Deep vein thrombosis

 

Deep vein thrombosis and pulmonary embolism are the manifestations of the same disease, so we name them with same term: venous thromboembolism (VTE). Their diagnostic and treatment approaches follow similar guidelines.

 

Epidemiology

VTE is the third most common cardiovascular disease, following ischemic heart disease and stroke. Its incidence is 1-2 cases/1000 persons/year. In Hungary, its annual mortality is 10/100,000; that is, 3‑10 times higher than the EU average. Its most common manifestation is DVT on the lower extremities (80%), 10% occurs on the upper extremities, while the remainder are found at rare sites (brain, viscera).

Etiology

The underlying process of VTE is thrombus formation in the venous system, which may result in local symptoms of obstruction; if the thrombus drifts with the bloodstream, it may also lead to pulmonary embolism. A thrombus may form due to several factors, Virchow’s triad sums up the pathophysiological aspects: 1. stasis, 2. vessel wall injury, 3. changes in the composition of the blood (hypercoagulability).

We differentiate between thromboembolic diseases based on whether the provoking factor can be established (provoked), or not (unprovoked), and whether these factors are treatable or not.

Various anatomical anomalies may also contribute to the development of DVT. In May-Thurner syndrome e.g., the right common iliac artery compresses the left common iliac vein, which runs below it. The injury of the venous wall is recurring (because of the arterial pulse wave) and this chronic effect leads to injury of the vein’s endothelium, thrombus forms on it, and the vein becomes chronically stenotic. This may cause DVT (75% of lower limb DVTs are diagnosed on the left side). On the upper extremity, thoracic outlet syndrome may cause the thrombosis of the subclavian vein (Paget-Schroetter syndrome).

Types of DVT

• We can classify the cases whether they are provoked or unprovoked. These factor has great influence on the duration and method of treatment, as well as VTE prevention. While provoked and idiopathic (unprovoked) thromboses of the lower extremities have approximately similar rates, 80% of the thromboses of the upper extremity are caused by venous lines or thoracic outlet syndrome (TOS).
• Depending on the site of the thrombosis, two major groups are distinguished on the lower extremity.
  • Distal: thrombosis is only detected in the calf veins; this constitutes around 20% of the cases.
  • Proximal: thrombosis occurs in the popliteal vein or even more proximally in the deep veins; this constitutes around 80% of the cases.

Symptoms

The symptoms of deep vein thrombosis of the extremities are non-specific, and many other diseases cause similar anomalies. The general feature of the symptoms is that they are stronger when the patient is in a vertical position and are mitigated by lying down.

1. Unilateral swelling of the limb (except for superior or inferior vena cava thrombosis),
2. Tightness of the limb,
3. Livid, marbled, shiny skin,
4. Increased dilatation of the subcutaneous veins directly below the skin,
5. Pain,
6. Sensitivity to pressure along the deep veins (e.g. Homans’ sign: pain in the calf muscles provoked by the dorsiflexion of the foot; it is worth noting that this is a non-specific symptom, its predictive value (both positive and negative) is low, and the diagnosis is never based on it!),
7. Phlegmasia cerulea dolens or phlegmasia alba dolens: if the onset is sudden, proximal, and extensive, the total occlusion of the venous circulation leads to a condition that could cause possible limb loss as venous circulation ceases. If venous pressure suddenly increases, the growing pressure of the tissues compresses the arterial In this case, both venous congestion and the symptoms of acute ischemia are present, leading to tissue necrosis and venous gangrene. When this occurs, the affected extremity becomes very tight, livid, marbled, and the patient complains of severe pain. If the occlusion persists over an extensive period of time, bulla formation and tissue necrosis develop.

The type and severity of deep vein thrombosis symptoms depends on the site of the occlusion and the speed of onset. More noticeable anomalies occur if the process affects more proximal veins, while crural thromboses are predominantly characterized by pain. In the latter case, other symptoms (difference in circumference, lividity of the skin) are absent. Similarly, if a process causes chronic stricture in the proximal venous system (e.g. May-Thurner syndrome, TOS) before deep vein thrombosis occurs, the previously gradually developed collateral network may lead to the acute occlusion remaining asymptomatic (“acute on chronic”). The onset of symptoms is also modified by individual variations in the venous system (e.g. thrombosis in one half of duplicated deep veins; in the case of congenital inferior caval vein atresy the formerly opened collateral network can mask the symptoms of newly occluded veins).

Diagnosis

Due to the non-specific clinical symptoms, DVT may not be ruled out or verified using simple physical examination. If there is clinical suspicion, the following examinations are necessary.

• Laboratory test: D-dimer testing. D-dimer levels may also be elevated due to other pathological processes (e.g.: tumor, inflammation, muscle damage, pregnancy, or myocardial infarction). For this reason, only a negative result of this test is diagnostically valuable, which indicates the absence of an acute thrombotic event. If D-dimer results are positive, that is not an evidence of thrombosis. If the likelihood of DVT is very low, this test is recommended first (cf. diagnostic algorithm below). Other laboratory measurements are not useful; in extensive thrombosis we can find mild leukocytosis, elevated CRP, fever as well without any specificity.
• Duplex ultrasound: this method is used to visualize dilated, incompressible veins that have no measurable blood flow. Another use of this modality is differential diagnosis (e.g. Baker’s cyst).
• Venous CT angiography: this technique is used to assess the exact extent of pelvic diseases, as well as any comorbidities that may also be causal factors (tumor, May-Thurner syndrome, retroperitoneal fibrosis, etc.); venous CT is required for intervention planning.
• Venous MR angiography: if CT is contraindicated, or the presence of visceral tumor or malformation is suspected.

Diagnostic steps are planned according to Wells’s score system, following the detailed interview of the patient.

Differential diagnosis must consider the following diseases: cardiac failure, renal insufficiency, myxedema, hypoproteinemia, lymph circulation flow disorders (e.g. lymph node metastasis), erysipelas, Baker’s cyst, popliteal aneurysm, venous compression caused by pelvic tumor, and the side effects of calcium channel blockers.

Complications

Acute:

• Pulmonary embolism symptoms include shortness of breath, chest pain, hemoptysis, tachycardia, syncope, circulatory failure. This complication occurs in at least 50% of pelvic thrombosis cases, usually without significant clinical symptoms.
• Phlegmasia cerulea and alba dolens ( above)

Chronic:

• Chronic venous insufficiency (post-thrombotic syndrome); usually develops in 30-50% of proximal thromboses within 2 years; for details cf. relevant section (due to adequate collateralization and lower hydrostatic strain, this is a rare complication of upper extremity cases)
• Recurring DVT
• Chronic pulmonary embolization resulting in pulmonary hypertension

 

Treatment

The primary treatment of deep vein thrombosis is conservative (except for phlegmasia). Its aim is to prevent PE, recurring VTE, and post-thrombotic syndrome. It consists of anticoagulation and compression bandaging with mobilization as early as possible.

Anticoagulation:

• Heparin: (a) LMWH adjusted to weight twice daily, (b) Na-heparin i.v. bolus first, then continuously with infusion pump or in v./s.c. portions adjusted to aPTT (target range: the 1.5-2.5x prolongation of the control value). Intravenous heparin is given in case of unstable PE, severe renal insufficiency, and if invasive intervention is planned [a side effect of heparin may be heparin-induced thrombocytopenia (HIT) – for this reason, platelet count must be monitored during heparin treatment].
• Vitamin K antagonists: acenocoumarol, warfarin. Parenteral treatment is continued after LMWH pretreatment; the transition should include an overlap period (“bridging”). Effectiveness is controlled by monitoring INR values. The target INR range is 2-3 (advantage: relatively safe even in case of poor renal function; disadvantage: instability due to the vitamin K content in food, drug interactions may occur, thus monitoring is required)
• DOAC (direct oral anticoagulant): direct thrombin inhibitor dabigatran, Factor X inhibitors rivaroxaban, apixaban, or edoxaban (advantage: monitoring is not required, there are no interactions with food and very few with other drugs; disadvantage: they cannot be used if renal function is significantly impaired; the availability of an antidote is limited). Transition from LMWH is much easier (no overlap is necessary between the two treatments – “switching”) 

Duration of anticoagulant treatment:

Anticoagulation may be divided into three stages:

(a) initial: 5-21 days of medical treatment

(b) long-term treatment: the first 3-6 months

(c) extended treatment: after the 6 months of treatment. The first two stages are necessary for every patient. As a general principle, if the provoking factor (DVT caused by plaster cast, surgery, hospitalization, etc.) can be eliminated, a 3-month treatment may be sufficient. Extended treatment is required in case of high‑risk thrombophilia (e.g. homozygous Factor V Leiden mutation, antithrombin III deficiency, antiphospholipid syndrome), as well as proximal thromboses, idiopathic or recurrent thrombosis, and partial recanalization.

Mobilization and compression treatment

Mobilization as early as possible is part of the treatment. Mobilization should occur after the application of tight, elastic bandaging or stocking, with the goal of avoiding future venous insufficiency. If the DVT is not associated with pulmonary embolism or the pathological process is distal, complete bed rest is not required following adequate initial treatment. If the thrombosis is proximal or complicated by pulmonary embolism, hospitalization is indicated for observation. Mobilization should be commenced only when the condition of the patient is stable and the treatment has adequately begun.

Local thrombolysis (catheter-directed thrombolysis, preferably combined with thrombus aspiration and stenting; CDT – catheter-directed thrombolysis, PMT – percutaneous mechanical thrombectomy)

The conservative treatment described above does not result in the dissolution of the thrombus, it only prevents additional thrombus formation. As such, if the circulation of the affected extremity has suffered severe damage, these methods are insufficient, and the active endovascular removal of the thrombus may be required.

During CDT, the catheter is introduced e.g. through a direct puncture of the popliteal vein, then tissue plasminogen activator (rtPA) is injected into the thrombus located in the iliac vein, and the loose thrombus is removed by aspiration. If there is a remaining chronic, stenotic, thrombotic lesion, or if external compression is still present, a stent is implanted into the affected portion.

• Indication: (a) absolute: phlegmasia; iliac-level DVT with severe symptoms that do not ease even after the start of treatment; (b) relative: young patient, left-sided thrombosis (in the case of May-Thurner syndrome, the stenting of the compressed venous portion reduces the chance of recurrent thrombosis).
• Treatment following thrombolysis: same as conservative treatment guidelines

Direct venous thrombectomy:

This method is very rare nowadays. Only if thrombolysis is contraindicated or unreachable and phlegmasia is present. The risk of rethrombosis is high.

Vena cava filter:

Only in select cases (recurrent PE in spite of adequate (!) anticoagulation; or if other contraindications of anticoagulants are present). It is very important to remove the filters as soon as possible.

 

Take-home message

• Thromboembolism often has mild or no symptoms.
• If thrombosis is suspected, further examinations are required.
• The underlying cause should always be investigated: if the patient is young (under 45 years), thrombophilia may be suspected; if the patient is older, a thorough examination for tumors is recommended, given the possibility of paraneoplastic thrombosis.
• The majority of VTEs may be prevented with sufficient thrombosis prophylaxis.
• Adequately long anticoagulation is the most important part of VTE therapy. Lower limb thromboses are the most common, early mobilization with daytime compression is recommended in these cases