Hereditary thrombophilia is a genetically determined increased risk of venous thrombosis and thromboembolism.

Epidemiology

• Prevalence
  • Inherited thrombophilias detected in 40-50% of venous thromboembolic events in U.S.
  • Rare - ATIII, Protein C, Protein S - 1-5% of population
  • Prothrombin G20210A - 2-6% of population
  • Factor V Leiden - 5-10% of population

Etiologies

• Most common thrombophilias
  • Factor V Leiden
  • Prothrombin G20210A
  • Homocysteinemia

Less Common Thrombophilias

• Protein C deficiency
• Protein S deficiency
• Antithrombin deficiency
• Rare thrombophilias associated with increased clotting factors
• Antiphospholipid syndrome - refer to specific topic in ARUP Consult

Factor V Leiden

• Risk Factors
  • Many patients with recurrent episodes of thrombosis have more than 1 genetic risk factor, such as concomitant factor II (prothrombin) G20210A mutation, protein C deficiency or homocystinemia
• Genetics
  • The factor V Leiden (FVL) mutation is the most common genetic risk factor for thrombosis and accounts for more than 90% of patients with APC resistance
    • Inherited thrombosis due to APC resistance is considered an autosomal dominant disease
    • Patients with increased risk of thrombosis
      • Heterozygote carriers of the FVL polymorphism 5 to 10 fold increased risk
      • Homozygote carriers 50-100 fold increased risk
  • A single point mutation in the factor V gene (at nucleotide position 1,691 - guanine to adenine substitution) predicts the synthesis of factor V molecule with arginine at amino acid residue 506 versus glutamine (wild-type)
  • This R506Q substitution prevents a peptide bond in the coagulation molecule from being cleaved by activated protein C (APC)
  • Additional risk factors
    • Pregnancy
    • Oral contraceptives
    • Immobilization
• Pathophysiology
  • During normal hemostasis, APC limits clot formation by proteolytic inactivation of factor Va and VIIIa
  • Resistance to this activity increases the risk of deep-vein thrombosis
• Clinical Presentation
  • Deep venous thromboses
  • Pulmonary embolus is less common than with other factor deficiencies
  • APC resistance (APC-R) is associated with recurrent miscarriage (loss of 3 or more consecutive pregnancies) in the second trimester of pregnancy
  • In utero stroke

Prothrombin G20210A

• Risk Factors
  • Genetics
    • The only common prothrombin mutation is a G-to-A substitution at nucleotide position 20210 in the 3' untranslated region of the factor II gene
    • The prothrombin mutation is second only to factor V Leiden in causing inherited thrombophilia
    • De novo mutations resulting in prothrombin thrombosis have not been reported in the factor II gene
    • A single copy of the G20210A mutation increases the lifetime risk of venous thrombosis by 3-11% while possessing two copies of the mutation leads to even greater risk
    • The G20210A allele of the prothrombin gene may be co-inherited with factor V Leiden. This combined heterozygosity for the 2 mutations leads to earlier onset, higher rate of recurrence and more severe thrombotic events than either by itself
• Clinical Presentation
  • Clinical expression of mutation carriers is variable with many individuals never developing thrombosis while others have recurrent venous thrombosis (characteristically deep-vein thrombosis in the legs and pulmonary embolism) at a young age
  • Venous thromboembolism and embolism in usual sites (mesenteric, hepatic, portal)
  • An increased risk for venous thrombosis, pregnancy loss and preeclampsia
  • Other possible pregnancy risks include fetal growth retardation and placental abruption

Protein C Deficiency

• Pathophysiology
  • Protein C is a naturally occurring vitamin K-dependent plasma anticoagulant
    • Anticoagulant effect is largely due to a rapid inactivation of factors Va and VIIIa
    • Protein C must be converted to an active serine protease, activated protein C (APC), to be physiologically functional
    • Protein S, cofactor of protein C, potentiates the binding of APC to the platelet or endothelial cell surface through a calcium ion bridge
    • APC (combined with protein S, the phospholipid surface and calcium ions) forms a functional enzyme complex
    • Acquired protein C deficiency occurs in disseminated intravascular coagulation (DIC), liver disease, vitamin K deficiency and can result in various thrombotic states (eg, deep-vein thrombosis)
      • Decreased protein C levels due to:
        • Medical conditions - abnormally elevated levels of factor VIII, liver disease, vitamin K deficiency
      • Increased protein C levels due to:
        • Medical conditions - diabetes, nephrotic syndrome
        • Drugs - oral contraceptives, heparin
      • Complete absence has led to fatal thrombosis in neonates
• Clinical Presentation
  • Clinical venous thrombosis and embolism at unusual sites (mesenteric, hepatic portal)
    • Homozygous deficiency - purpura fulminans shortly after birth
• Treatment
  • Care should be taken with the use of warfarin in patients with this deficiency
  • Patient may experience warfarin-induced skin necrosis

Protein S Deficiency

• Pathophysiology
  • Protein S is a plasma vitamin K-dependent protein which has a fundamental anticoagulant function
    • Acts as the cofactor of activated protein C with which it forms a stoichiometric complex
      • Complex inactivates thrombin-activated factors V and VIII
    • Greatly enhances the anticoagulant function of activated protein C, most likely by increasing protein C affinity for phospholipid membranes
  • Protein S exists in 2 forms
    • Free protein S represents about 40% of the total protein S; acts as the cofactor for activated protein C
    • Bound protein S (attached to C4b-binding protein) represents 60% of the total protein S; possesses no anticoagulant activity
  • Decrease of protein S levels due to:
    • Medical conditions - pregnancy, nephrotic syndrome, abnormally elevated levels of factor VIII,  inflammatory syndromes, disseminated intravascular coagulation (DIC) and liver disease 
    • Drugs - estrogen use
  • Increased functional protein S levels due to:
    • Oral anticoagulants such as heparin
• Clinical Presentation
  • Clinical venous thrombosis and embolism at unusual sites (mesenteric, hepatic portal)
  • Homozygous defect - purpura fulminans shortly after birth

Antithrombin Deficiency

• Pathophysiology
  • Antithrombin (AT), sometimes referred to as Antithrombin III (ATIII), is a naturally occurring plasma protein with anticoagulant activity
    • AT is a beta-globulin inhibitor of activated serine proteases; approximately 75% of the plasma coagulation inhibitory activity is derived from AT
    • AT irreversibly binds to and inactivates clotting factor X, (Xa) and thrombin
    • Inactivation is enhanced by heparin-like glycosaminoglycans on the endothelial surface and by commercial heparin
  • Acquired AT deficiency occurs in liver disease, disseminated intravascular coagulation (DIC), therapy with heparin, asparaginase or estrogens and nephrotic syndrome
  • Increased AT may occur with warfarin therapy
• Clinical Presentation
  • Venous thromboembolism and embolism at unusual sites
• Treatment
  • Patients with this defect should be considered for lifelong anticoagulation therapy after the first thrombotic event

Methylenetetrahydrofolate Reductase (MTHFR) (Hyperhomocysteinemia)

• Prevalence
  • The frequency of the C677T mutation is variable with 30-40% of Caucasians and 1.4% of African Americans being heterozygous
  • C677T homozygosity is seen in 5% of Dutch and Finnish populations and 12-15% in other European populations
  • The A1298C mutation has an allele frequency of 33% in the U.S.
  • Analytic sensitivity and specificity for detection of these mutations are 99.9%
• Risk Factors
  • Inheritance
    • Autosomal recessive
  • Genetics
    • The most common genetic defects of homocysteine metabolism are the MTHFR mutations C677T and A1298C
    • The C677T mutation is a thermolabile variant of MTHFR
    • Homozygosity for C677T is associated with intermediate and mild hyperhomocysteinemia and a three fold increased risk for premature cardiovascular disease in patients with mild hyperhomocysteinemia
    • Folic acid treatment effectively decreases plasma homocysteine levels
    • Compound heterozygosity for C677T and A1298C is associated with increased plasma homocysteine levels but it is unknown if this increases the risk for premature cardiovascular disease
    • Heterozygosity for the C677T or A1298C mutation does not increase the risk for premature cardiovascular disease
    • MTHFR C677T homozygotes and C677T/A1298C compound heterozygotes have been reported to have an increased risk for neural tube defects in some populations
    • CAP recommendation - run Homocysteine levels instead of this test
• Pathophysiology
  • Methylenetetrahydrofolate reductase (MTHFR) enzyme is involved with folate metabolism, catalyzing the reduction of 5,10-ethylenetetrahydrofolate to 5-methyltetrahydrofolate
    • Folate is a cofactor in remethylation of homocysteine
    • Without folate, homocysteine levels in the plasma increase
• Clinical Presentation
  • Venous thromboembolism
  • Coronary artery thrombosis and arteriosclerotic vascular disease
  • In pregnant females, folate defects play a role in neural tube defects, such as spina bifida and anencephaly

Refer to Hypercoagulable States topic at www.arupconsult.com for diagram of Clotting Cascade with an Emphasis on Inherited Thrombophilias

• Diagnosis
  • Laboratory testing
    • Factor V Leiden
      • Initial testing - APC resistance profile
      • Consider concomitant testing for other common thrombophilias
    • Prothrombin G20210A
      • Prothrombin G20210A testing
      • Consider concomitant testing for other common thrombophilias
    • Protein C deficiency
      • The functional assay will detect both quantitative and qualitative deficiency of protein C
      • The antigenic assay will detect quantitative protein C deficiency but will not detect qualitative abnormalities in protein C 
    • Protein S deficiency
      • The functional assay will detect both quantitative and qualitative deficiency of protein S
      • The antigenic assay will detect quantitative protein S deficiency, but not detect qualitative abnormalities in protein S
      • Antithrombin III levels
    • Methylenetetrahydrofolate Reductase (MTHFR) (Hyperhomocysteinemia)
      • Elevated plasma homocysteine is an independent risk factor for arteriosclerotic vascular disease and venous thrombosis
        • 10% of the risk for coronary artery disease may be attributable to elevated homocysteine levels
        • With each 5 µmol/L rise in total homocysteine levels, coronary artery disease increases by 60% for men and 80% for women
        • Both genetic and environmental (eg, dietary) factors affect homocysteine levels