Lupus Anticoagulant

1
Lupus Anticoagulant

• Michael J. Sanfelippo, M.S.
• Technical Director, Coagulation Services
• Marshfield Clinic Laboratories
• April 17, 2008

2
Historical Perspective

• 1954
• Conley Hartman observed inhibition in vitro
• 1960s Mayo Clinic
• Observed Inhibitor Associated w/Thrombosis
• 1970s
• Inhibitor considered lab nuisance reagent
  manufacture made reagents unresponsive to
  Inhibitor
• 1972
• Lupus Anticoagulant term used by Feinstein and
  Rapaport
• 1976
• Test developed to demonstrate inhibition of
  phospholipid tissue factor inhibition.

3
Historical Perspective (contd)

• 1980s
• Development of ELISA assay to demonstrated
  antibody to cardiolipin.
• More laboratory tests-dilute Russells Viper
  Venom Time and Platelet Neutralization.
• Recognition of LA as risk factor for spontaneous
  abortion.
• Recognition of risk factor for arterial and
  venous thrombosis.
• Identification of mechanisms of thrombosis
• Recognition of antiphospholipid syndrome

4
Definition of Lupus Anticoagulant

• Antibody directed against protein-bound
  phospholipid which delays in vitro coagulation
  without a bleeding tendency but associated with
  significant thrombotic risk.

5
Nature of the Antibodies

• Real antigen is B2-glycoprotein I (B2GPI).
• Protein binding to negatively charge surface
  exposes antigenic sites.
• Some antibodies bind to B2GPI directly.
• Antibodies may react with other proteins most
  frequently prothrombin.

6
Other Phospholipid Binding Proteins

• Antiphospholipid antibodies may also be directed
  against
• Protein C
• Protein S
• Annexin V
• High Molecular Weight Kininogen
• Factor XI

7
How do APA affect Coagulation in vitro?

• Antibody complexes with B2GPI or prothrombin have
  high affinity for phospholipids
• Complexes compete with coagulation factors for
  catalytic surfaces.

8
Proposed Mechanisms of Thrombosis

• Impaired Fibrinolysis
• Inhibition of Protein C and S system
• Inhibition of Prostacyclin release from
  endothelial cells
• Inhibition of Annexin V Tissue Pathway Down
  Regulation
• Inhibition of B2GPI may affect Protein S

9
Pathology Associated with APLS

• Arterial thrombosis
• Venous thrombosis
• Recurrent spontaneous abortion
• Catastrophic APLS

10
Diagnostic Criteria of the APLS

• Vascular Thrombosis
• One or more episode venous or arterial thrombosis
• Complication of Pregnancy
• Fetal death
• Premature birth
• Recurrent spontaneous abortion
• Laboratory Criteria
• Anticardiolipin antibodies
• Lupus Anticoagulant

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Laboratory Tests

• APTT
• Dilute Russells Viper Venom Time
• Hexagonal Phase Assay
• ELISA Assays
• Anticardiolipin Antibody
• Anti Beta-2 Glycoprotein I Antibody
• Sero-negative

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Criteria for Lupus Anticoagulant

• Prolongation of one or more assays that are
  phospholipid dependent.
• Evidence that test plasma is acting as an
  inhibitor on normal plasma.
• Evidence that inhibitory activity is phospholipid
  dependent.

13
Bleeding Complications with APLS

• Thrombocytopenia
• Qualitative Platelet Defect (Renal Failure)
• Prothrombin Deficiency
• Spontaneous Inhibitor to Factor VIII

14
Catastrophic APLS

• Evidence of involvement three or more organs,
  systems, or tissues.
• Development of manifestation in one week or less.
• Confirmation of small vessel occlusion by
  histopathology.
• Lab identification of LA or antiphospholipid
  antibodies.

15
Association of Antiphospholipid Syndrome (APLS)
with other Conditions

• APLS has been associated with the following
  conditions
• Systemic Lupus Erythematosis (SLE)
• Other autoimmune diseases
• Recurrent spontaneous abortion
• Hepatic vein thrombosis
• Malignancy
• Infectious Diseases

16
Drug Induced Antiphospholipid Syndrome

• There are several drugs that have been
  associated with drug induced SLE and the
  antiophospholipid syndrome. They are as follows
• 1. Procainamide
• 2. Phenothiazines
• 3. Chlorpromazine
• 4. Hydralazine
• 5. Quinine and Quinidine
• 6. Some antibodies
• Many of these drugs are not in common use at
  this time.

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Laboratory Tests for APLS

• Coagulation Tests for APLS
• APTT and PT
• Dilute Russells Viper Venom Time (DRVVT)
• Hexagonal Phase Assay (StaClot LA)
• Tissue Factor Inhibition (Dilute Prothrombin
  Time)
• ELISA Methods
• Anticardiolipin Antibody IgG, IgM, IgA, Anti
  Beta-2 Glycoprotein I Antibody, IgG, IgM, IgA

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Treatment of APLS

• Treatment of APLS
• Thrombotic complications
• Spontaneous abortion heparin
• Venous or arterial thrombosis warfarin long
  term
• Associated Factor VIII Inhibitor
• Replacement support (VIII concentrates)
• Immunosupression rituximab and cyclophosphamide

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Problems with Anticoagulant Therapy

• Problems with Anticoagulant Therapy
• Monitoring Heparin (unfractionated)
• Prolonged initial APTT
• Use specific Heparin Assay
• Monitoring Warfarin
• Prolonged initial PT
• Measure Factor VII and X
• Erratic PT in reliable patient
• Measure Factor X with chromogenic assay
• Problem in 6.5 of patients with Lupus
  Anticoagulant

20
Case of False Elevation of INR in Patient with
Lupus Anticoagulant

• A 66-year-old male was referred for study
  because he was continuing to have transient
  ischemic attacks while on Warfarin with an INR of
  approximately 2.0.
• Lab results at 1 mg qd.
• INR 1.83 Factor X 131
• Lab results at 3 mg qd.
• INR 2.55 Factor X 67
• Lab results at 4 mg qd.
• INR 4.84 Factor X 31
• Therapeutic range
• INR 2.0 3.5 Factor X 43 - 17

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Case History 1

• 19-year-old female with venous thrombosis.
  Patient admitted with hot, swollen left leg. Past
  history or false positive VDRL.

22
Case History 2

• 35-year-old nurse complained of vision changes
  and headaches. Neurologic exam suggested
  thrombosis of retinal vein.

23
Case History 3

• 38-year-old white female referred for study due
  to a history of three spontaneous abortions.
  Patient had no history of thrombosis or bleeding
  tendency. The family history was also negative.