mp-096 - Medical Policies - Alabama
Policy Number: MP-096
Latest Review Date: June 2019
Policy Grade: Active Policy but no longer scheduled for regular literature reviews and updates.
DESCRIPTION OF PROCEDURE OR SERVICE:
Antiphospholipid antibodies are a heterogeneous group of immunoglobulins that bind to several anionic phospholipids, to phospholipid-protein complexes and to certain proteins in the absence of phospholipids. Several plasma proteins mostly associated with the coagulation system and characterized with strong phospholipid binding properties, have been labeled as antiphospholipid cofactors. These are thought to play an important part in the antiphospholipid syndrome (APS). The most common and extensively studied cofactors are Beta 2-Glycoprotein 1 and Prothrombin. The four clinical features common in patients with antiphospholipid syndrome are venous thrombosis, arterial thrombosis, pregnancy loss, and thrombocytopenia. Thrombosis is the most common presentation of antiphospholipid syndrome.
APS is much more common than previously appreciated. Young patients presenting with thrombosis, myocardial infarction or stroke or a woman with a history of pregnancy loss should be investigated for APS. The diagnosis depends on finding at least one of the hallmark features and a positive laboratory test. The laboratory findings include the presence of antiphospholipid antibodies (aPL). Clinically, elevated levels of these antibodies (Beta 2-Glycoprotein 1 or Prothrombin) are associated with increased risk for antiphospholipid syndrome. Recently, enzyme linked immunosorbent assay (ELISA) methods to measure antiprothrombin (aPT) antibodies have become available and many clinical laboratories are incorporating them for the serologic evaluation of APS. Protein cofactors for aPL are thought to play an important role in the pathogenesis of thrombosis in patients with APS.
Antiprothrombin antibody is considered not medically necessary and investigational.
Policy was updated with literature review performed on May 24, 2019.
Lim defines the antiphospholipid syndrome (APS) by venous or arterial thrombosis and/or pregnancy morbidity in patient with persistent presence of antiphospholipid antibodies (aPLs). Patients with APS and catastrophic APS (associated with rapid development of microvascular thrombosis resulting in multiorgan failure in patient with aPLs) have a high risk of recurrent thrombosis that can occur despite anticoagulant therapy. Although antithrombotic therapy remains the mainstay of treatment, bleeding manifestations can complicate management and contribute to increasing morbidity. The optimal type, intensity, and duration of anticoagulation in the treatment of APS remain controversial, particularly for arterial thrombosis and recurrent thrombosis. Future studies that delineate thrombotic risk in APS and evaluate current novel anticoagulants as well as nonanticoagulant therapies are required.
Merrill states that due to the heterogeneity of autoantibodies found in patients with this syndrome, the detection of antiphospholipid antibodies by currently available tests does not predict the likelihood of thrombosis or the time at which such an event may occur. A direct pathogenic role for the antibodies is supported by the observation that high titer and IgG isotype confer an increased risk of thrombosis. Merrill also questions if there are currently available assays that can at least improve the prediction of pathogenicity and allow treatments to be initiated for some patients before a life-threatening event. His response is no, citing that the sensitivity, specificity and consistency of currently available diagnostic tests remain inadequate for this purpose. There is a need to have prospective studies and multivariate analysis to define antibody-associated risk markers remain be performed. In the summary, Merrill states that while there is an effort to improve diagnosis and treatment of antiphospholipid syndrome (Hughes syndrome), there remain problems of lack of standardization and lack of analyses that restrict the diagnostic and predictive ability of commercially available tests.
Giannakopoulous et al and Reber et al examine the laboratory and key clinical aspects of APS with particular focus on anti-beta 2-glycoprotein I (beta(2)GPI) antibodies in view of their recent inclusion in the APS classification criteria. The laboratory is as follows: The presence of one or more of the following antiphospholipid antibodies (aPL) on two or more occasions at least 12 weeks apart:
- IgG and/or IgM anticardiolipin antibodies (aCL) in moderate or high titer (>40 GPL or MPL units, respectively, or a titer >99th percentile for the testing laboratory), measured by a standardized enzyme-linked immunosorbent assay (ELISA).
- IgG and/or IgM anti-beta2-glycoprotein (GP) I >40 GPL or MPL units, respectively, or a titer >99th percentile for the testing laboratory, measured by a standardized ELISA according to recommended procedures.
- Lupus anticoagulant (LA) activity detected according to published guidelines.
The revised Sapporo criteria also indicate that the presence or absence of additional risk factors for thrombosis should be recognized among patients. Such patient stratification provides additional information that may be useful for research and for treatment, but does not alter the diagnosis. The revised Sapporo criteria are considered useful in clinical practice to avoid “over-diagnosis” of APS.
Atsumi et al (2010) stated that anticardiolipin antibodies (aCL), anti-beta (2)-glycoprotein I (beta (2) GPI) antibodies and lupus anticoagulant (LA) are the only laboratory tests considered within the revised criteria for the classification of the antiphospholipid syndrome (APS).Recently, the significance to assay the antibodies against phosphatidylserine-prothrombin complex (aPS/PT) has been discussed, and these antibodies, rather than antibodies against prothrombin alone, are closely associated with APS and LA. The sensitivity and specificity of aPS/PT for the diagnosis of APS were assessed in a population of patients with a variety of autoimmune disorders. The aCL and aPS/PT have similar diagnostic value for APS, and most of APS patients with aPS/PT had positive LA. Therefore, aPS/PT should be further explored, not only for research purposes, but also as a candidate for one of the enzyme-linked immunosorbent assay (ELISA)-based confirmatory test for APS associated LA.
The Laboratory Diagnostics and Trends APS Task Force of the 14th International Congress on aPL concluded that low-quality evidence exists to include IgA isotype as part of the APS Classification Criteria, especially since these isotopes are usually associated with other aPL, making it difficult to understand the role of IgA alone. Current classification criteria for definite APS require the use of three laboratory assays to detect antiphospholipid antibodies in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive.
Summary of Evidence
At this time, antiprothrombin antibody patient stratification provides additional information that may be useful for research and for treatment, but does not alter the diagnosis. The utility of this testing cannot be proven at this time and therefore is considered not medically necessary and investigational.
Practice Guidelines and Position Statements
Guidelines on Anti-phospholipid syndrome (APS) from the American College of Obstetricians and Gynecologists (ACOG, 2005) stated that testing for anti-prothrombin antibodies "cannot be recommended for clinical use at this time."
U.S. Preventative Services Task Force
Prothrombin, antiprothrombin antibody, antiphospholipid antibody, APL, antiphospholipid syndrome, APS, Hughes syndrome, beta-2 glycoprotein I, thrombosis, pregnancy loss, thrombocytopenia
APPROVED BY GOVERNING BODIES:
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply. Refer to member’s benefit plan.
Unlisted Immunology procedure
- American College of Obstetricians and Gynecologists (ACOG). Clinical Management Guidelines for Obstetrician-Gynecologists. ACOG Practice Bulletin, November 2005, No. 68.
- Atsumi T and Koike T. Antiprothrombin antibody: why do we need more assays? Lupus, 2010 Apr; 19(4):436-9
- Aziz, Douglas C. Antiphospholipid syndrome, Tiwary Clinical Lab online, www.tclonline.com/referance/antiphospho.htm.
- Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, de Groot P, Lakos G, Lambert M, Meroni P, Ortel TL, Petri M, Rahman A, Roubey R, Sciascia S, Snyder M, Tebo AE, Tincani A, Willis R. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014 Sep;13(9):917-30. Epub 2014 May 10.
- Bertolaccini ML, Gomez S, et al. Antiphospholipid antibody tests: Spreading the net. Annals of the Rheumatic Diseases 2005; 64: 1639-1643.
- Corgenix, Inc. Antibodies to cofactors: Significance of anti-prothrombin antibodies in the antiphospholipid syndrome. The Reader, February 2000, Vol. 10, No. 1.
- Donohoe, Siobhan. Detection and clinical associations of antiprothrombin antibodies. American Journal of Medicine, February 2001, Vol. 110, No. 3.
- Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood. 2009;113(5):985
- Kalashnikova, L.A., Korczyn, A.D., et al. Antibodies to prothrombin in patients with Sneddon’s syndrome. Neurology, July 1999, Vol. 53, No. 1.
- Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2013;2013:675-80.
- Lopez Luis R, Dier Ken J, et al. The prevalence and clinical significance of antiprothrombin antibodies in patients with antiphospholipid syndrome. American Biotechnology Laboratory, April 2003.
- Merrill, Joan T. Which antiphospholipid antibody tests are most useful?, Rheumatic Diseases Clinics of North America, August 2001, Vol. 27, No. 3.
- 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.
- Oku K, Atsumi T, Amengual O, Koike T. Antiprothrombin antibody testing: Detection and clinical utility. Semin Thromb Hemost. 2008; 34(4):335-339.
- Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, De Groot PG, Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7(10):1737.
- Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC, Standardization group of the European Forum on Antiphospholipid Antibodies. Proposals for the measurement of anti-beta2-glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost. 2004;2(10):1860.
- Thomas, Rhonda. Anti-prothrombin antibody assay IgG and IgM. CompuNet Clinical Laboratories, www.compunetlab.com/home/publication/0402a.htm.
Medical Policy Group, February 2003, (1)
Medical Policy Administration Committee, February 2003
Available for comment February 19-April 7, 2003
Medical Policy Group, February 2005 (1)
Medical Policy Group, February 2007 (1)
Medical Policy Group, February 2009 (1)
Medical Policy Group, June 2011 (1) Update to Key Points and References
Medical Policy Group, September 2012 (3): Active Policy but no longer scheduled for regular literature reviews and updates.
Medical Policy Group, November 2012: 2013 Coding Update – added Code 86849
Medical Policy Group, June 2019 (9): Update to Description, Key Points and References. No change to policy statement.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
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