Pulmonary Embolism: Causes

Pathogenesis (development of disease)

Approximately 80-90% of thrombi in the pulmonary arteries originate from deep vein thrombosis (TBVT) and 10-20% from thrombosis of the iliac, axillary, jugular veins or from the right heart. If a thrombus (blood clot) detaches from its association, it closes via the heart into a pulmonary artery and then relocates a corresponding caliber (= thromboembolism; main cause of pulmonary embolism). Other forms of LE are: septic embolism, bone marrow embolism, fat embolism, air embolism, tumor embolism, and embolism with foreign material. For the development of thrombus, see “Thrombosis/Causes/Virchow Triad.”

Etiology (Causes)

Biographic 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).
  • Blood type – blood type A, B or AB (relative risk of deep vein thrombosis and pulmonary embolism is increased by almost double compared to 0-blood group carriers (incidence rate ratio, IRR: 1.92 and 1.80, respectively)).
  • Age – the older the age, the higher the risk; exponential increase starting at age 50; maximum between ages 60 and 70

Behavioral causes

  • Nutrition
    • Inadequate fluid intake – leads to desiccosis (dehydration) and thus increases thrombophilia (tendency to thrombosis)
  • Consumption of stimulants
    • Tobacco (smoking)
  • Physical activity
    • Frequent prolonged sitting or immobility (bedriddenness).
    • Prolonged sitting in front of the TV – ≥ 5 h/d in front of the TV: twice the risk of developing a fatal pulmonary embolism than people who watch < 2.5 h of TV
    • Long-haul flights (“economy-class syndrome”).
  • Overweight (BMI ≥ 25; obesity) – overweight from a BMI (body mass index) > 30 – risk increase of 230% due to increase in clotting and inhibition of fibrinolysis – inhibition of the dissolution of blood clots.

Disease-related causes

  • Antiphospholipid syndrome (APS; antiphospholipid antibody syndrome) – autoimmune disease; it predominantly affects women (gynecotropia); characterized by the following triad:
    • Venous thrombosis (blood clot (thrombus) and/ or arterial thrombosis.
    • Thrombocytopenia (lack of platelets (thrombocytes) in the blood).
    • Recurrent spontaneous abortions (occurrence of three or more consecutive spontaneous abortions before 20 weeks’ gestation/pregnancy).
  • Arterial hypertension (high blood pressure).
  • Leg vein thrombosis
  • Chronic obstructive pulmonary disease (COPD)
  • Factor V Leiden mutation (APC resistance).
  • Factor II mutation
  • Heart failure (weakness)
  • Immobility
  • Infections
    • Respiratory infections: Patients had a 3.2-fold increased risk of venous thromboembolism (VTE) in the 7-day window
    • Skin infections: Patients had a 5.4-fold increased risk of VTE in the 7-day window
  • Metabolic syndrome – clinical name for the symptom combination of obesity (overweight), hypertension (high blood pressure), elevated fasting glucose (fasting blood sugar) and fasting insulin serum levels (insulin resistance), and dyslipidemia (elevated VLDL triglycerides, lowered HDL cholesterol). Furthermore, a coagulation disorder (increased tendency to clotting), with an increased risk of thromboembolism can often be detected.
  • Thrombophilia (thrombosis tendency).
  • Trauma (injury):
    • Fractures (broken bones) of long bones or severe injuries to the extremities (significantly higher incidence of early pulmonary embolism)
    • Patients with polytrauma, severe traumatic brain injury, spinal cord injury, and blood transfusion (significantly higher incidence of late pulmonary embolism)
    • One in five pulmonary emboli was on day 1
  • Tumor disease – known or occult malignancy: 4 times the risk of venous thromboembolism (VTE) compared with the general population
    • Absolute: patients with lung, colon, and prostate cancer.
    • Relative: plasmacytoma (multiple myeloma) – 46 times higher compared with healthy people of the same age, brain (20 times) and pancreatic (pancreas) tumors (16 times)

    Malignant hematologic systemic diseases (malignancies affecting the blood (-forming) system): 28-fold increased risk compared to the study population without cancer.

Laboratory diagnoses – laboratory parameters considered independent risk factors.

  • Antiphospholipid antibodies
  • Antithrombin III deficiency
  • Disseminated intravascular coagulopathy
  • Dysfibrinogenemia
  • Iron status, higher – Results of a Mendelian randomization study: higher genetic iron status was associated with an increased risk of venous thromboembolism. Odds ratios per SD increase in biomarker levels were 1.37 (95% CI 1.14-1.66) for serum iron, 1.25 (1.09-1.43) for transferrin saturation, 1.92 (1.28-2.88) for ferritin, and 0.76 (0.63-0.92) for serum transferrin (with higher transferrin levels representing lower iron status); in contrast, higher serum iron and transferrin saturation levels (iron supersaturation) had a protective effect against carotid plaques.
  • Factor V Leiden mutation – so-called APC resistance.
  • Factor II mutation (prothrombin mutation)
  • Factor VIII (antihemophilic globulin A)
  • Hyperhomocysteinemia – increased concentration of the amino acid homocysteine in the blood.
  • Hypercoagulability – increased coagulability of the blood.
  • Protein C and protein S deficiency

Medication

Operations

  • Especially in the area of the pelvis and hip.
  • Bes. Knee or hip replacement
  • Surgery duration poses is an independent risk factor for the occurrence of venous thromboembolism (VTE).

Other causes

  • Blood transfusions during surgery-0.6% as deep vein thrombosis and 0.3% as pulmonary embolism; 2.1-fold increased risk of venous thromboembolism (VTE); risk increased to 4.5-fold with ≥ 3 blood transfusions
  • Hospitalization for heart failure (cardiac insufficiency), myocardial infarction (heart attack), atrial fibrillation/flutter, history of venous thromboembolism (VTE)
  • Pregnancy and puerperium:
    • Increased risk of venous thromboembolism (VTE); 1.2 per 1,000 pregnancies on (95% confidence interval [95% CI] 0.6-1.8).