Thrombophlebitis: Etiology, Pathogenesis, Classification, Diagnosis, Treatment

Thrombophlebitis is an inflammation of a venous wall accompanied by a blood clot. Superficial veins of the lower limbs are most commonly affected.

• Patients aged 60 to 70 are more susceptible to the disease.
• Moreover, thrombophlebitis is more prevalent among females, particularly in those with varicose veins.

Etiology

Thrombophlebitis develops as a result of multiple factors collectively referred to as Virchow’s triad.

1. Damage to the venous wall — a key trigger of the inflammatory and prothrombotic process — may occur under the following circumstances:

• Catheterization and injections (especially in arm veins): a common cause of iatrogenic thrombophlebitis;
• Surgical procedures (such as open leg surgeries, venectomy, or bypass surgery);
• Soft tissue trauma, including contusions, burns, and venipunctures;
• Skin and soft tissue infections, resulting in septic thrombophlebitis, frequently associated with cellulitis, abscesses, or erysipelas.

2. Venous Stasis and Impaired Outflow

• Varicose veins of the lower limbs — the most common concomitant disease associated with superficial thrombophlebitis;
• Immobilization — including bed rest, prolonged air travel, and plaster casts;
• Cardiac failure — especially in decompensated cases;
• Obesity — a contributing factor to reduced venous return and blood congestion in the lower limbs;
• Pregnancy and the postpartum period — due to pelvic vein compression and hormonal changes.

3. Hypercoagulability (increased blood clotting)

• Malignancies
• Thrombophilias, including antithrombin III deficiency, protein C and S deficiencies, factor V Leiden, and antiphospholipid syndrome;
• Hormonal therapy — estrogen use (oral contraceptives, hormone replacement therapy);
• Systemic inflammatory and autoimmune diseases — including systemic lupus erythematosus and inflammatory vasculitis;
• COVID-19 — a known cause of transient hypercoagulability and thrombosis, including in the superficial veins.

Pathogenesis

Damage to Endothelial Lining of Venous Wall

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

Coagulation Cascade Activation

Following intimal injury and tissue factor activation, the extrinsic pathway of blood coagulation is initiated:

• Coagulation factors VIIa and X are activated;
• Prothrombin is converted to thrombin;
• Fibrin is produced, stabilizing the clot;
• Simultaneously, platelets aggregate to form a “white” platelet matrix — particularly in areas of turbulent blood flow.

A local decrease in blood flow velocity promotes and sustains site-specific thrombogenesis. This process is facilitated by several mechanisms:

• Enhanced contact interaction between formed elements of blood and the vascular wall;
• Elevated concentration of procoagulants in the affected area;
• Reduced washout of thrombogenic molecules.

Inflammatory infiltration of venous wall (sterile inflammation):

• Migration of neutrophils and monocytes;
• Secretion of matrix metalloproteinases, which promote intimal destruction;
• Production of IL-6, IL-8, and other proinflammatory mediators;
• Fibrosis and thickening of the venous wall in chronic stages;
• In cases of secondary infection, the process may become purulent, resulting in septic thrombophlebitis.

Thrombus Organization or Embolization

Further progression may follow one of two scenarios:

• Organization — the thrombus becomes infiltrated by fibroblasts, covered by endothelium, and transforms into a fibrous, scar-like strand. This leads to obliteration of the venous lumen, and the process becomes chronic.
• Embolization — if the thrombus is unstable and extends into the deep venous system, it may fragment and migrate, resulting in thromboembolism.

NOTE: Although thrombophlebitis is often confined to subcutaneous veins and considered “clinically insignificant”, when a vein adjacent to the saphenofemoral or saphenopopliteal junction is involved, the disease may progress into the deep venous system. Therefore, even a “superficial” inflammation should be regarded as a potential risk for thromboembolism.

Thrombophlebitis Classification

Location:

• Superficial thrombophlebitis: Involvement of the subcutaneous veins, most commonly the great saphenous vein of the lower limb.
• Deep thrombophlebitis: Involvement of the deep veins, associated with an increased risk of thromboembolism.

Clinical course:

• Acute: Sudden onset with pronounced symptoms.
• Chronic: Prolonged course with intermittent exacerbations.

Presence of infection:

• Aseptic: No associated infection.
• Septic: Accompanied by infection.

Clinical Manifestations

Clinical manifestations of thrombophlebitis depend on the anatomical location, extent of inflammation, depth of the affected veins, and associated complications. Acute superficial thrombophlebitis of the saphenous veins in the lower limbs has the most typical presentation, although symptoms may vary.

1. Common Symptoms of Acute Thrombophlebitis

• Pain along the affected vein — dull or burning in nature, intensified upon palpation or movement.
• Induration along the vein — palpable as a firm, tender, immobile strand.
• Skin redness — over the site of inflammation, often linear and following the course of the vein.
• Localized elevation in skin temperature.
• Tissue swelling — mild and localized.
• Limited limb mobility — typically observed when a large segment of the vein is involved.

2. Clinical Features of Deep Thrombophlebitis

When inflammation affects the deep veins, more pronounced symptoms may occur:

• Diffuse swelling of the entire limb, often asymmetrical;
• Cyanosis or mottled skin;
• Intense pain in the calf or thigh during walking or upon compression (Homan’s sign);
• Sensation of tension and heaviness in the affected limb.
• Unlike the superficial forms of the disease, deep thrombophlebitis often presents without prominent signs of cutaneous inflammation.

3. Location and Symptom Characteristics:

• Lower limb veins — the most common site. Typical clinical manifestations are observed.
• Upper limb veins — often associated with catheterization; characterized by localized pain and induration, with symptoms typically resolving rapidly following catheter removal.
• Thoracic and cervical veins (e.g., Paget — Schroetter syndrome or superior vena cava thrombophlebitis) — accompanied by arm swelling, cyanosis, and engorgement of the venous network.
• Perianal and genital veins — possibly involved in specific inflammation such as Behçet disease or penile vein thrombophlebitis.

4. Complications

• Once a blood clot affects deep veins, patients may experience progressive edema, intensified pain, and poorly localized symptoms.
• Pulmonary embolism (PE) is associated with sudden onset of dyspnea, tachycardia, chest pain, and syncope.
• Septic thrombophlebitis presents with fever, chills, purulent discharge from the catheter site, and signs of systemic inflammation.

Diagnosis of Thrombophlebitis

Physical examination (see Clinical Manifestations).

Venous duplex ultrasound is the gold standard for diagnosis. It helps assess:

• Presence of a blood clot within the vein lumen (echogenic structure);
• Loss of venous compressibility (a vein fails to collapse under probe pressure);
• Absence or disturbance of venous blood flow on Doppler imaging;
• Increased wall thickness and hyperechogenicity of the vein;
• Thrombus extension into deep veins or venous junctions (e.g., saphenofemoral, saphenopopliteal).

CT angiography or MR angiography is utilized in complex or atypical cases, including:

• Thrombophlebitis involving the pelvis, neck, or thorax;
• Suspected thrombosis not confirmed by ultrasound;
• Extrinsic compression of veins (e.g., by tumors or lymph nodes).

Laboratory tests

• Possible elevation in leukocytes, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).
• D-dimer levels may be moderately increased, particularly when deep veins are involved.

Note: A normal D-dimer level does not rule out thrombophlebitis; however, elevated results warrant further evaluation to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).

• Coagulation panel (activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR)).
• Blood tests (creatinine — prior to initiating low-molecular-weight heparins or fondaparinux; liver function tests — necessary in cases of long-term anticoagulant therapy.
• Thrombophilia screening is indicated in cases of:
  • Recurrent thrombophlebitis of unclear etiology;
  • Family history of thrombotic complications;
  • Thrombosis in atypical locations (e.g., neck, upper limbs, brain);
  • Tests include: Protein C and S; antithrombin III; genetic mutations: Factor V Leiden, prothrombin G20210A; antiphospholipid antibodies (anti-β2 glycoprotein I, anticardiolipin antibodies, lupus anticoagulant).

Treatment of Thrombophlebitis

Risk Factor Modification

• Smoking cessation;
• Bodyweight management;
• Physical activity;
• Avoidance of prolonged standing and sitting;
• Management of diabetes mellitus, hyperlipidemia, and hypertension;
• Compression stockings (class II) — particularly in cases of varicose veins, following an acute phase.

Medical Therapy

Anticoagulant therapy is indicated not only for DVT, but also for superficial vein thrombophlebitis when associated with high-risk features or complicated progression.

Indications:

• Thrombus length ≥ 5 cm;
• Proximity within 3 cm of the saphenofemoral or saphenopopliteal junction;
• Severe pain and inflammation;
• Risk factors for DVT/PE (e.g., malignancy, recent surgery, pregnancy, thrombophilia).

Recommended medications:

• Fondaparinux, 2.5 mg/day, subcutaneously — for 45 days;
• Low-molecular-weight heparins (e.g., enoxaparin);
• Rivaroxaban — used off-label; permissible when injections are contraindicated.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed for all patients with acute inflammation, especially in the presence of pain and swelling.

• Ibuprofen, nimesulide, meloxicam, ketoprofen;
• Duration: 7–10 days, or until inflammation regresses.

Antibiotic therapy is prescribed only when infectious (septic) thrombophlebitis is suspected.

• First-line agents: amoxicillin/clavulanate, cefazolin, ceftriaxone. For MRSA — vancomycin, linezolid.

Find more scientifically accurate content on our social media

Subscribe and don’t miss out the latest resources

Surgical treatment

Indications:

• Thrombus extension to the saphenous vein junction;
• High risk of thromboembolism accompanied by contraindications to anticoagulation therapy;
• Septic thrombophlebitis;
• Ineffective medical therapy;
• Recurrent episodes associated with varicose vein disease.

Methods:

• Ligation of the affected vein (typically performed at the junction of the great saphenous vein);
• Thrombectomy — rarely indicated; reserved for cases unresponsive to other therapies;
• Combined phlebectomy (removal of varicose veins) — carried out following resolution of the acute phase.