Hypercoagulable States - Thrombophilia

 

Hereditary thrombophilia is a genetically determined increased risk of thrombosis and thromboembolism.  Hypercoagulable states may also be acquired.

Epidemiology

  • Prevalence
    • Inherited thrombophilias detected in 30-50% of venous thromboembolic events in U.S.

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 (heterozygous with FVL)0.6-0.1210.010
7 [single heterozygote (no FV)]

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
Adapted from Perry, Ortel and references included within
DVT, deep vein thrombosis; VTE, venous thromboembolism

Whitlatch, NL and Ortel TL.  Thrombophilias: When should we test and how does it help?  Seminars in respiratory and critical care medicine. 2008; 29(1):27.

Etiologies

  • Most common thrombophilias
    • Factor V Leiden  
    • Prothrombin G20210A
    • Homocysteinemia (acquired or inherited)
  • 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
    • Protein S deficiency
    • Antithrombin deficiency
    • Impaired clot lysis (dysfibrinogenemia, abnormal fibrinolysis)
  • Antiphospholipid syndrome is an acquired thrombophilic state – refer to specific topic in ARUP Consult

Select topics are discussed below

Factor V Leiden

  • Genetics and pathophysiology
    • The factor V Leiden (FVL) point mutation 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 as a screening test for FVL
        • DNA tests are used to confirm positive screening tests and to differentiate between heterozygotes and homozygotes
    • Autosomal dominant inheritance
      • Heterozygous carriers 5 to10-fold increased risk
      • Homozygous carriers 50 to100-fold increased risk
  • Clinical Presentation
    • Venous thromboembolism (VTE) is the most common arterial thrombosis that may occur
      • Recurrent VTE may be uncommon in heterozygous patients unless additional risk factors present
      • Risk of recurrent VTE is increased in homozygous carriers
    • Recurrent miscarriage in the second trimester of pregnancy
  • Additional risk factors
    • Presence of factor V R2 A4070G mutation in addition to FVL mutation increases risk of thrombotic event tenfold
    • Many patients with FVL mutations and recurrent episodes of thrombosis have more than 1 genetic risk factor, such as concomitant prothrombin (factor II) G20210A mutation, protein C deficiency or homocystinemia
    • Factors such as pregnancy, oral contraceptives, hormone replacement therapy, and immobilization increase the risk

Prothrombin G20210A

  • Genetics and pathophysiology
    • The prothrombin G20210A mutation is the second most common inherited thrombophilia
      • Results in elevated levels of plasma prothrombin which leads to hypercoagulability (gain of function)
      • Detected using DNA tests
        • Factor II (prothrombin) activity levels are not an appropriate test
    • Autosomal dominant inheritance
      • 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
  • Clinical Presentation
    • Venous thromboembolism
    • Pregnancy complications
  • Additional risk factors
    • Combined heterozygosity for the prothrombin G20210A mutation and FVL leads to earlier onset, higher rate of recurrence and more severe thrombotic events than either by itself
    • Risk of thrombosis appears increased during pregnancy and with oral contraceptive use

Protein C Deficiency

  • Pathophysiology
    • Protein C is a vitamin K-dependent plasma anticoagulant that inactivates factors Va and VIIIa after being activated to APC
      • Inherited protein C deficiency is uncommon and may be either quantitative (type I) or qualitative (type II)
        • Functional assays (rather than antigenic assays) are preferred for diagnosis
        • Protein C levels vary with age
      • Protein C levels are decreased in acute thrombotic states, disseminated intravascular coagulation (DIC), liver disease, malnutrition (vitamin K deficiency) and with warfarin therapy
        • Elevated FVIII levels (acute phase reactant) may interfere in some functional assays and result in falsely decreased values
      • Increased protein C levels may be seen in diabetes, nephrotic syndrome, during pregnancy, and in patients on oral contraceptives 
        • Heparin and direct thrombin inhibitors may interfere in some functional assays, resulting in falsely elevated values
  • Clinical Presentation
    • Additional risk factors likely necessary to provoke thrombosis
    • Venous thromboembolism in heterozygotes
    • Neonatal purpura fulminans (DIC) in homozygous infants
    • Warfarin-induced skin necrosis is seen rarely

Protein S Deficiency

  • Pathophysiology
    • Protein S is a vitamin K-dependent plasma anticoagulant which acts as a cofactor for activated protein C
    • Protein S exists in 2 forms
      • Free protein S represents 40% of the total and is physiologically active
      • Bound protein S (attached to C4b-binding protein) represents 60% of the total and possesses no anticoagulant activity
    • Inherited protein S deficiency is uncommon and may be either quantitative (type 1) or qualitative (type 2)
      • Functional assays or antigenic tests for free protein S are preferred for diagnosis
    • Protein S levels are decreased in acute thrombotic states, nephrotic syndrome, inflammatory syndromes (due to increased C4b-binding protein), disseminated intravascular coagulation (DIC), liver disease, malnutrition (vitamin K deficiency), pregnancy, estrogen therapy, and with warfarin therapy
      • Elevated FVIII levels may interfere in some functional assays and result in falsely decreased values
      • APC resistance may interfere in some functional assays and result in falsely decreased values
      • Heparin and direct thrombin inhibitors may interfere in some functional assays and result in falsely elevated values
  • Clinical Presentation
    • Additional risk factors likely necessary to provoke thrombosis
    • Venous thromboembolism most common, arterial thrombosis may occur
    • Neonatal purpura fulminans (DIC) in homozygous infants
    • Warfarin-induced skin necrosis is seen rarely

Antithrombin Deficiency

  • Pathophysiology
    • Antithrombin (AT) is a plasma anticoagulant that inactivates thrombin, factor Xa and other activated clotting factors
      • Antithrombin activity is enhanced by heparin-like glycosaminoglycans on the endothelial surface and by commercial heparin
    • Inherited antithrombin deficiency may be either quantitative (type 1) or qualitative (type 2)
      • Functional assays are preferred for diagnosis
    • Decreased antithrombin occurs in acute thrombotic states, liver disease, DIC, nephrotic syndrome and therapy with heparin.  Mild decreases may be seen in pregnancy or with oral contraceptive use.
    • Increased AT may occur with long-term warfarin therapy in some patients
  • Clinical Presentation
    • Venous thromboembolism (may be recurrent) and embolism at unusual sites
    • Recurrent thrombosis may occur even in the absence of additional risk factors
    • Some patients are resistant to heparin therapy

Hyperhomocysteinemia

  • Independent risk factor for thromboembolic events
  • Most patients with hyperhomocysteinemia do not have genetic mutations or polymorphisms
  • Regardless of the underlying etiology, hyperhomocysteinemia is the result of deranged homocysteine metabolism which may be acquired (deficiency of vitamins B6, B12, or folic acid) or inherited (deficiency of cystathionine β-synthase or expression of a thermolabile form of methylenetetrahydrofolate reductase)
  • Thrombotic risk is most closely associated with increased fasting plasma homocysteine levels regardless of the underlying etiology
    • Plasma homocysteine testing is recommended rather than DNA-based tests

Methylenetetrahydrofolate Reductase (MTHFR) mutations

  • Genetics
    • Autosomal recessive inheritance
    • The most common genetic defects of homocysteine metabolism are the MTHFR mutations C677T and A1298C
      • The C677T mutation results in a thermolabile variant of MTHFR
  • Clinical Presentation
    • Elevated plasma homocysteine levels have been associated with atherosclerotic disease, venous thromboembolism and arterial thrombosis
Click here for diagram of Clotting Cascade with an Emphasis on Inherited Thrombophilias