if necessary, a bed-side echocardiogram to look for right heart chamber dysfunction.

2. deep vein thrombosis

In cases of low probability, a D-dimer assay is recommended to rule out DVT.
In cases of high probability, or when D-dimer levels are above the threshold value (adapted to age after 50), a complete venous Doppler ultrasound of the proximal and distal venous network is recommended, together with a compression test: a normal vein can be compressed without any problem; it's the incompressibility that makes the diagnosis. If a simple proximal venous compression ultrasound is performed and is negative, it is recommended to perform a full Doppler ultrasound within 7 days.




Prognostic evaluation of pulmonary embolism.

In the event of shock or arterial hypotension defined by PAS < 90 mmHg or a fall in PAS > 40 mmHg for at least 15 minutes, the patient is identified as being at high risk of early mortality and PE is qualified as severe PE with a mortality risk of 10%.

Conclusion

The diagnosis of VTE is based on a number of stages, beginning with the assessment of the probability of the disease's occurrence via scores. If there is a strong clinical suspicion, imaging tests (pulmonary angioscanner) will be performed as a first-line procedure, in the absence of contraindications and if the patient's condition allows.
If there is a contraindication to pulmonary angioscanning, pulmonary scintigraphy should be considered, along with a search for associated deep-vein thrombosis. Ultrasound evaluation of right ventricular function is recommended, especially in the event of an unstable hemodynamic state that precludes angioscan.
On the other hand, if the diagnosis is unlikely, D-dimer assay is recommended as a first-line procedure.
In the case of DVT, a systematic search for PE is not recommended in the absence of symptoms.

Reference:
Approach and diagnosis of venous thromboembolic disease
L. Gey, B. Leclercq, S. El Harake, P. Suchon, G. Plu-Bureau, S. Cohen, A. Elias, P. Morange, G. Sarlon
Presse Médicale Formation - 2023.

Key words: Venous thromboembolic disease (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE).

2 - Venous thromboembolic disease: assessment

"When elements or details, however trivial, recur regularly in an investigation, they must always be retained, because they undoubtedly conceal a deeper meaning".
Jean- Christophe Grangé.

As we saw earlier, venous thromboembolic disease (VTE) encompasses two clinical entities: pulmonary embolism (PE) and deep vein thrombosis (DVT).
It is a multifactorial disease resulting from the interaction of acquired, environmental and genetic risk factors.
Age, the presence of transient risk factors, signs suggestive of cancer, a family history of thrombosis and the recurrent nature of thrombosis will determine the need for and content of an etiological work-up (i.e. the search for a cause).

A number of risk factors for thrombosis have been identified and classified into 4 categories: major transient, minor transient, major persistent and minor persistent (see table).

VTE is said to be "provoked" when it occurs in the presence of major permanent or transient risk factors.
VTE is said to be "unprovoked" when it occurs in the absence of major risk factors.

Determining whether a VTE is provoked or unprovoked influences the etiological work-up, but also makes it possible to assess the risk of recurrence, and therefore the duration of treatment.

Indeed, the risk of recurrence in unprovoked (or spontaneous) DVT is estimated at 10% in the first year, versus 3% in provoked VTE.

Etiological assessment is therefore guided by the provoked nature of the condition, but also by the recurrent nature and location of the thrombosis, and/or the existence of a family history of VTE.
For patients with an episode of VTE provoked by a major transient risk factor, the duration of anticoagulant treatment is 3 to 6 months. If a major risk factor persists over time, the duration of treatment may be extended. For example, the onset of VTE in a patient with active cancer will lead to the continuation of anticoagulant therapy throughout the oncological treatment. Cancer is said to be "active" if there is detectable tumour disease, if anti-tumour treatment is continued (including hormonal treatment), or if there has been no remission for more than 6 months.

In patients presenting with a first unprovoked episode of VTE, it is recommended that an etiological approach be undertaken, i.e. a search for the cause of the thrombosis.

Search for an unknown cancer

The first step in the investigation of cancer in VTE is clinical.
Cancer is present in 5-10% of VTE patients, and patients with active cancer are 4-7 times more likely to develop venous thromboembolism than the general population.
Nearly a third of undiagnosed cancers are clinically evident at the time of VTE diagnosis.
The rate of occult cancer diagnosis is multiplied by 3 in the 6 months following the thrombo-embolic event.
The most frequently diagnosed cancers are lung, digestive, breast and prostate.
Several studies have compared targeted screening for cancer with extended screening after the onset of VTE, in the hope of reducing the time to diagnosis to a less severe stage, and thus increasing patients' life expectancy. Unfortunately, these studies showed no improvement in outcomes with extended screening, and have led to the current recommendations for limited cancer screening in patients with VTE.
When to look for underlying cancer
The search for cancer is therefore indicated in cases of unexplained VTE.
The following diagnostic approach is suggested:
1. minimal clinical and paraclinical examination :

- Carry out a careful physical examination
- Take a personal and family history of cancer
- Chest X-ray
- Biological work-up including: complete blood count, blood ionogram, standard hepatic work-up and assessment of renal function.
- Repeat this assessment during the first 6 months of follow-up, and orientate investigations according to any abnormalities observed.

2 Update on recommended generalized and public health screenings:

If not performed in the year preceding the thrombo-embolic event:
- Smear test for all women
- Mammography for all women aged 50 and over
- PSA test (for prostate cancer) for all men aged 50 and over
- Testing for occult blood in stools (hemoccult test).

In patients with an unprovoked recurrence of VTE despite a well-managed anticoagulant regimen, an active search for occult cancer is essential, with a thoraco-abdomino-pelvic CT scan (TAP scan) and/or a CT scan coupled with scintigraphy (PET scan).
Among complementary examinations, the initial thoracic CT scan (for the diagnosis of pulmonary embolism) and the TAP scan have been shown to be the most cost-effective, in contrast to thoracic radiography, abdomino-pelvic ultrasound and fecal occult blood tests.

Testing for thrombophilia

Biological factors of hypercoagulability may be involved in the onset of VTE; this is known as thrombophilia (or "tendency to thrombose").
Biological thrombophilia corresponds to the presence of a constitutional or acquired biological risk factor predisposing to VTE.
It is proposed that all these abnormalities, which increase the risk of a first thrombotic event, should only be investigated after the occurrence of a venous thromboembolic event, severe DVT or spontaneous PE (or in women in a hormonal context) in patients under 50 years of age, and not systematically.
In patients over 50, this assessment should be discussed when there is a documented family history.


1- Constitutional thrombophilia

This is characterized by the presence of a deficiency in certain proteins (3 in number) that limit clot formation, or by the presence of a variation in two coagulation factors (Factor V or Factor II).

Among constitutional thrombophilias, mutations in these factors are (with a few exceptions) minor thrombophilias which do not increase the risk of recurrence in a clinically significant way.
On the other hand, the risk is higher and said to be major in other thrombophilias, i.e. deficiencies.
Fortunately, the severe forms of these deficiencies are the least frequent, while the mutations are fairly widespread (up to 10% in certain populations).

2- Acquired thrombophilia

This rare anomaly consists in the presence of antibodies (known as "anti-phospholipid" antibodies) and/or a "circulating anti-coagulant" (CAC) corresponding to the anti-phospholipid syndrome (APS), which significantly promote thrombosis, including arterial thrombosis.
This is the only thrombophilia for which the benefits of prolonged anticoagulation have been formally demonstrated. Patients under 50 years of age should be screened for SAPL in the event of a first episode of proximal DVT or unprovoked PE, thrombosis at an unusual site or recurrent VTE.

Conclusion

The etiological assessment of VTE is based primarily on the search for major transient or permanent favouring factors. In the absence of such factors in a first episode, it is essential to look for cancer, by updating generalized screening tests (breast, cervical and colon cancer), as well as PSA testing in men over 50.
In the event of VTE recurrence under well-managed treatment, further investigations may include CAT or PET scans.
Finally, a family history of VTE is essential to guide the thrombophilia work-up.

VTE risk factors . Vascular Medicine Referential 2022





Reference :
Etiological workup for venous thromboembolic disease
S. El Harake, B. Leclercq, L. Gey, P. Suchon, G. Plu-Bureau, S. Cohen, A. Elias, G. Sarlon, P. Morange
Presse Médicale Formation - 2023.

Key words: Venous thromboembolic disease (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE).


3 - Venous thromboembolic disease: treatment

Treatment of venous thromboembolism (VTE) is based primarily on anticoagulant therapy. This treatment must be started as early as possible once the diagnosis has been made, to halt the spread of thrombosis, which could make matters worse. Anticoagulant treatment has evolved considerably in recent years, with the arrival on the market of new molecules: direct oral anticoagulants.

Different phases of treatment

Anticoagulant treatment for VTE can be divided into three distinct phases:
First, the initial phase of treatment (up to 10 days), with the aim of rapidly initiating anticoagulant therapy to prevent the spread of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), by limiting the hemorrhagic and thrombotic complications that arise in the first few weeks.
This is followed by the main treatment phase (first three months) to maintain therapeutic levels of anticoagulation to prevent the spread of DVT and PE and reduce the risk of early recurrence.
Finally, the extended treatment phase (beyond three months, with no planned end date) with the specific aim of reducing the long-term risk of VTE recurrence.
After the main treatment period (three months), the risk of recurrence varies according to risk factors. Prolonged anticoagulant therapy may be necessary for specific patient groups at high risk of VTE recurrence.
Treatment modalities in the initial and main phases of VTE vary according to location, severity and associated pathologies.

For a long time, the gold standard of anticoagulant treatment was heparin. It is administered either by continuous infusion: unfractionated heparin (UFH), or by subcutaneous injections: low-molecular-weight heparin (LMWH) 1 or 2 times a day.
In recent years, direct oral anticoagulants (DOACs) in tablet form have come to dominate the treatment of VTE, outstripping the classic anti-vitamin K (AVK). They carry less risk of major bleeding and are much easier to use, as they do not require regular coagulation monitoring (the famous INR - International Normalized Ratio - with VKAs). However, their use is problematic in cases of severe renal insufficiency.





Anticoagulant treatment of PE with or without DVT
The initial assessment must determine the level of severity (using a prognostic score), which determines the course of treatment:

1. low-risk DVT and PE

These are patients with few comorbidities for whom outpatient treatment can be organized.
The latest European recommendations on the management of pulmonary embolism suggest the first-line use of direct oral anticoagulants (DOACs), except in certain specific situations.
In France, 2 AODs are available, and their introduction requires no prior parenteral anticoagulation, but an initially increased dosage that is reduced when the risk of recurrence is lower.

2. intermediate-risk PE

In this case, initial anticoagulation with subcutaneous heparin (LMWH) is recommended for the first 48 to 72 hours. The time required to switch to oral anticoagulation depends on the patient's clinical progress.
3. high-risk PE

The first-line anticoagulant treatment is based on continuous intravenous administration of UFH, combined with "systemic thrombolysis", i.e. administration of an additional substance to rapidly lyse ("melt") the clot. In the event of failure or contraindication to this treatment, surgical embolectomy or catheter-directed treatment may be performed, with the clot being directly removed from the vessel.
The time required to initiate the switch to oral anticoagulant therapy and the use of AODs takes into account the patient's clinical progress, in the same way as in the previous case.

Anticoagulant treatment of isolated DVT

Drug therapies are systematically combined with compression therapy using class 3 (strongest) stockings or bands, ideally, or class 2 if they are not well tolerated. Their introduction in the acute phase of treatment improves symptomatology (edema, pain) in the first 7 days and quality of life in the long term, as well as reducing chronic venous obstruction. Treatments aimed at directly reducing the clot, such as surgical or mechanical thrombectomy, catheter thrombolysis or endovenous treatments, are exceptionally indicated.
They may be discussed in an expert center in cases of severe extensive thrombosis, or thrombosis with associated arterial ischemia threatening the functional prognosis of the limb. While these treatments show better short-term patency than conventional anticoagulants, their effect on preventing post-thrombotic syndrome has not been demonstrated.

In the event of treatment failure, anticoagulation dosage must be re-evaluated, taking into account renal function, patient body weight and the risk of bleeding.
This may involve changing the anticoagulation molecule (e.g. to LMWH if an oral anticoagulant is being used), increasing LMWH doses by 25%, increasing OAD doses or switching to VKAs with a higher INR target.
In this context, it is necessary to reassess the presence of thrombophilia or underlying neoplasia.
Special situations
1. severe renal failure
The European Society of Cardiology does not recommend the use of AODs in patients with severe renal impairment. However, expert opinions state that they can be used with caution, without any dosage adjustment being recommended, as is the case in atrial fibrillation, but there is a lack of solid evidence.
Only unfractionated heparin and VKAs can be prescribed in cases of very severe renal insufficiency.
2 Anti-phospholipid syndrome (APS):
AODs have no marketing authorization in this indication, and treatment is based on the introduction of VKAs under cover of LMWH until 2 INRs within the target range (between 2 and 3) are achieved at 48-hour intervals.
3 Pregnancy and breast-feeding:
VTE is 10 times more frequent during pregnancy in the first weeks and 25 times more frequent in the weeks following delivery. AODs, VKAs and Fondaparinux cannot be used during pregnancy, as they may cross the placental barrier. LMWH are recommended throughout pregnancy, and continued for 6 weeks after delivery. It should be noted that if DVT occurs less than two weeks before the due date, the risk of extension of DVT and/or PE is high. Therefore, scheduled delivery combined with IV UFH may be preferable to minimize the anticoagulation-free window.
4 Superficial venous thrombosis (SVT) of the lower limbs:
These are the superficial veins responsible for varicose veins, which can also be victims of thrombosis. A single study has shown a benefit for treatment with Fondaparinux, which is an injectable treatment "close" to heparin, for 45 days when the TVS measures ≥ 5 cm in length and is located ≥ 3 cm from the junction with the deep veins.
If the venous thrombosis is located less than 3 cm from the deep vein network, the treatment will be that of a deep vein thrombosis.

5 VTE and cancer:
The association between VTE and cancer is well established, and a number of recent trials have made it possible to include AODs in the VTE treatment strategy for patients with active cancer. The latter is defined in a non-consensual way either as a tumour mass that is present and/or metastatic, or recurrent, or in a patient who has received oncological treatment within the last 6 months. The choice of treatment for cancer-associated VTE should ideally be made in a multidisciplinary consultation meeting, in order to limit the adverse effects of potential interactions between anticoagulant and anticancer therapy. AODs should be considered as an alternative to LMWH for initial, main and long-term treatment if the cancer is not located in the gastro-urinary tract. LMWH will be preferred if the VTE is severe or recurrent, if there is a bleeding risk factor, notably a history of recent bleeding or a gastrointestinal pathology likely to bleed; if the patient has gastrointestinal or genitourinary cancer, or a brain tumour or metastases, or if a drug interaction with AODs is possible and important. The patient must also be able to play an active role in the final decision, which remains the doctor's responsibility.

Reference:
Treatment of thrombo-embolic venous disease in the acute phase
B. Leclercq, S. Cohen, W. Radix, L. Gey, S. El Harake, P. Suchon, G. Plu-Bureau, , A. Elias, P. Morange,
G. Sarlon.
Presse Médicale Formation - 2023.