Phlebothrombosis: aetiology, pathogenesis, symptoms, diagnosis, treatment

Phlebothrombosis is the formation of a blood clot in the venous system, most commonly the deep veins of the lower extremities, with partial or complete disruption of blood flow. The term deep vein thrombosis (DVT) is often used in the international literature.

Epidemiology

The main cause of a blood clot formation is a disorder in one of the factors of Virchow’s triad: blood stasis, damage to the vascular wall, and hypercoagulability.

Causes of deep vein thrombosis

Aetiologic factors can act individually or synergistically to lead to blood clot formation in the venous system.

• Decreased venous blood flow velocity: prolonged immobilisation, flight, bed rest, chronic venous insufficiency.
• Endothelial injury: surgery, trauma, catheters, thrombophlebitis.
• Hypercoagulability:
  • Congenital: deficiency of antithrombin III, C/S proteins, factor V (Leiden) mutation, prothrombin mutation.
  • Acquired: cancer, pregnancy, antiphospholipid syndrome, taking oral contraceptives.
• Additional factors: obesity, smoking, chronic inflammatory diseases.

Blood clot formation begins with the activation of platelets and the coagulation cascade in response to damage to the vascular wall or blood stasis.

Stages of thrombosis

1. Platelet activation

Once the endothelium of the vein is damaged, platelets are activated and begin to adhere to the damaged area of the vascular wall. In this case, platelets:

• Release substances that activate blood clotting (e.g., thromboxanes and serotonin).
• Platelet activation promotes the release of adenosine diphosphate, which activates other platelets and increases aggregation.
• A primary platelet plug forms, which begins to restrict blood flow in the injured area.

2. Activation of the coagulation cascade

Activation of the coagulation system leads to the formation of fibrin, the main component of the blood clot:

• Thrombin, formed during coagulation activation, converts fibrinogen into fibrin, which forms a network that anchors platelets and stabilises the plug.
• This process occurs through several steps, including activation of clotting factors (V, VII, IX, X and prothrombin).

3. Primary and secondary blood clot formation

• Primary blood clot: firstly, a fibrin-platelet plug forms, which is not structurally stable.
• Secondary blood clot: the fibrin network stabilises the clot. At this time, other blood components such as white blood cells and red blood cells begin to participate, resulting in a more organised and mature clot. The clot is thickened and better fixed in the vascular lumen.

4. The organisation of the blood clot

Over time, fibroblasts and endothelial cells sprout into the clot, and collagen fibres are formed. This process can lead to the development of fibrosis and calcification of the blood clot, which can lead to chronic changes in the venous wall and the development of post-thrombotic syndrome.

5. Blood clot progression

• The blood clot may spread proximally, increasing venous hypertension and impairing outflow.
• Its fragments (especially in the floating type of blood clot) can break off, entering the bloodstream and causing pulmonary embolism (PE), stroke, or infarction of internal organs.
• In some cases, venous outflow is restored as a result of recanalisation.

Clinical manifestations of phlebothrombosis

Phlebothrombosis is often asymptomatic and is detected only when complications develop, primarily pulmonary embolism.

When symptoms are present, the leading signs are pain, swelling, and discoloration of the limb:

• Pain: usually dull, pulling, worsens on exertion and palpation;
• Oedema: forms due to venous hypertension and is more often unilateral, involving the lower leg or the entire limb;
• Skin discoloration: ranges from pallor to cyanosis, and, in massive thrombosis, marked venous stasis with threat of ischemia may occur.

These manifestations reflect impaired venous outflow and increased venous pressure.

Some patients have local hyperthermia and increased body temperature, which is associated with a systemic reaction to thrombosis. In rare cases, a severe course develops, blue phlegmasia (phlegmasia cerulea dolens), accompanied by sharp pain, massive oedema and critical blood flow disruption.

Diagnosis of phlebothrombosis

Laboratory Methods

• D-dimer detection is the primary screening test. A low level with a low to moderate clinical probability allows phlebothrombosis to be excluded. Its elevation is nonspecific and requires confirmation by imaging.
• Coagulation profile (INR, PTT, prothrombin time) is used to evaluate the coagulation system and monitor anticoagulant therapy.
• Thrombophilia screening (factor V Leiden mutation, protein C/S deficiency, antithrombin III, antiphospholipid antibodies) is performed for recurrent or unprovoked thrombosis when the result affects the duration of treatment.

Instrumental methods

• Ultrasound duplex scanning is the method of choice. The diagnostic criterion is the absence of complete compression of the vein by the transducer; additional signs are visualisation of echogenic masses and decreased blood flow.
• CT and MR venography are used in cases of difficult visualisation of pelvic veins or questionable ultrasound findings. They allow to accurately determine the localisation and extent of the blood clot.
• Phlebography is of limited use, mainly before interventional procedures.

Thus, the diagnosis of phlebothrombosis relies on a stepwise approach: clinical probability according to the Wells scale, laboratory screening by D-dimer and confirmation by instrumental methods, among which duplex scanning remains key.

Wells scale

Probability of deep vein thrombosis:

• Low: –2 to 0;
• Moderate: 1 to 2;
• High: >3.

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Treatment of deep vein thrombosis

Prevention of phlebothrombosis

Prevention of thrombosis in at-risk patients is key. Early mobilisation after surgery, adequate hydration, use of elastic compression during prolonged immobilisation and flights are recommended. Prophylactic doses of anticoagulants (low-molecular-weight heparins or fondaparinux) are administered to high-risk patients in hospitals.

Medical Therapy

In the acute phase of phlebothrombosis, the key goal is to rapidly suppress the activity of the coagulation system to prevent thrombus growth and embolisation.

The following groups of parenteral anticoagulants are used for this purpose:

• Low molecular weight heparins (LMWH) are the drugs of choice for starting therapy and are administered subcutaneously in therapeutic doses (e.g., enoxaparin, dalteparin).
• Fondaparinux (a selective factor Xa inhibitor) may be used as an alternative to LMWH, especially when there are contraindications to heparin or a high risk of heparin-induced thrombocytopenia.
• Unfractionated heparin is used less frequently, predominantly in patients with severe renal impairment or when rapid control (IV infusion with PTT monitoring) is required.

After 5–10 days of initial treatment, medications should be switched to oral anticoagulants:

• Direct oral anticoagulants (DOACs): rivaroxaban, apixaban, dabigatran, edoxaban. They provide a stable anticoagulant effect and do not require routine monitoring.
• Rivaroxaban and apixaban can be administered immediately after diagnosis, without an LMWH phase.
• Dabigatran and edoxaban require a 5–7 day pretreatment with a parenteral anticoagulant.

Vitamin K antagonists (warfarin) are used if DOACs are contraindicated (e.g., severe renal failure, antiphospholipid syndrome, low drug availability). They require regular monitoring of INR (target values 2.0–3.0).

Duration of anticoagulant therapy

Surgical Therapy

Surgical and endovascular methods are used to a limited extent, in cases of massive ileofemoral thrombosis with the threat of ischemia or with a severe risk of post-thrombotic syndrome. The following are used:

• Catheter-directed thrombolysis;
• Pharmacomechanical thrombectomy;
• Surgical thrombectomy for threatening conditions (e.g., phlegmasia cerulea dolens);
• Placement of a cava filter is indicated only in contraindications to anticoagulation or recurrence of PE on adequate treatment.