Section 10 - Disorders of Secondary Hemostasis - Inhibitors

Inhibitors

• Antibody directed against one or more coagulation factors

• Interferes with normal coagulation

• Can be specific (targeting a factor) or nonspecific (e.g. lupus anticoagulant)

True Autoantibody Inhibitors

• Type: Specific inhibitors (e.g., anti-FVIII)

• Mechanism: Bind and inactivate clotting factors or promote their clearance

• Result:

  • ↓ factor activity

  • Often leads to bleeding (acquired hemophilia if FVIII involved)

  • Mixing study: No correction of prolonged APTT

  • Associated with autoimmune disease, malignancy, pregnancy, elderly

Acquired Circulating Anticoagulants

• Type: Nonspecific inhibitors

• Mechanism: Interfere with phospholipid-dependent coagulation (e.g., lupus anticoagulant) or enhance natural anticoagulants (e.g., heparin → ↑ antithrombin activity)

• Result:

  • Prolonged PT and/or APTT

  • Mixing study: No correction

  • Heparin: Prolongs TT, APTT, and often PT

  • Lupus anticoagulant: Prolonged APTT, but patient may clot, not bleed

Factor VIII:C Inhibitor
Mechanism

• Autoantibody (usually IgG) directed against Factor VIII

• Neutralizes infused or endogenous FVIII

• Can occur in:

  • Hemophilia A patients (treatment complication)

  • Non-hemophiliacs ("Acquired hemophilia") due to autoimmune disorders, postpartum state, malignancy, or drugs

Factor VIII:C Inhibitor
Presentation

• Bleeding usually spontaneous, soft tissue, or mucosal

• Onset in previously healthy adults (50–80 years)

• Mild to severe bleeding; may be fatal

• No family history typically

• Common triggers: SLE, RA, postpartum, drugs

Factor VIII:C Inhibitor
Laboratory Findings

• APTT: Prolonged

• PT: Normal

• Mixing Study (50:50): Fails to correct APTT

• Factor assay: Isolated low FVIII:C level

• No other factor deficiencies

Factor VIII:C Inhibitor
Differential Diagnosis

• Mixing Study Interpretation:

  • Corrects → Factor deficiency (e.g. Hemophilia A)

  • Fails to correct → Circulating inhibitor (e.g. FVIII:C inhibitor, lupus anticoagulant)

• Distinction from Lupus Inhibitor: FVIII:C inhibitor causes clinical bleeding, not thrombosis

Factor VIII:C Inhibitor
Management

• Depends on inhibitor titer

• Bypass agents (e.g., rFVIIa, FEIBA) for bleeding

• Immunosuppressive therapy (steroids, rituximab) to eradicate antibody

• Rare spontaneous remission in acquired cases

Antiphospholipid Antibodies
Definition

• Group of immunoglobulins that bind protein–phospholipid complexes

• Includes:
  • Lupus anticoagulant (LA)
  • Anticardiolipin antibodies
  • Anti–β2 glycoprotein I antibodies
  • Other less defined antibodies

Antiphospholipid Syndrome (APS)
Clinical Presentation

• Recurrent arterial or venous thrombosis

• Pregnancy complications (e.g., miscarriage, preeclampsia)

• Unexplained skin/circulatory changes

• Thrombocytopenia

• Hemolytic anemia

• Nonbacterial thrombotic endocarditis

Lupus Anticoagulant (LA)
Mechanism

• Not factor-specific; interferes with phospholipid-dependent coag assays

• Binds phospholipid in test systems but not to platelets themselves

• Prolongs APTT in vitro

• Not associated with bleeding

Lupus Anticoagulant (LA)
Clinical Manifestations

• Prothrombotic despite “anticoagulant” name

• Inhibits prostacyclin from endothelium
  • Prostacyclin normally prevents platelet adhesion

• Increased risk of clot formation

• No bleeding tendency

Antiphospholipid Antibodies
Prevalence and Context

• Present in 1–2% of healthy individuals (often transient)
  • Post-infection or drug exposure

• 5–15% of patients with recurrent thrombosis test positive

• Associated with autoimmune diseases:
  • SLE, RA, Sjögren’s syndrome

PT/INR and APTT in the Presence of Inhibitors

• APTT prolonged in most acquired inhibitors (e.g., factor VIII inhibitor, lupus anticoagulant)

• PT/INR typically normal in lupus anticoagulant and factor VIII inhibitors

• Both PT and APTT prolonged in inhibitors targeting common pathway or multiple factors

50:50 Mixing Study

• Purpose: Distinguish factor deficiency from inhibitor

• Correction = factor deficiency

• No correction = inhibitor present

• Time-dependent inhibition may show initial correction with prolongation upon incubation (e.g., acquired factor VIII inhibitor)

Silica Clotting Time (SCT)

• Contact pathway-based APTT analog (uses silica as activator)

• Prolonged SCT with no correction on mix = possible lupus anticoagulant

• Often run in tandem with dRVVT in LA panels

Dilute Russell Viper Venom Time (dRVVT)

• Activates factor X directly (bypasses VIII and IX)

• Sensitive and specific for lupus anticoagulant

• Prolonged screen + correction with confirm reagent = LA present

• Screen/confirm ratio >1.2 = Positive

Kaolin Clotting Time (KCT)

• Kaolin activates contact factors

• Prolonged KCT with no correction = consistent with lupus anticoagulant

• Often included in LA-sensitive testing panels

Dilute Thromboplastin Time (dTT or dPTT)

• Uses diluted tissue factor; sensitive to phospholipid-dependent inhibitors

• Prolonged result without correction = LA

• Especially useful when dRVVT is equivocal

Platelet Neutralization Procedure (PNP)

• Confirms lupus anticoagulant

• Replaces reagent phospholipids with PL-rich platelet lysate

• Shortened APTT with platelet lysate = LA confirmed

• Helps distinguish LA from factor inhibitors

Anti-cardiolipin Antibody (aCL)

• Autoantibody against phospholipid-bound proteins

• Positive IgG or IgM aCL = antiphospholipid syndrome

• Does not prolong clot-based assays, but supports diagnosis

Anti-β2 Glycoprotein I Antibody

• Autoantibody against β2-glycoprotein I-phospholipid complex

• Confirms antiphospholipid syndrome when present

• Measured by ELISA; does not interfere with clot-based testing

Antiphospholipid Syndrome (APS)
Mechanism

• Autoantibodies against phospholipid-protein complexes (e.g., β2-glycoprotein I)

• Promote thrombosis despite in vitro prolongation of clotting times

APS
Lab Findings

• ↑ APTT

• dRVVT screen: prolonged

• dRVVT confirm: corrects

• 50:50 mix: no correction

• Anti-cardiolipin or β2GP1 Ab

APS
Clinical Features

• Venous and arterial thrombosis

• Recurrent miscarriage

• Stroke in young adults

• Often asymptomatic until thrombotic event

APS
Treatment

• No treatment if asymptomatic

• Steroids may reduce antibody activity

• Plasmapheresis in emergencies

• Antithrombotic therapy for active thrombosis