Coverage Policy Manual
Policy #: 2003047
Category: Laboratory
Initiated: July 2003
Last Review: June 2018
  Antiprothrombin Antibody

Description: 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.

Policy/
Coverage:
Antiprothrombin antibody testing does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, antiprothrombin antibody testing is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
Donohoe in an editorial states that antiprothrombin antibodies are members of the ill-defined, heterogeneous family of antiphospholipid antibodies and helps define the antiphospholipid syndrome as presented in thromboembolic complications, recurrent miscarriage, or immune thrombocytopenia (Donahue, 2001). How antiphospholipid antibodies contribute to the pathophysiology of clinical complications in vivo is poorly understood.
 
The classic assays used for the detection of antiphospholipid antibodies measure a heterogenous mixture of antibodies, without distinguishing antigenic specificity. Antibodies to beta-2 glycoprotein I are strongly associated with thrombosis, but their role in other clinical presentations is less clear.
 
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 (Merrill, 2001). 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 (Merrill, 2001). 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.
 
2010 Update
A search of the MEDLINE database was conducted through January 2010. There was no published literature identified that would prompt a change in the coverage statement.
 
In 2007, Tincani and colleagues compared the performance of different antiprothrombin assays (Tincani, 2007). Samples from patients positive for lupus anticoagulant activity and/or anticardiolipin antibodies with or without antiphospholipid syndrome and from patients with rheumatoid arthritis negative for antiphospholipid antibodies were evaluated for IgG and IgM using five different methods. The authors report, “While aPT and aPS/PT assays could be of interest from a clinical perspective, their routine performance cannot yet be recommended because of problems connected with the reproducibility and interpretation of the results”.
 
2012 Update
A literature review was conducted using the MEDLINE database through May 2012.  There was no new literature identified that would prompt a change in the coverage statement.  
 
2013 Update
A search of the MEDLINE database was conducted through May 2013. No randomized controlled trials or  other publications were identified which would prompt a change in the coverage statement.
 
In 2012, the American College of Obstetricians and Gynecologists published an updated practice bulletin on antiphospholipid syndrome (ACOG, Practice Bulletin 132, 2012). The bulletin outlines laboratory criteria for the diagnosis of antiphospholipid syndrome. There is no mention of antiprothrombin antibody testing for the diagnosis or management of antiphospholipid syndrome.
 
2014 Update
A literature search conducted using the MEDLINE database through May 2014 did not reveal any new information that would prompt a change in the coverage statement.
   
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Amengual and colleagues performed a comparative analysis of different enzyme immunoassays for assessment of phosphatidylserine-dependent antiprothrombin antibodies (Amengual, 2014). Phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) were strongly correlated with the presence of lupus anticoagulant showing a high specificity for the diagnosis of antiphospholipid syndrome. However, the main criticism for the clinical applicability of aPS/PT testing is the lack of reproducibility of the results among laboratories. In this study, we measured IgG and IgM aPS/PT using our original in-house enzyme-linked immunosorbent assays (ELISA) and commercial ELISA kits to assess the assay performance and to evaluate the accuracy of aPS/PT results. The study included 111 plasma samples collected from patients and stored at our laboratory for aPS/PT assessment. Sixty-one samples were tested for IgG aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite™ aPS/PT IgG ELISA kit (INOVA Diagnostics, Inc., USA). Fifty samples were evaluated for IgM aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite™ aPS/PT IgM ELISA kit (INOVA Diagnostics). Ninety-eight percent of samples yielded concordant results for IgG aPS/PT and 82 % for IgM aPS/PT. There was an excellent agreement between the IgG aPS/PT assays (Cohen κ = 0.962) and moderate agreement between the IgM aPS/PT assays (κ = 0.597). Statistically significant correlations in the aPS/PT results were obtained from both IgG and IgM aPS/PT assays (r = 0.749, r = 0.622, p < 0.001, respectively). The conclusion, of this study is IgG and IgM detection by ELISA is accurate. The performance of aPS/PT is reliable, and concordant results can be obtained using different ELISA methods.
 
2016 Update
A literature search conducted through May 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search conducted through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
 

CPT/HCPCS:
86849Unlisted immunology procedure

References: Amengual O, Horita T, Binder W, et al.(2014) Comparative analysis of different enzyme immunoassays for assessment of phosphatidylserine-dependent antiprothrombin antibodies. . Rheumatol Int. 2014 Sep;34(9):1225-30.

American College of Obstetricians and Gynecologists (ACOG). Antiphospholipid syndrome. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2012 December 120(6). (ACOG practice bulletin; no. 132).

Aziz, Douglas C.(2000) Antiphospholipid syndrome. Tiwary Clinical Lab online 2000, http://www.tclonline.com/referance/antiphospho.htm.

Corgenix, Inc.(2000) Antibodies to cofactors: Significance of antiprothrombin antibodies in the antiphospholipid syndrome. The Reader 2000; February, Vol 10, #1.

Donohoe, Siobhan.(2001) Detection and clinical associations of antiprothrombin antibodies. Am J Med 2001; February; Vol 110, No 3.

Kalashnikova LA, Korczyn AD, et al.(1999) Antibodies to prothrombin in patients with Sneddon’s syndrome. Neurology 1999; July, Vol 53, #1.

Merrill JT.(2001) Which antiphospholipid antibody tests are most useful. Rheumatic Diseases Clinics North America; August 2001, Vol 27, #3.

Thomas, Rhonda.(2001) Anti-prothrombin antibody assay IgG and IgM. CompuNet Clinical Laboratories 2001, http://www.compunetlab.com/home/publication/0402a.htm.

Tincani A, Morozzi G, Afeltra A, et al.(2007) Antiprothrombin antibodies: a comparative analysis of homemade and commercial methods. A collaborative study by the Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA). Clin Exp Rheumatol. 2007 Mar-Apr;25(2):268-74.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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