DESCRIPTION

Antiphospholipid antibodies (APA) are a group of heterogenous autoantibodies, including anticardiolipin and lupus anticoagulant autoantibodies, against phospholipid binding proteins.

• Clinical presentation is most commonly deep venous thrombosis of the legs; up to 50% of these patients will also have pulmonary emboli.
• Arterial thrombolic events are comparatively less common but up to 50% are transient ischemic attacks and stroke.
• Cardiac manifestations include coronary occlusions, valvular vegetations, intracardiac thrombi, and nonbacterial thrombolic endocarditis, pericardial effusions, myocardial infarction in young patient, early graft failure after coronary bypass grafting, and pulmonary HTN.

EPIDEMIOLOGY

• Young patients (<45 yr).
• APA antibodies are found in ~10% of patients with thromboembolic events.

RISK FACTORS

• Smoking
• Atherosclerosis
• HTN
• Long-term steroid administration

Pregnancy Considerations

• APA syndrome associated with:
  • Pregnancy morbidity consisting of recurrent fetal loss before the 10th wk of gestation, 1 or more fetal deaths at or beyond 10 wk of gestation
  • Premature birth due to placental insufficiency, eclampsia, or preeclampsia
  • Intrauterine growth retardation.

Genetics

APA positive families exist, association with HLA DR7, DR4, and DQW7 plus DRW53.

ETIOLOGY

• Unknown.
• Proposed mechanisms:
  • Inhibition of the protein C pathway.
  • Inactivation of factor Va-VIIa.
  • Inhibition of antithrombin III activation.
  • Impaired fibrinolysis.
  • Enhanced platelet activation.
  • Factor Xa generation.

COMMONLY ASSOCIATED CONDITIONS

• Primary APA syndrome:
• No evidence of underlying disease.
• Secondary APA syndrome:
  • Rheumatic and connective tissue disorders
  • Infections (HIV, Lyme disease, adenovirus, rubella, varicella, klebsiella, syphilis, hepatitis C)
  • Lymphoproliferative diseases
  • Medications (procainamide, hydralazine, chlorpromazine, quinidine, isoniazid, methyl-DOPA). Note: Acquired APA secondary to infection or medication is generally not associated with thrombosis
  • Acute alcohol intoxication

Outline

• Description
• Epidemiology
• Risk Factors
  • Pregnancy Considerations
  • Genetics
• Etiology
• Commonly Associated Conditions

Signs and symptoms:

• Asymptomatic
• Chest pain/shortness of breath: Acute mi/pulmonary embolus
• Transient ischemic attack/stroke or multicerebral infarcts
• Venous or arterial thrombosis
• Aortic or mitral murmurs
• Peripheral arterial/venous disease

DIAGNOSTIC TESTS & INTERPRETATION

EKG, echo

Lab

Initial lab tests

• Thrombocytopenia (50%); platelet dysfunction.
• Leukopenia, ITP
• Prolonged prothrombin time.
• Activated partial thromboplastin time prolonged.
• Plasma clot time prolonged.
• Anticardiolipin antibody enzyme-linked immunosorbent assay (ELISA).
• Lupus anticoagulant.
• Medium to high titers of IgG or IgM anticardiolipin antibodies or lupus anticoagulant on 2 or more occasions 6 wk apart.
• False-positive VDRL test result

Imaging

Initial approach

• Echo, M-mode, 2D, Doppler, and 3D
• Valve thickening
• Vegetations (Libman-Sacks): predilection for the ventricular surface of the mitral valve; typically sessile, small and firmly attached to the valve surface without independent motion
• Atrial thrombi.
• Ventricular enlargement/dysfunction.
• Mitral and aortic valve regurgitation: mitral > aortic
• Pulmonary HTN
• Pericardial effusion

DIFFERENTIAL DIAGNOSIS

• Hypercoagulable conditions: Protein C, S, antithrombin III deficiencies and plasminogen resistance
• Valvular heart disease
• Infective endocarditis.
• Atrial myxoma or neoplasm (primary and secondary)
• Coronary artery disease

Outline

• Information
• Diagnostic Tests & Interpretation
  • Lab
  • Imaging
• Differential Diagnosis

First Line

• Anticoagulants:
  • Unfractionated heparin
  • Enoxaparin (1 mg/kg q12h SC); obviates the need for laboratory monitoring.
  • Warfarin
• Aspirin:
  • Possible prophylactic value in asymptomatic patients
• Corticosteroids/immunosuppressants:
  • Value uncertain

• Treatment of asymptomatic patient with APA syndrome has not been defined because only 10–15% develop significant medical events, requires patient by patient determination.
• Patients with thrombolic events are appropriate patients for long-term anticoagulation with warfarin; the INR needs to be individualized to the clinical circumstance.

SURGERY

Cardiovascular surgery for valve disease based upon symptoms and severity of valve abnormalities

IN-PATIENT CONSIDERATIONS

Admission Criteria

Consider hospitalization for anticoagulation in thromboembolic events that have associated morbidity and mortality.

Outline

• Information
• Surgery
• In-Patient Considerations
  • Admission Criteria

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Careful monitoring of INR to maintain identified therapeutic range.

PROGNOSIS

• 10–15% of asymptomatic patients with APA antibodies will develop life-threatening thromboembolic events.
• Patients receive PO anticoagulants have no recurrence of venous/arterial thrombi up to 8 yr; patient that stop PO anticoagulants have had a 50% probability of recurrent thromboembolic events after 2 yr.
• Catastrophic APA syndrome has been reported with renal failure, myocardial infarction, and stroke.

Outline

• Follow-Up Recommendations
  • Patient Monitoring
• Prognosis

CODES

ICD9

289.81 Primary hypercoagulable state

SNOMED

• 26843008 antiphospholipid syndrome (disorder)
• 239892009 primary antiphospholipid syndrome (disorder)
• 239895006 secondary antiphospholipid syndrome (disorder)
• 19267009 lupus anticoagulant disorder (disorder)

ADDITIONAL READING

• Antiphospholipid antibody syndrome: Rapid, sensitive, and specific. How cytometric assay for determination of antiplatelet phospholipid autoantibodies. J Lab Clin Med Vol 2002;139(3):147–154.
• Greaves M. Antiphospholipid antibodies and thrombosis. Lancet 1999;353:1348–1358.
• Kuruvilla A. Warfarin in antiphospholipid antibody syndrome. Lancet 2001;358(9291):1461–1462.
• Murphy JG, Lloyd MA. Mayo Clinic Cardiology: Concise Textbook, 3rd ed. New York: Mayo Clinic Scientific Press; 2007.
• Rochella A, Ostrowski MD, Robinson JA. Antiphospholipid antibody syndrome and autoimmune diseases. Hematol Oncol Clin North Am 2008;22(1):53–65.
• Wendell W, Azzudin G, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Report of an international workshop. Arthritis Rheum. 1999;42:1309–1311.

Zachary Paterick

Timothy Paterick