Antiphospholipid syndrome (APS) is an autoimmune disorder in which autoantibodies are directed against phospholipid-protein complexes. APS is characterized by thrombosis (arterial, venous, or small vessel) and/or pregnancy complications and persistently positive tests for antiphospholipid-protein (aPL) antibodies.

Epidemiology

• Prevalence
  • aPL antibodies are an acquired thrombotic risk factor
    • Present in a small percentage of young healthy subjects (1-5%) and in up to 10% of patients with venous thrombosis
      • Estimates of prevalence are hampered by the variety of testing systems available for diagnosis
  • Higher prevalence in patients with connective tissue disease, but most patients with aPL antibodies do not have an underlying autoimmune disease

Risk Factors

• Connective tissue disease
  • Systemic lupus erythematosus  – up to 50% of patients
• Infections – no increase in thrombotic risk
• Malignancy
• Liver disease
• Vascular disease
• Medications – increased thrombotic risk

Pathophysiology and Basis for Laboratory Tests

• Proposed mechanisms for thrombosis include endothelial cell damage or activation, platelet activation, and interference with the function of anticoagulant protein function
• LAs are autoantibodies that target complexes of phospholipids with either β2GP1 or another plasma protein such as prothrombin
  • LAs usually demonstrate an inhibitor effect in laboratory clotting tests by interfering with phospholipid-dependent clotting reactions
  • Prolongation of clotting times (apparent anticoagulation) is an in vitro laboratory phenomenon; in vivo thrombosis is much more common than bleeding
• aPL antibodies are often classified as either lupus anticoagulant (LA), or anticardiolipin (aCL) antibodies, or anti-beta-2 glycoprotein 1 (β2GP1) antibodies
  • Thrombosis appears to be more common in patients with LA activity
  • Positivity for all 3 (LA activity, aCL and β2GP1 antibodies) is a strong independent risk factor for thrombosis
• Transient aPL antibodies may occur in association with infections and with certain medications (procainamide, hydralazine, quinidine, chlorpromazine, penicillin)

Clinical Presentation

• Venous, arterial, or small vessel thrombosis, and/or obstetric complications
• Other potential abnormalities include cytopenias or other hematologic disorders, and neurologic, dermatologic, or cardiopulmonary abnormalities
• Catastrophic APS is a multi-organ illness caused by diffuse small vessel thrombosis and tissue ischemia

Treatment

• Treatment decisions depend on the extent of clinical symptoms and may range from no treatment to long-term anticoagulation therapy

Indications for Testing

• Recurrent vascular thromboses, recurrent pregnancy loss, unexplained prolonged PTT in an asymptomatic patient (indication for lupus anticoagulant testing)
• Additional indications for testing may also include the presence of endocarditis, livedo reticularis, thrombocytopenia, hemolytic anemia, and thrombotic microangiopathy

Criteria for Diagnosis

• Revised classification criteria for the antiphospholipid antibody syndrome

  Revised Classification Criteria for the Antiphospholipid Antibody Syndrome
  (At least 1 clinical and 1 laboratory criterion must be met)
  Clinical criteria Vascular thrombosis – One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ validated by imaging studies or histopathology Pregnancy morbidity One or more unexplained deaths of a morphologically normal fetus after 10th week of gestation One or more premature births of a morphologically normal neonate before the 34th week of gestation due to preeclampsia, eclampsia, or placental insufficiency Three or more unexplained, consecutive, spontaneous abortions before 10th week of gestation, and with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded	Laboratory criteria Positive test on 2 or more occasions at least 12 weeks apart Lupus anticoagulant – detected in plasma according to the guidelines of the International Society on Thrombosis and Hemostasis aCL antibody – IgG and/or IgM isotype present in a medium or high titer (>40 GPL or MPL or >99th percentile), measured by standardized ELISA Anti-β2GP1antibody – IgG and/or IgM isotype in high titer (>99th percentile), measured by standardized ELISA
  GPL – IgG phospholipid antibody; MPL – IgM phospholipid antibody; ELISA – enzyme-linked immunosorbent assay

Laboratory Testing

• Current recommendations for first-line laboratory testing should include the following
  • LA activity
    • At least 2 phospholipid-dependent clotting assays, based on different principles, should be performed to identify LA activity
  • aCL IgG and IgM antibodies
  • β2GP1 IgG and IgM antibodies
• Repeat positive laboratory tests after 12 weeks to confirm persistent positivity
• Repeat testing if a strong clinical suspicion exists for APS but criteria laboratory tests are negative (seronegative APS)
  • Also consider the following tests
    • aCL antibody, IgA
    • β2GP1 antibody, IgA
    • Phosphatidylserine antibodies, IgG, IgM, & IgA
    • Prothrombin antibodies, IgG and IgM

Differential Diagnosis

• Inherited thrombophilia
• Connective tissue disease
  • SLE
• Malignancy

• Not recommended for patients with single deep vein thrombosis unless a risk factor is present
• Test for antibodies in the following situations
  • Thrombosis
    • Arterial thrombosis <50 years
    • Unprovoked venous thrombosis <50 years
    • Recurrent thrombosis
    • Thrombosis at unusual site
    • Patients with both arterial and venous thrombotic events
    • Patients admitted with thrombotic microangiopathy of unknown etiology
  • Obstetric manifestations
    • ≥1 unexplained fetal loss after 10th week of gestation
    • Unexplained severe intrauterine growth restriction
    • Early or severe preeclampsia
    • ≥3 spontaneous miscarriages before 10th week of gestation
  • Patients with SLE 
    • Perform baseline test
    • Repeat testing
      • Before pregnancy, surgery, transplantation, and use of estrogen-containing treatments
      • Presence of a new neurologic, vascular or obstetric event

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Antiphospholipid syndrome. American College of Obstetricians and Gynecologists - Medical Specialty Society. 2005 November (Revised 2011 January). NGC:008207
• Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006; 4 (2) :295-306.PubMed
• Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, De Groot PG. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost. 2009; 7 (10) :1737-1740.PubMed
• Wong RC, Favaloro EJ. A consensus approach to the formulation of guidelines for laboratory testing and reporting of antiphospholipid antibody assays. Semin Thromb Hemost. 2008; 34 (4) :361-372.PubMed

General

• Avcin T. Antiphospholipid syndrome in children. Curr Opin Rheumatol. 2008; 20 (5) :595-600.PubMed
• Baker WF Jr, Bick RL. The clinical spectrum of antiphospholipid syndrome. Hematol Oncol Clin North Am. 2008; 22 (1) :33-vi.PubMed
• Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ. 2010; 340 :c2541-.PubMed
• Devreese K, Hoylaerts MF. Challenges in the diagnosis of the antiphospholipid syndrome. Clin Chem. 2010; 56 (6) :930-940.PubMed
• Galli M. Clinical utility of laboratory tests used to identify antiphospholipid antibodies and to diagnose the antiphospholipid syndrome. Semin Thromb Hemost. 2008; 34 (4) :329-334.PubMed
• George D, Erkan D. Antiphospholipid syndrome. Prog Cardiovasc Dis. 2009; 52 (2) :115-125.PubMed
• Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood. 2009; 113 (5) :985-994.PubMed
• Hoppensteadt DA, Fabbrini N, Bick RL, Messmore HL, Adiguzel C, Fareed J. Laboratory evaluation of the antiphospholipid syndrome. Hematol Oncol Clin North Am. 2008; 22 (1) :19-32, v.PubMed
• Horstman LL, Jy W, Bidot CJ, Ahn YS, Kelley RE, Zivadinov R, Maghzi AH, Etemadifar M, Mousavi SA, Minagar A. Antiphospholipid antibodies: paradigm in transition. J Neuroinflammation. 2009; 6 :3-.PubMed
• Lim W, Crowther MA. Antiphospholipid antibiodies: a critical review of the literature. Curr Opin Hematol. 2007; 14 (5) :494-499.PubMed
• Rigante D, Gaspari S, Bersani G, Stabile A. Anti-phospholipid syndrome: clinical spectrum and therapeutical/prophylactic strategies in the pediatric population. Eur Rev Med Pharmacol Sci. 2008; 12 (1) :47-53.PubMed
• Saultz A, Mathews EL, Saultz JW, Judkins D. Clinical inquiries. Does hypercoagulopathy testing benefit patients with DVT?. J Fam Pract. 2010; 59 (5) :291-294.PubMed
• Uthman I, Godeau B, Taher A, Khamashta M. The hematologic manifestations of the antiphospholipid syndrome. Blood Rev. 2008; 22 (4) :187-194.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Jaskowski TD, Wilson AR, Hill HR, Branch WD, Tebo AE. Autoantibodies against phosphatidylserine, prothrombin and phosphatidylserine-prothrombin complex: identical or distinct diagnostic tools for antiphospholipid syndrome?. Clin Chim Acta. 2009; 410 (1-2) :19-24.PubMed
• Smock KJ, Rodgers GM. Laboratory identification of lupus anticoagulants. Am J Hematol. 2009; 84 (7) :440-442.PubMed
• Tebo AE, Jaskowski TD, Hill HR, Branch DW. Clinical relevance of multiple antibody specificity testing in anti-phospholipid syndrome and recurrent pregnancy loss. Clin Exp Immunol. 2008; 154 (3) :332-338.PubMed
• Tebo AE, Jaskowski TD, Phansalkar AR, Litwin CM, Branch DW, Hill HR. Diagnostic performance of phospholipid-specific assays for the evaluation of antiphospholipid syndrome. Am J Clin Pathol. 2008; 129 (6) :870-875.PubMed

Factor Deficiencies, Uncommon
Hypercoagulable States
Infertility
N-methyl-D-Aspartate (NMDA) type Glutamate Receptor Autoantibody Disorders
Systemic Lupus Erythematosus
Thrombotic Microangiopathies
Treponema pallidum
Venous Thromboembolism