Thrombophlebitis: Etiology, Pathogenesis, Classification, Diagnosis, Treatment

Thrombophlebitis – inflammation of the venous wall with thrombus formation, most often affects the superficial veins of the lower extremities.

• It is most common between the ages of 60-70.
• Women are affected somewhat more often, especially if varicose veins are present.

Etiology

Thrombophlebitis develops against the background of a complex of factors that reflect Virchow’s triad.

1. Damage to the venous wall (a key trigger of the inflammatory-thrombotic process):

• Catheterizations and injections (especially of the veins of the arm) are a frequent cause of iatrogenic thrombophlebitis;
• Surgical interventions (open leg surgeries, after venectomy, shunt placement);
• Soft tissue injuries – including bruises, burns, vein punctures;
• Infections of the skin and soft tissues – septic thrombophlebitis, often accompanying phlegmona, abscess, and urosepsis.

2. Venous stasis and outflow disorders

• Lower extremity varicose veins are the most common background for the development of superficial thrombophlebitis;
• Immobilization – bed rest, long flights, plaster casts;
• Heart failure – especially when decompensated;
• Obesity – leads to decreased venous return and blood stasis in the lower extremities;
• Pregnancy and postpartum – pelvic vein compression + hormonal changes.

3. Hypercoagulability (increased blood clotting)

• Cancer;
• Thrombophilias (antithrombin III, protein C and S deficiency; factor V Leiden mutation; antiphospholipid syndrome);
• Hormonal therapy – taking estrogen (oral contraceptives, substitution therapy);
• Systemic inflammatory and autoimmune diseases – systemic lupus erythematosus, inflammatory vasculitis;
• COVID-19 is a cause of transient hypercoagulability and thrombosis, including superficial veins.

Pathogenesis

Damage to the endothelium of the venous wall

Damaged endothelium loses antithrombotic properties, expresses adhesion molecules (ICAM-1, VCAM-1), activates platelets and leukocytes, and triggers the production of proinflammatory cytokines (IL-1β, TNF-α).

Activation of the coagulation cascade

Against the background of intima damage and activation of tissue factor, the external chain of blood coagulation is launched:

• Factors VIIa and X are activated;
• Conversion of prothrombin to thrombin;
• Fibrin formation and thrombus stabilization;
• In parallel, platelet aggregation occurs, forming a “white” platelet matrix, especially in areas of turbulent flow.

Local slowing of blood flow increases and maintains local thrombosis:

• Strengthening of contact interaction of blood formers with the vascular wall;
• Increase in procoagulant concentrations;
• Reduced “flushing” of thrombogenic molecules.

Inflammatory infiltration of the venous wall (sterile inflammation):

• Migration of neutrophils and monocytes;
• Secretion of metalloproteinases that provoke intimal destruction;
• Production of IL-6, IL-8, and proinflammatory mediators;
• Fibrosis and thickening of the venous wall with chronicization;
• In cases of secondary infection, the process may become purulent (septic thrombophlebitis).

Arrangement or embolization of the thrombus

Further development could follow two scenarios:

• Organization – the thrombus is infiltrated by fibroblasts, grows endothelium and turns into a scar-fibrous mass. This contributes to obliteration of the vein lumen and chronicization of the process.
• Embolization – if the thrombus is unstable and spreads into the deep vein system, it may fragment and migrate with the development of thromboembolism.

IMPORTANT! Although thrombophlebitis is more often limited to the saphenous veins and is considered “of little significance,” when involving a vein adjacent to the sapheno-femoral or sapheno-subcutaneous junction, it can progress to the deep vein system. Therefore, even “superficial” inflammation should be considered a potentially thromboembolically dangerous condition.

Classification of thrombophlebitis

By localization:

• Superficial thrombophlebitis: lesion of the saphenous veins, most commonly the great saphenous vein of the leg.
• Deep thrombophlebitis: deep vein involvement, increased risk of thromboembolism.

Downstream:

• Acute: sudden onset, severe symptoms.
• Chronic: prolonged course with periods of exacerbation.

Presence of infection:

• Aseptic: without infection.
• Septic: with the attachment of infection.

Clinical manifestations

The clinical picture of thrombophlebitis depends on the localization, the extent of the inflammatory process, the depth of the affected veins and the presence of complications. Acute superficial thrombophlebitis of saphenous veins of the lower extremities is considered to be the most typical, but symptoms may vary.

1. Сommon symptoms of acute thrombophlebitis

• Pain in the projection of the affected vein – aching or burning, increases with palpation or movement.
• A thickening along the course of the vein – palpated as a mass, painful and immobile.
• Reddening of the skin – over the area of inflammation, often linear, follows the course of the vein.
• Localized increase in skin temperature.
• Tissue edema – moderate, localized.
• Limitation of limb mobility – when a large area is involved.

2. Peculiarities of course in deep thrombophlebitis

If the process spreads to the deep veins, more pronounced manifestations are possible:

• Diffuse edema of the entire limb, often asymmetrical
• Cyanosis or marbling of the skin
• Intense pain in the calf or thigh when walking or pressing (Homans test)
• Feeling of tension and heaviness in the leg
• Deep thrombophlebitis often proceeds without pronounced signs of inflammation of the skin, which distinguishes it from superficial forms.

3. Localization and specificity of symptoms

• Veins of the lower extremities are the most frequent localization. Clinical manifestations are usually classical.
• Upper extremity veins – often associated with catheterization; localized pain and thickening, possible rapid improvement after catheter removal.
• Thoracic and neck veins (e.g., Paget-Schretter syndrome or EPO thrombophlebitis) – accompanied by arm swelling, cyanosis, and tension in the venous network.
• Perianal and penile veins – possible in specific inflammatory conditions such as Behçet’s disease or penile vein thrombophlebitis.

4. Complications

• Spread of thrombus into deep veins – increasing swelling, increasing pain, disappearance of clear localization of symptoms
• Pulmonary embolism (TELA) – sudden shortness of breath, tachycardia, chest pain, syncope
• Septic thrombophlebitis – fever, chills, purulent discharge from catheter site, signs of systemic infection

Diagnosis of thrombophlebitis

Examination (see under “Clinical manifestations”).

Duplex ultrasound vein scanning is the “gold standard” of diagnosis. It evaluates:

• Presence of thrombus in the vein lumen (echopositive mass);
• Loss of compression (vein does not contract when pressure is applied with the transducer);
• Absence or impairment of venous blood flow on Doppler;
• Thickness and hyperechogenicity of the vein wall;
• Spread of thrombus to deep veins or joints (sapheno-femoral, sapheno-femoral).

CT venography or MR venography is used in complicated or atypical cases:

• Thrombophlebitis of the pelvis, neck, chest;
• Suspicion of thrombosis not confirmed by ultrasound;
• Compression of veins from outside (tumors, lymph nodes).

Laboratory tests

• There may be an increase in leukocytes, COE and C-reactive protein.
• D-dimer may be moderately elevated, especially when deep veins are involved.

Important: a normal D-dimer does not rule out thrombophlebitis, but an elevated D-dimer is a reason to rule out DVT and TELA.

• Coagulogram (ACTH, PTV, INR).
• Biochemical blood analysis (Creatinine – before administration of low molecular weight heparins and fondaparinux; Liver tests – in case of long-term anticoagulant therapy).
• Тромбофилический скрининг проводится при: 
  • Recurrent thrombophlebitis with no obvious cause;
  • Family history of thrombotic complications;
  • Thrombosis in atypical localization (neck, upper extremities, brain);
  • Investigated: Protein C and S; Antithrombin III; Mutations: factor V Leiden, prothrombin G20210A; Antiphospholipid antibodies (antibodies to β2-glycoprotein, cardiolipin, lupus anticoagulant).

Treatment of thrombophlebitis

Risk factor modification

• Smoking cessation;
• Weight control.
• Physical Activity;
• Avoiding prolonged standing/sitting;
• Control of diabetes mellitus, hyperlipidemia and blood pressure;
• Compression knitwear (class II) – especially for varicose veins, after an acute episode.

Drug therapy

Anticoagulant therapy is used not only for deep venous thrombosis, but also for superficial venous thrombophlebitis if it has high-risk features or has a complicated course.

Indications:

• Thrombus length ≥5 cm;
• Location closer than 3 cm to the sapheno-femoral or sapheno-subclavian joint;
• Severe pain and inflammation;
• DVT/TELA risk factors (oncology, recent surgery, pregnancy, thrombophilia).

Recommended medications:

• Fondaparinux 2.5 mg/day subcutaneously – for 45 days;
• Low molecular weight heparins (e.g. enoxaparin);
• Rivaroxaban is off-label but is acceptable when injections are not possible.

NSAIDs (non-steroidal anti-inflammatory drugs) are prescribed for all patients with acute inflammation, especially for pain and swelling.

• Ibuprofen, Nimesulide, Meloxicam, Ketoprofen;
• Duration – 7-10 days (until the regression of inflammation).

Antibiotics are prescribed only if infectious (septic) thrombophlebitis is suspected.

• Antibiotics of choice: amoxicillin/clavulanate, cefazolin, ceftriaxone. For MRSA, vancomycin, linezolid.

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Surgical treatment

Indications:

• The spread of the thrombus to the mouth of the saphenous vein;
• High risk of thromboembolism and inability to anticoagulate;
• Septic thrombophlebitis;
• Ineffectiveness of drug treatment;
• Repeated episodes against the background of varicose veins.

Methods:

• Ligation of the affected vein (more often – the orifice of the BPV);
• Thrombectomy – rarely, in case of ineffectiveness of other therapy;
• Combined venectomy (removal of varicose veins) – is performed after the acute process has subsided.