Thrombosis: Causes

Pathogenesis (development of disease)

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

Venous thrombosis usually occurs in the legs (deep vein thrombosis, TBVT), less commonly in the arms (arm vein thrombosis). Venous thrombosis in the upper extremities (TVT-OE) has increased in recent years. The probable cause is the increased placement of central venous catheters (CVCs) and pacemakers. More than half of patients with DVT-OE have a “foreign body in the vascular system.” Other risk factors include age 40 years or older and tumor disease. Note: Thromboses in the arterial and venous pathways also appear to have common pathologies. Some risk factors for cardiovascular disease, namely older age, smoking, and obesity, are also risk factors for venous thromboembolism (VTE).

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 from age 50 onward.
  • Height – risk of venous thromboembolism increases with height: in men who were <1.60 meters, the risk decreased by about 65 percent compared with men >1.90 meters
  • Hormonal factors – pregnancy and puerperium.

Behavioral causes

  • Nutrition
    • Insufficient fluid intake – causes the body to dry out (desiccosis) and increases the tendency to clot.
    • Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
  • Consumption of stimulants
    • Tobacco (smoking)
  • Drug use
    • Cocaine
  • Physical activity
    • Postpartum
    • Frequent, prolonged sitting; “travel thrombosis” at a desk.
    • Long-haul flights (flight travel time > 6 hrs; “economy-class syndrome”).
    • Immobility
  • Overweight (BMI ≥ 25; obesity) – obesity from a BMI (body mass index) > 30 – 230% increase in risk 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 and/or arterial thrombosis (blood clot (thrombus) in a blood vessel).
    • Thrombocytopenia (lack of platelets (thrombocytes) in the blood).
    • Recurrent spontaneous abortions (occurrence of three or more consecutive spontaneous abortions before 20 weeks’ gestation/pregnancy).
  • Atherosclerosis (arteriosclerosis, hardening of the arteries).
  • Chronic heart failure (cardiac insufficiency)
  • Ulcerative colitis – chronic inflammatory disease of the mucous membrane of the colon (large intestine) or rectum (rectum); the affection is usually continuous and originates from the rectum
  • Cushing’s syndrome – group of disorders leading to hypercortisolism (hypercortisolism; excess of cortisol).
  • Diabetes mellitus
  • Increased blood viscosity:
    • Exsiccosis (see below nutrition).
    • Polyglobulia (multiplication of erythrocytes, i.e. red blood cells in the blood).
    • Thrombocytosis (multiplication of platelets / blood platelets).
  • Diseases associated with thrombocythemia (disease of the bone marrow characterized by a marked increase in the number of platelets (thrombocytes) in the blood) or platelet dysfunction.
  • Hemolytic uremic syndrome (HUS) – triad of microangiopathic hemolytic anemia (MAHA; form of anemia in which erythrocytes (red blood cells) are destroyed), thrombocytopenia (abnormal decrease in platelets/platelets), and acute kidney injury (AKI); Mostly occurring in children in the context of infections; most common cause of acute renal failure requiring dialysis in childhood.
  • Heart failure (cardiac insufficiency)
  • Infections
  • Metabolic syndrome – clinical name for the symptom combination 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.
  • Behçet’s disease (synonym: Adamantiades-Behçet’s disease; Behçet’s disease; Behçet’s aphthae) – multisystem disease from the rheumatic form circle, which is associated with a recurrent, chronic vasculitis (vascular inflammation) of the small and large arteries and mucosal inflammation; The triad (the occurrence of three symptoms) of aphthae (painful, erosive mucosal lesions) in the mouth and aphthous genital ulcers (ulcers in the genital region), as well as uveitis (inflammation of the middle eye skin, which consists of the choroid (choroid), the corpus ciliary (corpus ciliare) and the iris) is stated as typical for the disease; a defect in cellular immunity is suspected
  • Crohn’s disease – chronic inflammatory bowel disease; it usually progresses in relapses and can affect the entire digestive tract; characteristic is the segmental affection of the intestinal mucosa (intestinal mucosa), that is, several intestinal segments may be affected, which are separated by healthy sections from each other
  • Myeloproliferative neoplasms (MPN) (formerly chronic myeloproliferative disorders (CMPE))
    • Chronic myeloid leukemia (CML).
    • Essential thrombocythemia (ET) – chronic myeloproliferative disorder (CMPE, CMPN) characterized by chronic elevation of plateletsOsteomyelofibrosis (OMF; synonym:
    • Osteomyelosclerosis, PMS) – myeloproliferative syndrome; represents a progressive disease of the bone marrow.
    • Polycythaemia vera (PV, also called polycythemia or polycythemia) – rare myeloproliferative disorder in which all cells in the blood multiply excessively (particularly affected are erythrocytes (red blood cells), and to a lesser extent platelets (thrombocytes) and leukocytes – white blood cells).
  • Postthrombotic syndrome – chronic venous congestion affecting the lower extremity as a result of deep vein thrombosis.
  • Systemic lupus erythematosus (SLE) – group of autoimmune diseases in which the formation of autoantibodies occurs.
  • Thrombangiitis obliterans (synonyms: endarteritis obliterans, Winiwarter-Buerger disease, Von Winiwarter-Buerger disease, thrombangitis obliterans) – vasculitis (vascular disease) associated with recurrent (recurring) arterial and venous thrombosis (blood clot (thrombus) in a blood vessel); symptoms: Exercise-induced pain, acrocyanosis (blue discoloration of the body appendages), and trophic disorders (necrosis/tissue damage resulting from the death of cells and gangrene of the fingers and toes in advanced stages).
  • Thrombophilias (tendency to thrombosis), acquired:
  • Tumor diseases (cancer; known or occult malignancy (occult malignancy: rather very rare); thrombosis in up to 30% of cases).
  • Varices (varicose veins)
  • Inferior vena cava syndrome – occurs during pregnancy when (especially in the supine position) the uterus (womb) presses on the inferior vena cava (inferior vena cava).Symptoms: shock symptoms such as pallor, sweating, and shortness of breath
  • Condition after myocardial infarction (heart attack).
  • Condition after deep vein thrombosis (TVP) or pulmonary embolism (LE).

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

  • Antiphospholipid antibodies
  • Antithrombin III deficiency
  • Disseminated intravascular coagulopathy
  • Dysfibrinogenemia
  • 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.
  • Hyperprolactinemia – in men taking antipsychotics.
  • Protein C and protein S deficiency

Medication

Operations

  • Surgeries (especially after major orthopedic or urologic surgery) – the duration of surgery represents an independent risk factor for the occurrence of venous thromboembolism (VTE)
  • Fracture-op distal to the knee/bone fracture surgery below the knee (patella/patella, tibia/tibia, ankle, or foot) with venous thromboembolism (VTE): incidence rate (incidence of new cases) was 7.28 events per 100 person-years before discharge, decreasing to a stable level below one event per 100 person-years at week 13 to 14 after discharge. Use of oral contraceptives (birth control pills) by patients aged 18 to 50 years (hazard ratio [HR] = 5.23, 95% confidence interval [CI] = 3.35 to 8.18), prior DVT (HR = 6.27, 95% CI = 4.18-9.40), prior LE (HR = 5.45, 95% CI = 3.05-9.74), coagulopathy (HR = 2.47, 95% CI = 1.07-5.72), and peripheral arterial disease (paVK) (HR = 2.34, 95% CI = 1.20-4.56) were the factors associated with the highest risk of postoperative DVT/PE. The study involved 57,619 patients.

Other causes

  • Bed confinement, e.g., after surgery (e.g., cesarean section) or severe illness (e.g., paralyzed extremities from stroke or paraplegia)
  • 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); with ≥ 3 blood transfusions, risk increased to 4.5-fold
  • “Foreign bodies in the vascular system” (venous catheters (CVCs), pacemakers) → venous thrombosis in the upper extremities (DVT-OE).
  • Mobility restriction (insb. in old age).
  • Plaster cast
  • Pregnancy – from the first weeks of pregnancy to about six weeks postpartum (after delivery), thromboembolism, that is, deep vein thrombosis (DVT) and pulmonary embolism (LE) or cerebral thrombosis, is up to ten times more common than outside this time period; in weeks 7 to 12, the risk of thrombosis is still increased by a factor of 2.2
  • Trauma (injury):
    • Head 54 %
    • Pelvic fractures (pelvic fractures) 61 %.
    • Tibia fractures (fractures of the tibia) 77%.
    • Femur fractures (fractures of the femur) 80%.