Inhibitors

Overview of Coagulation Inhibitors

Definition: Substances that interfere with the normal function of coagulation factors, leading to impaired thrombin generation and an increased risk of bleeding or, in some cases, thrombosis
Classification:
- Acquired Inhibitors: Antibodies (usually IgG) that develop against specific coagulation factors or phospholipid-binding proteins
- Congenital Inhibitors: Rare, inherited deficiencies of natural anticoagulant proteins (Protein C, Protein S, Antithrombin). These are typically categorized as hypercoagulable states rather than factor deficiencies
Key Features:
- Prolonged clotting time (PT and/or aPTT) that does not correct upon mixing with normal plasma (demonstrates the presence of an inhibitor)
- May target specific coagulation factors or phospholipid-binding proteins
- Clinical manifestations range from bleeding to thrombosis, depending on the specific inhibitor and underlying mechanism

Acquired Coagulation Inhibitors

These are antibodies that develop against coagulation factors or phospholipid-binding proteins, interfering with their function

Factor VIII Inhibitors (Acquired Hemophilia A):
- Definition: Autoantibodies (usually IgG) that develop against Factor VIII (FVIII), leading to FVIII deficiency and a bleeding disorder
- Etiology:
  - Idiopathic (most common)
  - Associated with:
    - Autoimmune disorders (e.g., SLE, rheumatoid arthritis)
    - Pregnancy
    - Malignancies
    - Medications (e.g., penicillin, sulfonamides)
- Pathophysiology:
  - Autoantibodies bind to FVIII and neutralize its activity or accelerate its clearance from the circulation
  - Leads to impaired thrombin generation and increased risk of bleeding
- Clinical Features:
  - Bleeding manifestations similar to hemophilia A
    - Easy bruising
    - Prolonged bleeding after cuts or surgery
    - Nosebleeds
    - Hemarthrosis (bleeding into joints) - less common than in inherited hemophilia A
    - Intracranial hemorrhage (rare but life-threatening)
- Laboratory Findings:
  - CBC: Normal platelet count
  - Prothrombin Time (PT): Normal
  - Activated Partial Thromboplastin Time (aPTT): Prolonged
  - Mixing Study: aPTT does not correct upon mixing with normal plasma (demonstrates the presence of an inhibitor)
  - Factor VIII Assay: Decreased FVIII activity level
  - Factor VIII Inhibitor Assay (Bethesda Assay or Nijmegen-Bethesda Assay): Measures the titer (concentration) of the FVIII inhibitor
    - The Bethesda titer is expressed in Bethesda Units (BU)
    - One BU is defined as the amount of inhibitor that neutralizes 50% of FVIII in normal plasma
- Treatment:
  - Control of Bleeding Episodes:
    - Bypassing agents:
      - Activated prothrombin complex concentrates (aPCCs)
      - Recombinant Factor VIIa (rFVIIa)
    - These agents promote thrombin generation independently of FVIII
  - Eradication of the Inhibitor:
    - Immunosuppressive Therapy:
      - Corticosteroids (e.g., prednisone)
      - Cyclophosphamide
      - Rituximab (anti-CD20 antibody)
    - Immune Tolerance Induction (ITI): High-dose FVIII infusions combined with immunosuppressive therapy
  - Avoid FVIII Concentrates (unless necessary to control bleeding)
    - Repeated exposure to FVIII can boost the inhibitor titer
Lupus Anticoagulant (LA):
- Definition: Autoantibodies that bind to phospholipids and phospholipid-binding proteins, interfering with phospholipid-dependent coagulation assays in vitro
- Etiology:
  - Primary (idiopathic)
  - Secondary: Associated with:
    - Autoimmune disorders (e.g., SLE)
    - Infections
    - Medications
    - Malignancies
- Pathophysiology:
  - Antibodies bind to phospholipids and phospholipid-binding proteins (e.g., prothrombin, β2-glycoprotein I)
  - Interferes with the assembly of coagulation complexes on phospholipid surfaces in vitro, leading to prolonged clotting times
  - In vivo, the LA can promote thrombosis through complex mechanisms involving:
    - Activation of endothelial cells and platelets
    - Decreased production of prostacyclin
    - Inhibition of natural anticoagulant pathways
- Clinical Features:
  - Paradoxical: Despite prolonging clotting times in vitro, LA is associated with an increased risk of thrombosis (both arterial and venous)
  - Thrombotic events:
    - Deep vein thrombosis (DVT)
    - Pulmonary embolism (PE)
    - Stroke
    - Recurrent pregnancy loss
  - May be asymptomatic
- Laboratory Findings:
  - Screening Test:
    - Prolonged aPTT: Most common finding, but PT may also be prolonged in some cases
  - Mixing Study:
    - aPTT does not correct upon mixing with normal plasma (demonstrates the presence of an inhibitor)
  - Confirmatory Tests:
    - Phospholipid-Dependent Coagulation Assays:
      - Dilute Russell’s viper venom time (dRVVT): Prolonged and does not correct with the addition of phospholipid
      - Silica Clotting Time (SCT): Prolonged and does not correct with the addition of phospholipid
    - Hexagonal Phase Phospholipid Neutralization Assay:
      - Demonstrates that the prolonged clotting time is due to a phospholipid-dependent inhibitor
      - Clotting time corrects when hexagonal phase phospholipids are added to the test system
  - Anticardiolipin Antibodies and Anti-β2 Glycoprotein I Antibodies:
    - Often present, but not required for the diagnosis of LA
- Treatment:
  - Anticoagulation:
    - Warfarin (Coumadin)
    - Direct oral anticoagulants (DOACs) may be used in some cases, but there is less data on their effectiveness in patients with LA
    - The intensity and duration of anticoagulation depend on the severity of the thrombosis and the presence of other risk factors
  - Antiplatelet Therapy:
    - Aspirin may be used in some patients to reduce the risk of arterial thrombosis
  - Management of Obstetric Complications:
    - Low-dose aspirin and prophylactic heparin during pregnancy to prevent recurrent pregnancy loss
Factor V Inhibitors
- Very rare, but when it happens results in prolonged PT and PTT

Congenital (Inherited) Coagulation Inhibitor Deficiencies

These are better classified as hypercoagulable states

Protein C Deficiency
Protein S Deficiency
Antithrombin Deficiency

Key Laboratory Tests for Coagulation Inhibitors

Prothrombin Time (PT): Measures the function of the extrinsic and common pathways
Activated Partial Thromboplastin Time (aPTT): Measures the function of the intrinsic and common pathways
Mixing Studies: To differentiate factor deficiencies from factor inhibitors
Factor Assays: To measure the activity of specific coagulation factors
Factor Inhibitor Assays: To detect and quantify factor inhibitors
Lupus Anticoagulant Testing:
- Dilute Russell’s viper venom time (dRVVT)
- Silica Clotting Time (SCT)
- Hexagonal Phase Phospholipid Neutralization Assay
Anticardiolipin and Anti-β2 Glycoprotein I Antibody Assays
Genetic Testing: For inherited thrombophilia mutations

Key Terms

Coagulation Inhibitor: An antibody that interferes with the function of a coagulation factor
Lupus Anticoagulant (LA): An antibody that binds to phospholipids and proteins associated with the cell membrane
Mixing Study: A test to differentiate factor deficiencies from factor inhibitors
Bethesda Assay: A method for quantifying factor VIII inhibitors
Thrombosis: Formation of a blood clot inside a blood vessel
Antiphospholipid Syndrome (APS): An autoimmune disorder characterized by thrombosis, pregnancy morbidity, and the presence of antiphospholipid antibodies (including lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein I antibodies)

Acquired

Fibrinolytic