Hypercoagulable States - Thrombophilia

Hypercoagulable states may be acquired or inherited. Hereditary thrombophilia is a genetically determined increased risk for thrombosis and thromboembolism.

Epidemiology

• Adults
  • Incidence – 30-500/10,000 for all disorders
  • Ethnicity – slightly higher among African Americans; lower in Asian and Native Americans
    • Inherited thrombophilic disorders

      Inherited Thrombophilic Disorders
      Disorder	Prevalence in Normals (%)	Frequency in Patients with VTE+ (%)	Relative Risk of First Episode of DVT++
      Factor V Leiden (heterozygous)	0.05-4.8*	18.8	7
      Factor V Leiden (homozygous)	0.02	1.5	80
      Factor V with R2 mutation	0.06-0.12	10.0	7 (heterozygote) 10 (compound heterozygote)
      Prothrombin G20210A allele	0.06-2.7*	7.1	2.8
      Protein C deficiency	0.2-0.4	3.7	6.5
      Protein S deficiency	0.16-0.21	2.3	5.0
      Antithrombin deficiency	0.02	1.9	20
      Dysfibrinogenemia	<0.01	0.8	Unknown
      Hyperhomocysteinemia**	5-7	10	2.95
      Elevated factor VIII level	11	25	4.8
      Elevated factor IX level	10	20	2.8
      Elevated factor XI level	10	19	2.2
      Elevated lipoprotein (a) level	7	20	3.2
      Elevated thrombin-activatable fibrinolysis inhibitor (TAFI)	9	14	1.7
      *Percent lowest in Asian or African descent; highest in Caucasian descent **>18.5 µmol/L +VTE = venous thromboembolism ++DVT = deep vein thrombosis Whitlatch, 2008
• Pediatrics
  • Incidence – 0.05-14/100,000
  • Sex – M<F
  • Age – peak in neonates and infants <1 year
    • Second peak in puberty

Etiologies

Most common thrombophilias

• Factor V Leiden
  • Genetics and pathophysiology
    • Factor V Leiden (FVL) mutation of the F5 gene is the most common inherited thrombophilia
      • Accounts for more than 90% of patients with activated protein C resistance (APC-R)
        • During normal hemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa
        • FVL prevents inactivation of factor Va by APC at the normal rate, increasing the risk for thrombosis
      • Functional tests for APC-R are generally used to screen for FVL
        • DNA tests are used to confirm positive screening tests and to differentiate between heterozygotes and homozygotes
    • Autosomal dominant inheritance
      • Heterozygotes have a five- to tenfold increased risk
      • Homozygotes have a 50- to 100-fold increased risk
  • Clinical presentation
    • Venous thromboembolism (VTE) is the most common type of thrombotic event
      • Recurrent VTE (pulmonary embolism, DVT) is uncommon in heterozygotes unless additional risk factors are present
      • Increased risk of recurrent VTE in homozygotes
    • Pregnancy complications – recurrent miscarriage in the second trimester
  • Additional risk factors
    • Presence of F5 R2 (A4070G) mutation with FVL increases risk of thrombotic event tenfold
    • Patients with FVL mutation and recurrent episodes of thrombosis often have more than one genetic risk factor (eg, concomitant prothrombin G20210A mutation of F2, protein C deficiency, homocysteinemia)
    • Acquired factors such as pregnancy, oral contraceptives, hormone replacement therapy, and immobilization increase the risk​
• ​Prothrombin G20210A
  • ​Genetics and pathophysiology
    • Prothrombin G20210A mutation of the F2 gene is the second most common inherited thrombophilia
      • Results in elevated levels of plasma prothrombin leading to hypercoagulability (gain of function)
      • Detected using DNA tests
        • Factor II (prothrombin) activity testing may not identify the disease and should not be used for diagnosis
    • Autosomal dominant inheritance
      • Variable penetrance
        • Many patients who are either heterozygous or homozygous for G20210A do not experience VTE
      • Heterozygosity causes a two- to fourfold increase in thrombotic risk
      • Homozygosity is rare and increases thrombotic risk above that observed in G20210A heterozygotes
  • Clinical presentation
    • VTE
    • Pregnancy complications – preeclampsia, placental abruption
  • Additional risk factors
    • Combined heterozygosity for both prothrombin G20210A and FVL mutations leads to thrombophilia with earlier onset, higher rate of recurrence, and more severe thrombotic events than either mutation alone
    • Increased risk of thrombosis associated with oral contraceptive use and pregnancy

Less common thrombophilias

• Increased clotting factors
  • Elevated factor VIII (FVIII) levels are often found in patients with venous thrombosis, but routine testing is controversial
• Protein C deficiency
  • Genetics and pathophysiology
    • Protein C is a vitamin K-dependent plasma anticoagulant activated to APC by thrombin-thrombomodulin, which then inactivates factors Va and VIIIa
    • Inherited protein C deficiency is uncommon
      • Two forms
        • Type I – quantitative
        • Type II – qualitative
    • Autosomal dominant inheritance
      • Highly variable phenotypic expression
    • Functional assays preferred for diagnosis (rather than antigenic assays)
      • Protein C levels vary with age
    • Decreased levels in acute thrombotic states, disseminated intravascular coagulation (DIC), liver disease, malnutrition (vitamin K deficiency), and with warfarin therapy
    • Increased levels in diabetes, nephrotic syndrome, pregnancy, and with oral contraceptive use
      • Elevated FVIII levels may result in falsely decreased values for some functional assays
      • Heparin and direct thrombin inhibitors may result in falsely elevated values for some functional assays
  • Clinical presentation
    • Additional risk factors likely necessary to provoke thrombosis (eg, infection – VZV, meningococcal)
    • VTE in heterozygotes
    • Neonatal purpura fulminans (DIC) in homozygous infants – widespread thromboses with hemorrhagic skin necroses
    • Warfa​rin-induced skin necrosis is rarely seen
• Protein S deficiency
  • Genetics and pathophysiology
    • Protein S is a vitamin K-dependent plasma anticoagulant that acts as a cofactor for activated protein C and exists in two forms
      • Free protein S – 40% of the total; physiologically active
      • Bound protein S (attached to C4b-binding protein) – 60% of the total; no anticoagulant activity
    • Inherited protein S deficiency is uncommon
      • Three forms
        • Type I – quantitative
        • Type II – qualitative
        • Type III (also called type IIa) – quantitative with normal levels of total protein S
      • Autosomal dominant inheritance
      • Antigenic tests for free protein S preferred for diagnosis
        • Free protein S values are higher in males than in females
    • Decreased levels in acute thrombotic states, nephrotic syndrome, inflammatory syndromes (due to increased C4b-binding protein), DIC, liver disease, malnutrition (vitamin K deficiency), pregnancy, and with estrogen and warfarin therapy
      • Elevated FVIII levels and/or APC resistance may result in falsely decreased values in some functional assays
      • Increased levels in heparin and direct thrombin inhibitors for some functional assays
  • Clinical presentation
    • Additional risk factors likely necessary to provoke thrombosis
    • VTE most common; arterial thrombosis may occur
    • Neonatal purpura fulminans (DIC) in homozygous infants
    • Warfarin-induced skin necrosis (rare)
• Hyperhomocysteinemia (acquired or inherited)
  • Acquired
    • Independent risk factor for thromboembolic events
    • Most patients with hyperhomocysteinemia have no genetic mutations or polymorphisms
    • Acquired hyperhomocysteinemia is the result of defective homocysteine metabolism and may be the result of vitamin B6, B12, or folic acid deficiency
    • Thrombotic risk most closely associated with increased fasting plasma homocysteine levels regardless of underlying etiology
      • Plasma homocysteine testing is recommended over DNA-based tests
  • Inherited
    • Homocysteine metabolism defects caused by variants in of the MTHFR gene
      • Most common variants – c.665C>T (p.Ala222Val) (previously designated C677T) and c.1286A>C (p.Glu429la) (previously designated A1298C)
        • Only homozygotes for the c.665C>T variant have been significantly associated with elevated plasma homocysteine levels
    • Autosomal recessive inheritance
    • Elevated plasma homocysteine level may be a risk factor for atherosclerotic vascular disease and venous thrombosis independent of MTHFR status
    • Inherited hyperhomocysteinemia rare
      • Clotting cascade with an emphasis on inherited thrombophilias

        

• Antithrombin deficiency
  • Genetics and pathophysiology
    • Antithrombin (AT) – plasma anticoagulant; inactivates thrombin, factor Xa, and other activated clotting factors
      • AT activity enhanced by heparin-like glycosaminoglycans on the endothelial surface and by pharmaceutical heparin
      • Synthesized in the liver
    • Two forms of inherited antithrombin deficiency
      • Type I – quantitative
      • Type II – qualitative
    • Autosomal dominant inheritance
      • Functional assays preferred for diagnosis
      • Homozygous state is embryonic lethal
    • Decreased levels occurs in acute thrombotic states, liver disease, DIC, nephrotic syndrome, and heparin therapy; mild decreases may be seen in pregnancy or with oral contraceptive use
    • Increased levels may occur with long-term warfarin therapy
  • Clinical presentation
    • VTE
    • Recurrent thrombosis may occur even in the absence of additional risk factors
    • Some deficient patients are resistant to heparin therapy
• Impaired clot lysis (dysfibrinogenemia, abnormal fibrinolysis)​

Acquired thrombophilic state

• Antiphospholipid syndrome