Thrombophilia and Hypercoagulable States



  • 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): hypercoagulable disorder; prothrombotic state


  • VTE incidence is higher in ages 16 to 44 years; then, higher in men when >45 years of age
  • VTE incidence is higher in African American populations.
  • Inherited thrombophilias
    • An inherited thrombophilic defect or risk can be detected in up to 50% of patients with VTE.
    • Factor V Leiden (FVL) is the most common inherited thrombophilia (1/2 of all currently characterizable inherited thrombophilia cases involve the FVL 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.
  • Acquired thrombophilias:
    • Pregnancy: ~1 to 2/1,000 pregnancies affected by VTE
    • Cancer: ~20% of all VTEs occur in setting of active cancer; ~6% of unprovoked VTEs have undiagnosed cancer.
    • Antiphospholipid antibodies are found in ~50% of patients with systemic lupus erythematosus (SLE) and up to 5% of the general population.
    • See “Risk Factors.”

First-time thromboembolism

  • ~100/100,000/year among the general population
  • <1/100,000/year in those aged <15 years; ~1,000/100,000/year in those aged ≥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 venous stasis, vascular endothelial injury, and abnormalities in circulating blood constituents.
  • An imbalance between the hemostatic and fibrinolytic pathways leads to thrombus formation.
  • VTE is considered to be the result of inherited tendencies with other acquired risks.
  • Upper extremity DVT: >60% are associated with venous catheters. Malignancy is an additional significant risk.


  • The most common genetic thrombophilias (FVL, prothrombin G20210A mutation, proteins C and S defects, and antithrombin III deficiency) are inherited in an autosomal dominant pattern.
  • Homozygous mutations have a higher risk of VTE.
  • FVL/activated protein C (aPC) resistance:
    • Heterozygous FVL: 3–8% prevalence in Caucasians; 1.2% in African Americans
    • Heterozygous FVL carries 3- to 5-fold increase risk in first-time VTE; mild increase risk of recurrence
    • Homozygous FVL carries 18-fold increase risk in first-time VTE compared to patients without FVL mutation.
    • Other acquired risks are synergistic.
  • Prothrombin gene mutation G20210A:
    • Prevalence 6% among Caucasians, 2% of general U.S. population, 0.5% of African Americans
    • Heterozygous carriers have 3-fold increased risk in first-time VTE.
  • Antithrombin deficiency: <0.2% among the general population; acquired deficiency in disseminated intravascular coagulation (DIC), sepsis, liver disease, nephrotic syndrome; relative risk (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 Kdependent, 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

  • Previous thromboembolism
  • First-degree relative with VTE (2- to 4-fold increased risk; regardless of relative’s test results)
  • Immobilization or prolonged travel (e.g., flight time >8 hours)
  • Trauma
  • Surgery, especially orthopedic
  • Malignancies (especially pancreatic, ovarian, brain, and lymphoma)
  • Pregnancy (5- to 10-fold increased RR compared to nonpregnant women)
  • Postpartum state (15- to 35-fold increased risk)
  • Acute medical illness: pneumonia, particularly involving SARS-CoV, MERS-CoV, SARS-CoV-2
  • Exogenous female hormones/oral contraceptives
  • Androgen-deprivation therapy
  • Obesity
  • Nephrotic syndrome, hypoalbuminemia
  • APS and lupus anticoagulant
  • Myeloproliferative disorders (polycythemia vera, essential thrombocythemia)
  • Hyperviscosity syndromes (sickle cell, paraproteinemias)
  • Hyperhomocysteinemia secondary to vitamin deficiencies (B6, B12, folic acid) also due to “Whippets”
  • Tamoxifen, thalidomide, lenalidomide, bevacizumab, L-asparaginase, erythropoiesis-stimulating agents, pomalidomide, tranexamic acid
  • Dehydration
  • Inflammatory bowel disease
  • Presence of central venous catheter
  • Heart failure, congenital heart disease
  • Severe liver disease
  • Established genetic factors: FVL; prothrombin G20210A mutation; protein C deficiency; protein S deficiency; antithrombin III deficiency
  • Rare genetic factors: dysfibrinogenemia; methylene tetrahydrofolate reductase mutation
  • Indeterminate factors: elevated factor VIII
  • Age: >65 years

General Prevention

  • Consider medication prophylaxis in any hospitalized patient with VTE risk factors.
  • Consider mechanical prophylaxis in patients at increased risk for VTE in whom anticoagulation may be contraindicated.
  • Consider prophylaxis with low-molecular-weight heparin (LMWH) plus aspirin in pregnant patients with APS.
  • Consider prophylaxis using direct oral anticoagulants (DOACs) 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.

There's more to see -- the rest of this topic is available only to subscribers.