Thrombophilia

Audio Overview

Overview of Hypercoagulable States (Thrombophilia)

Definition: A group of inherited or acquired conditions that increase the risk of developing thrombosis (blood clots)
Pathophysiology:
- Alterations in the balance between procoagulant and anticoagulant factors in the blood
- Increased thrombin generation and decreased fibrinolysis
Classification:
- Inherited (Genetic) Thrombophilias: Caused by genetic mutations affecting coagulation factors or natural anticoagulants
- Acquired Thrombophilias: Caused by external factors that alter the coagulation system
Clinical Significance: Increased risk of venous and/or arterial thrombosis
- Deep vein thrombosis (DVT)
- Pulmonary embolism (PE)
- Stroke
- Myocardial infarction
- Recurrent pregnancy loss

Virchow’s Triad

Virchow’s triad describes the three broad categories of factors that contribute to thrombosis:

Hypercoagulability: Increased tendency to clot due to inherited or acquired abnormalities in the coagulation system
Hemodynamic Changes (Stasis or Turbulence): Altered blood flow, such as occurs with prolonged immobility or atrial fibrillation
Endothelial Injury: Damage to the blood vessel wall, exposing subendothelial collagen and tissue factor

Inherited Thrombophilias (Genetic)

Factor V Leiden Mutation:
- Definition: The most common inherited thrombophilia; caused by a point mutation in the F5 gene, which encodes Factor V
- Pathophysiology:
  - Mutation: A single nucleotide change (G to A) at position 1691 in the F5 gene, resulting in a glutamine (Q) to arginine (R) substitution at position 506 (FV R506Q)
  - Resistance to Activated Protein C (APC): The Factor V Leiden mutation makes Factor V resistant to inactivation by activated protein C (APC), a natural anticoagulant
  - Increased Thrombin Generation: Prolonged activity of Factor V leads to increased thrombin generation and a prothrombotic state
- Inheritance: Autosomal dominant
  - Heterozygous: One copy of the mutated gene (increased risk of thrombosis)
  - Homozygous: Two copies of the mutated gene (higher risk of thrombosis)
- Clinical Features:
  - Increased risk of venous thrombosis (DVT, PE)
  - Increased risk of recurrent pregnancy loss
  - The risk of thrombosis is higher in individuals with Factor V Leiden who also have other risk factors (e.g., oral contraceptives, pregnancy, surgery)
- Laboratory Findings:
  - Activated Protein C (APC) Resistance Assay:
    - Prolonged aPTT with normal plasma
    - aPTT does not prolong with APC
  - Factor V Leiden Mutation Analysis:
    - Confirms the presence of the Factor V Leiden mutation (DNA testing)
- Treatment:
  - Anticoagulation:
    - Warfarin (Coumadin)
    - Direct oral anticoagulants (DOACs): Rivaroxaban, apixaban, edoxaban, dabigatran
  - Prophylactic Anticoagulation:
    - May be considered in high-risk situations (e.g., surgery, pregnancy)
Prothrombin G20210A Mutation:
- Definition: The second most common inherited thrombophilia; caused by a point mutation in the F2 gene, which encodes prothrombin (Factor II)
- Pathophysiology:
  - Mutation: A single nucleotide change (G to A) at position 20210 in the 3’-untranslated region of the F2 gene
  - Increased Prothrombin Levels: Leads to increased prothrombin mRNA stability and increased prothrombin production
  - Increased Thrombin Generation: Elevated prothrombin levels result in increased thrombin generation and a prothrombotic state
- Inheritance: Autosomal dominant
  - Heterozygous: One copy of the mutated gene
  - Homozygous: Two copies of the mutated gene
- Clinical Features:
  - Increased risk of venous thrombosis (DVT, PE)
  - Increased risk of arterial thrombosis (stroke, myocardial infarction)
  - Increased risk of recurrent pregnancy loss
- Laboratory Findings:
  - Prothrombin G20210A Mutation Analysis:
    - Confirms the presence of the prothrombin G20210A mutation (DNA testing)
  - Prothrombin Level: May be elevated
- Treatment:
  - Anticoagulation:
    - Warfarin (Coumadin)
    - Direct oral anticoagulants (DOACs): Rivaroxaban, apixaban, edoxaban, dabigatran
  - Prophylactic Anticoagulation:
    - May be considered in high-risk situations (e.g., surgery, pregnancy)
Protein C Deficiency:
- Definition: Inherited deficiency of protein C, a natural anticoagulant
- Pathophysiology:
  - Protein C: A vitamin K-dependent serine protease that is activated by the thrombin-thrombomodulin complex
  - Activated Protein C (APC): Degrades Factors Va and VIIIa, inhibiting thrombin generation
  - Protein C Deficiency: Reduces the ability to inactivate Factors Va and VIIIa, leading to a prothrombotic state
- Inheritance: Autosomal dominant or autosomal recessive (more severe)
- Clinical Features:
  - Venous thrombosis (DVT, PE)
  - Warfarin-induced skin necrosis: A rare but serious complication that can occur when starting warfarin therapy in patients with severe protein C deficiency
- Laboratory Findings:
  - Protein C Activity Assay: Decreased protein C activity level
  - Protein C Antigen Assay: May be decreased or normal, depending on the type of deficiency
- Treatment:
  - Anticoagulation:
    - Warfarin (Coumadin)
      - Start with caution due to the risk of warfarin-induced skin necrosis
      - Overlap with a parenteral anticoagulant (e.g., heparin or low-molecular-weight heparin) is recommended when starting warfarin
    - Direct oral anticoagulants (DOACs): Rivaroxaban, apixaban, edoxaban, dabigatran
  - Prophylactic Anticoagulation:
    - May be considered in high-risk situations (e.g., surgery, pregnancy)
Protein S Deficiency:
- Definition: Inherited deficiency of protein S, a cofactor for activated protein C (APC)
- Pathophysiology:
  - Protein S: A vitamin K-dependent protein that acts as a cofactor for APC in the inactivation of Factors Va and VIIIa
  - Protein S Deficiency: Reduces the ability of APC to inhibit thrombin generation, leading to a prothrombotic state
- Inheritance: Autosomal dominant
- Clinical Features:
  - Venous thrombosis (DVT, PE)
  - Arterial thrombosis (less common)
  - Recurrent pregnancy loss
- Laboratory Findings:
  - Protein S Activity Assay: Decreased protein S activity level
  - Protein S Antigen Assays:
    - Total Protein S: Measures the total amount of protein S
    - Free Protein S: Measures the amount of protein S that is not bound to C4b-binding protein
  - Interpreting Protein S Assays:
    - Protein S activity and free protein S antigen levels are most reliable for diagnosis
- Treatment:
  - Anticoagulation:
    - Warfarin (Coumadin)
      - Start with caution due to the risk of warfarin-induced skin necrosis
      - Overlap with a parenteral anticoagulant (e.g., heparin or low-molecular-weight heparin) is recommended when starting warfarin
    - Direct oral anticoagulants (DOACs): Rivaroxaban, apixaban, edoxaban, dabigatran
  - Prophylactic Anticoagulation:
    - May be considered in high-risk situations (e.g., surgery, pregnancy)
Antithrombin Deficiency:
- Definition: Inherited deficiency of antithrombin (AT), a natural anticoagulant
- Pathophysiology:
  - Antithrombin: A serine protease inhibitor (serpin) that inhibits thrombin and other coagulation factors (Factors IXa, Xa, XIa, XIIa)
  - Antithrombin Deficiency: Reduces the ability to inhibit thrombin and other coagulation factors, leading to a prothrombotic state
- Inheritance: Autosomal dominant
- Types:
  - Type I: Quantitative deficiency (reduced production of antithrombin)
  - Type II: Qualitative deficiency (dysfunctional antithrombin molecule)
- Clinical Features:
  - Venous thrombosis (DVT, PE)
  - Arterial thrombosis (less common)
  - Resistance to heparin therapy
- Laboratory Findings:
  - Antithrombin Activity Assay: Decreased antithrombin activity level
  - Antithrombin Antigen Assay: May be decreased or normal, depending on the type of deficiency
  - Heparin-Induced Thrombocytopenia (HIT) Testing: May be necessary to rule out HIT, as heparin resistance is a common feature
- Treatment:
  - Anticoagulation:
    - Warfarin (Coumadin): Higher doses of warfarin may be required to achieve therapeutic anticoagulation
    - Direct thrombin inhibitors (e.g., argatroban, bivalirudin): May be used in patients with heparin resistance or HIT
  - Prophylactic Anticoagulation:
    - May be considered in high-risk situations (e.g., surgery, pregnancy)
  - Antithrombin Concentrates:
    - Used for prophylaxis or treatment of acute thrombotic events, especially during surgery or pregnancy

Acquired Thrombophilias

Antiphospholipid Syndrome (APS):
- Definition: An acquired autoimmune disorder characterized by thrombosis (arterial or venous) and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL)
- Antibodies:
  - Lupus Anticoagulant (LA)
  - Anticardiolipin Antibodies (aCL)
  - Anti-β2 Glycoprotein I Antibodies (anti-β2GPI)
- Pathophysiology:
  - Antiphospholipid Antibodies: Bind to phospholipids and phospholipid-binding proteins, interfering with coagulation and platelet function
  - Thrombosis: In vivo, aPL can promote thrombosis through mechanisms involving:
    - Activation of endothelial cells and platelets
    - Inhibition of natural anticoagulant pathways (e.g., protein C pathway)
    - Complement activation
  - Pregnancy Morbidity: aPL can interfere with placental development and function, leading to pregnancy loss
- Clinical Features:
  - Thrombosis:
    - Deep vein thrombosis (DVT)
    - Pulmonary embolism (PE)
    - Stroke
    - Myocardial infarction
  - Pregnancy Morbidity:
    - Recurrent pregnancy loss (especially in the second or third trimester)
    - Preeclampsia
    - Placental insufficiency
  - Other Manifestations:
    - Thrombocytopenia
    - Livedo reticularis (a mottled skin rash)
    - Cardiac valve abnormalities
- Laboratory Findings:
  - Lupus Anticoagulant (LA):
    - Prolonged aPTT that does not correct on mixing with normal plasma
    - Phospholipid-dependent coagulation assays (e.g., dRVVT, SCT) are prolonged and do not correct with the addition of phospholipid
  - Anticardiolipin Antibodies (aCL):
    - Increased levels of IgG and/or IgM aCL antibodies
  - Anti-β2 Glycoprotein I Antibodies (anti-β2GPI):
    - Increased levels of IgG and/or IgM anti-β2GPI antibodies
  - Persistent Positivity: aPL must be present on two or more occasions, at least 12 weeks apart, to meet the laboratory criteria for APS
- Treatment:
  - Anticoagulation:
    - Warfarin (Coumadin) is the traditional anticoagulant
    - Direct oral anticoagulants (DOACs): Rivaroxaban, apixaban, edoxaban, dabigatran - may be used in some patients, but caution should be used
  - Antiplatelet Therapy:
    - Low-dose aspirin may be used in some patients, especially those with arterial thrombosis
  - Management of Obstetric APS:
    - Low-dose aspirin and prophylactic heparin during pregnancy to prevent recurrent pregnancy loss
Acquired Antithrombin Deficiency
- Reduced levels can be seen in patients with:
  - Nephrotic syndrome (loss of antithrombin in urine)
  - Disseminated intravascular coagulation (DIC)

General Laboratory Tests for Thrombophilia

Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT): Used as screening tests to detect abnormalities in the coagulation pathways
Mixing Studies: To differentiate factor deficiencies from factor inhibitors
D-Dimer Assay: To assess for thrombotic activity
Specific Assays for Inherited Thrombophilias:
- Factor V Leiden Mutation Analysis
- Prothrombin G20210A Mutation Analysis
- Protein C Activity Assay
- Protein S Activity and Antigen Assays
- Antithrombin Activity and Antigen Assays
Antiphospholipid Antibody Testing:
- Lupus Anticoagulant (LA) testing
- Anticardiolipin (aCL) antibody assay
- Anti-β2 Glycoprotein I antibody assay

Key Terms

Hypercoagulable State (Thrombophilia): A condition with an increased risk of thrombosis
Factor V Leiden: A common genetic mutation that causes resistance to activated protein C
Prothrombin G20210A Mutation: A genetic mutation that leads to increased prothrombin levels
Protein C: A vitamin K-dependent anticoagulant protein
Protein S: A cofactor for activated protein C
Antithrombin: A serine protease inhibitor that inhibits thrombin and other coagulation factors
Antiphospholipid Syndrome (APS): An autoimmune disorder characterized by thrombosis, pregnancy morbidity, and antiphospholipid antibodies
Lupus Anticoagulant (LA): An antibody that interferes with phospholipid-dependent coagulation assays
Thrombosis: Formation of a blood clot inside a blood vessel
Embolism: A blood clot that travels from one location to another

Fibrinolytic

DIC