Superficial Phlebitis (Thrombophlebitis): Causes

Pathogenesis (development of disease)

Thrombophlebitis is a phlebitis (inflammation of the veins) of superficial veins that leads to thrombosis (occlusion of the vein) (= superficial venous thrombosis, OVT).

There are three factors that can contribute to the development of a thrombus (Virchow’s triad)

• Endothelial changes (vessel wall changes) such as those caused by atherosclerosis (hardening of the arteries), inflammation, trauma (injury), or surgery (especially after major orthopedic or urologic surgery)
• Reduced flow velocity of the blood such as after immobilization (bed rest, plaster), by local outflow obstructions (long sitting, tumors, etc.) and in diseases such as varices (varicose veins), post-thrombotic syndrome (PTS) or heart failure (heart failure).
• Changes in blood composition (hypercoagulability/increased blood clottability):
  • Hereditary thrombophilias (“congenital predisposition to thrombosis“; see biographical causes/genetic burden below).
  • Acquired thrombophilias (see below diseases).
  • Increased blood viscosity (viscosity of the blood; see diseases below).

Etiology (causes)

Biographical causes

• Genetic burden
  • Genetic risk depending on gene polymorphisms:
    • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
      • Genes: F2, F5, LPL, SELE.
      • SNP: rs6025 (factor V Leiden) in the F5 gene.
        • Allele constellation: AG (5-10 fold).
        • Allele constellation: AA (50-100-fold)
      • SNP: rs1799963 (prothrombin mutation (factor II mutation) in gene F2.
        • Allele constellation: AG (5.0-fold).
        • Allele constellation: AA (> 5.0-fold)
      • SNP: rs5361 in the gene SELE
        • Allele constellation: CC (4.0-fold).

        SNP: rs268 in the gene LPL

        • Allele constellation: AG (3.0-fold).
        • Allele constellation: GG (> 3.0-fold)
  • Genetic diseases
    • Antithrombin III deficiency (AT-III) – autosomal dominant inheritance.
    • APC resistance (factor V Leiden) – autosomal dominant inheritance (very common).
    • Factor VIII (antihemophilic globulin A); – autosomal recessive inheritance.
    • Hyperhomocysteinemia – prevalence for carriers of the homozygous MTHFR mutation (methylenetetrahydrofolate reductase (MTHFR) deficiency) is 12-15% in the normal population, and up to 25% in patients with deep vein thrombosis. The proportion of heterozygous carriers may be as high as 50%. (very common)
    • Prothrombin mutation (factor II mutation) – autosomal dominant inheritance (very common).
    • Protein C deficiency – autosomal dominant inheritance.
    • Protein S deficiency – usually with autosomal dominant inheritance; caused by mutations in the PROS1 gene.
    • Sickle cell anemia (med.: drepanocytosis; also sickle cell anemia, sickle cell anemia) – genetic disease with autosomal recessive inheritance affecting erythrocytes (red blood cells); it belongs to the group of hemoglobinopathies (disorders of hemoglobin; formation of an irregular hemoglobin called sickle cell hemoglobin, HbS).
• Age – older age (> 60 years).

Behavioral causes

• Consumption of stimulants
  • Tobacco (smoking)
• Obesity (overweight)

Disease-related causes

Blood, blood-forming organs – immune system (D50-D90).

• Thrombophilia (tendency to thrombosis) – e.g., heterozygous factor V mutation (65%), protein C deficiency (15%), protein S deficiency (10%), hyperhomocysteinemia (10%), antiphospholipid antibodies (5%).

Cardiovascular System (I00-I99).

• Asymptomatic pulmonary embolism (2-13%; confirmed by systematic lung scans).
• May occur associated with deep vein thrombosis (DVT; predominantly distal; 6-36%)
• Mondor’s disease (synonyms: Mondor’s disease; iron wire phlebitis, phlebitis Mondor) – thrombophlebitis of the thoracoepigastric veins or their branches on the front of the thorax (chest). This may also involve the mammae (breasts).
• Thrombangiitis obliterans (synonyms: endarteritis obliterans, Winiwarter-Buerger disease, Von Winiwarter-Buerger disease, thrombangitis obliterans) – vasculitis (vascular disease) associated with recurrent (recurring) arterial and venous thromboses (blood clots (thrombus) in a blood vessel); symptoms: Exercise-induced pain, acrocyanosis (blue discoloration of the body appendages), and trophic disturbances (necrosis/tissue damage resulting from the death of cells and gangrene of the fingers and toes in advanced stages).
• Varicosis (varicose veins)

Neoplasms – tumor diseases (C00-D48)

• May occur associated with malignancy (lung, prostate).

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

• Hyperhomocysteinemia – increased concentration of the amino acid homocysteine in the blood.

Medication

• Hormone replacement therapy (HRT)
• Oral contraceptives (birth control pills).

Other causes

• Immobility
• Hospitalization
• Pregnancy and puerperium; risk factors:
  • Maternal age > 35 years
  • Obese patient
  • Multiples
  • Preeclampsia – pregnancy-induced hypertension (high blood pressure) and proteinuria (increased excretion of protein in the urine).
  • Trauma
  • High peripartum blood loss – bleeding that occurs in the mother shortly before, during, or shortly after birth (peripartum).
  • Emergency cesarean section
• Trauma (injuries)
• Vein wall injury (local trauma) and possibly also bacterial infection with inflammation of the vein wall (= secondary thrombus/blood clot) → infusion thrombophlebitis (most common form of OVT in non-varicose veins).
  • Intravenous catheter (indwelling venous cannula).
  • Intravenous infusions of vein-irritating drugs such as potassium or cytostatics (drugs used to treat malignant neoplasms)
• Zust. n. operations