Thrombophilia and Hypercoagulable States

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  • An inherited or acquired disorder of the coagulation system predisposing an individual to thromboembolism (the formation of a venous, or less commonly, an arterial blood clot)
  • Venous thrombosis typically manifests as deep venous thrombosis (DVT) of the lower extremity in the legs or pelvis and pulmonary embolism (PE).
  • System(s) affected: cardiovascular, nervous, pulmonary, reproductive, hematologic
  • Synonym(s): hypercoagulation syndrome; prothrombotic state


  • An inherited thrombophilic defect or risk can be detected in up to 50% of patients with venous thromboembolism (VTE).
  • Factor V Leiden is the most common inherited thrombophilia (1/2 of all currently characterizable inherited thrombophilia cases involve the factor V Leiden mutation), and it is present in its heterozygous form in up to ~20% of patients with a first VTE.
  • Heterozygous prothrombin G20210A mutation, the second most common inherited thrombophilia, is present in up to ~8% of patients with VTE.
  • Overall VTE incidence higher in African American populations and lower in Asian, Asian American, and Native American populations (1)
  • VTE rates are higher in women during childbearing years (16 to 44 years), then higher in men when >45 years of age (1).


First-time thromboembolism

  • ~100/100,000/year among the general population
  • <1/100,000/year in those age <15 years
  • ~1,000/100,000/year in those age ≥85 years
  • 40–80% of lower extremity orthopedic procedures can result in DVT if prophylaxis is not used.
  • VTE accounts for ~1.2 to 4.7 deaths per 100,000 pregnancies.

Etiology and Pathophysiology

  • Virchow triad as a cause of VTE includes blood stasis, vascular endothelial injury, and abnormalities in circulating blood constituents (i.e., hypercoagulability).
  • An imbalance between the hemostatic and fibrinolytic pathways leads to thrombus formation.
  • VTE is considered to be the result of genetic tendencies with other acquired risks.
  • Upper extremity DVT: >60% are associated with venous catheters. Malignancy is an additional significant risk (2).

  • The most common genetic thrombophilias (factor V Leiden, prothrombin G20210A, proteins C and S defects, and antithrombin III deficiency) are inherited in an autosomal dominant pattern.
  • Homozygous mutations generally have a higher risk of VTE.
  • Factor V Leiden/activated protein C (aPC) resistance is the most common inherited thrombophilia.
    • 2–5% prevalence among Caucasians; rare in African Americans or Asians
    • aPC does not cleave factor Va, so thrombin formation continues.
    • Other acquired risks are synergistic (3).
  • Prothrombin gene mutation G20210A: prevalence 6% among Caucasians. Heterozygous carriers have increased risk of thrombosis.
  • Hyperhomocysteinemia: 5–6% among the general population; increases risk of coronary artery disease/myocardial infarction, cerebrovascular accident, and DVT/PE; acquired in those with folate, vitamin B12, and vitamin B6 deficiencies
  • Antithrombin deficiency: <0.2% among the general population; produced in the liver; acquired deficiency in disseminated intravascular coagulation (DIC), sepsis, liver disease, nephrotic syndrome; RR of 8.1 for thrombosis
  • Protein C and S deficiencies: 0.5% and 1% incidences, respectively, among the general population. Homozygotes and heterozygotes are hypercoagulable. Vitamin K–dependent, produced in the liver. Protein C inactivates Va and VIIIa. Protein C may become an acquired deficiency in liver disease, sepsis, DIC, acute respiratory distress syndrome, and after surgery. RR of 7.3 for thrombosis. Protein S is a cofactor for protein C, and it may become an acquired deficiency with oral contraceptive pill (OCP) use, pregnancy, liver disease, sepsis, DIC, HIV, and nephrosis; RR of 8.5 for thrombosis

Risk Factors

  • Acquired risk factors
    • Immobilization or prolonged travel
    • Trauma
    • Surgery, especially orthopedic
    • Malignancies (especially pancreatic, ovarian, brain, and lymphoma)
    • Pregnancy
    • Acute medical illness
    • Exogenous female hormones/oral contraceptives
    • Obesity
    • Nephrotic syndrome
    • Antiphospholipid syndrome (APS) and lupus anticoagulant
    • Myeloproliferative disorders (polycythemia vera, essential thrombocythemia)
    • Hyperviscosity syndromes (sickle cell, paraproteinemias)
    • Hyperhomocysteinemia secondary to vitamin deficiencies (B6, B12, folic acid)
    • Tamoxifen, thalidomide, lenalidomide, bevacizumab, L-asparaginase, erythropoiesis-stimulating agents
    • Previous thromboembolism
  • Established genetic factors
    • Factor V Leiden
    • Prothrombin G20210A mutation
    • Protein C deficiency
    • Protein S deficiency
    • Antithrombin III deficiency
  • Rare genetic factors
    • Dysfibrinogenemia
    • Hyperhomocysteinemia (methylene tetrahydrofolate reductase mutation)
  • Indeterminate factors
    • Elevated factor VIII
  • Age: >60 years
  • Sex: male
  • Race: See “Epidemiology.”

General Prevention

  • Consider medication prophylaxis in any hospitalized patient with VTE risk factors; hospitalized patients should be encouraged to ambulate as soon as possible (4)[A].
  • Consider mechanical prophylaxis in patients at increased risk for VTE in whom anticoagulation may be contraindicated (4)[A].
  • Consider prophylaxis with low-molecular-weight heparin (LMWH) plus aspirin in pregnant patients with APS or other thrombophilia.
  • Consider prophylaxis using LMWH in patients with solid tumors who have additional risk factors for VTE.
  • Prophylaxis with unfractionated heparin (UFH) or LMWH should be considered in patients with genetic or acquired risks of thrombosis and an anticipated additional risk, such as the immobilization associated with surgery.
  • Use caution with procoagulant medicines (e.g., OCPs) in asymptomatic individuals who have a known hereditary predisposition.

Commonly Associated Conditions

Advanced age, cancer, pregnancy, obesity, prior history of thrombosis, surgery, immobilization

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