Thrombophilia and Hypercoagulable States

Descriptive text is not available for this image BASICS

DESCRIPTION

  • 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 or pulmonary embolism (PE).
  • Synonym(s): hypercoagulable disorder; prothrombotic state

EPIDEMIOLOGY

  • Venous thromboembolism (VTE) incidence in men versus women changes with age. It is higher in women than men during the ages of 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 40–50% of patients with first idiopathic 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: ~20% of patients with DVT or PE have moderate to high antiphospholipid antibodies before a thrombotic event.
    • See “Risk Factors.”

Incidence

Incidence rate of thrombophilias is 1 in 1,000 in adults each year.

Prevalence

The prevalence of any thrombophilia in a patient with VTE is 38%.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Virchow triad 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 or acquired risks.

Genetics

  • The most common genetic thrombophilias (FVL, prothrombin G20210A, 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 in the United States; it carries a 3- to 8-fold increased risk in VTE.
    • Homozygous FVL: seen in 1/5,000 people carries up to 80-fold increase risk in VTE compared to patients without FVL mutation.
  • 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
  • Protein C and S deficiencies: Incidence is unknown, but believed to be approximately 1/500. 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. 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.

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 (4- to 5-fold increased relative risk [RR] compared to nonpregnant women)
    • Postpartum state (20-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
    • Rare genetic factors: dysfibrinogenemia; methylene tetrahydrofolate reductase mutation
    • Indeterminate factors: elevated factor VIII
    • Age: >65 years
  • Inherited risk factors
    • FVL; prothrombin G20210A mutation; protein C deficiency; protein S deficiency; antithrombin III deficiency

GENERAL PREVENTION

  • Consider medication prophylaxis in any hospitalized patient with VTE risk factors.
  • Consider mechanical prophylaxis in patients at increased risk for VTE whom anticoagulation may be contraindicated.
  • Consider prophylaxis with low–molecular-weight heparin (LMWH) plus aspirin in pregnant patients with APS.
  • Consider anticoagulation prophylaxis in patients with solid tumors who have additional risk factors for VTE per Khorana score.
  • 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.

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