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Background
Anti-phospholipid syndrome (APS) is an autoimmune condition characterized by moderate-to-high levels of circulating anti-phospholipid antibodies and the presence of venous and arterial thromboses, autoimmune thrombocytopenia, fetal loss, and other clinical features, including transient ischemic attacks, amaurosis fugax, Coombs-positive hemolytic anemia, and livedo reticularis.
Most patients with APS have lupus anti-coagulant and anti-cardiolipin antibodies. However, some patients with APS have either lupus anti-coagulant or anti-cardiolipin antibodies, but not both. Thus, tests for both antibodies should be performed to confirm the diagnosis of APS (ACOG, 1998). Anti-cardiolipin antibodies are detected by conventional immunoassays. There is no direct test for the lupus anti-coagulant (LA); detection is based upon its inhibitory actions on coagulation.
Other autoantibodies have been associated with APS, including those reactive with prothrombin. However, current guidelines state that the clinical significance of anti-prothrombin antibodies has not been defined (British Committee for Standards in Haematology, 2000; ACOG, 1998). The Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology reached the following conclusion: “Antiprothrombin antibodies generally exhibit poor specificity for venous thrombosis and recurrent fetal loss and may be found in patients with infection. Their precise clinical significance is not yet clear. One report has claimed an association with myocardial infarction, but more work is required to clarify the clinical importance of this observation.”
In a review of the literature, Galli and Barbui (1999) stated that "[t]he question whether antiprothrombin antibodies increase the risk of thromboembolic events remains unanswered .…The retrospective nature of these studies [of antiprothrombin antibody and antiphospholipid syndrome] prevents from drawing definite conclusions. Only 1 prospective study has been performed that confirmed the association between high titers of antiprothrombin antibodies and an increased risk of developing myocardial infarction, which is not one of the typical features of the antiphospholipid syndrome. Therefore, more "cross-sectional" or prospective clinical studies are warranted to establish the clinical relevance of antiprothrombin antibodies."
Donohoe (2001) has concluded that “[l]ongitudinal studies are required to asses the predictive value of these antibodies. Pending those results, testing for antiprothrombin antibodies should remain a research procedure, as the detecting of those antibodies adds little to the clinical diagnosis and management of individual patients.”
Identification of APS means that many patients who were in the past diagnosed as suffering from a "vasculitis" and treated with anti-inflammatory regimes and high-dose corticosteroids, will, if found to be suffering from APS, respond better to anti-coagulation therapy (GP Notebook, 2001). First-line treatment for APS is low-dose aspirin. Patients with APS who have had a documented major thrombotic event require long-term treatment with warfarin or coumarin anti-coagulation.
Women with APS should be treated during pregnancy with thromboprophylactic doses of heparin and low-dose aspirin. Close obstetric care is indicated in all cases because of an increased risk of pregnancy-induced hypertension, fetal growth restriction, and a non-reassuring fetal heart rate pattern (ACOG, 1998).
von Landenberg et al (2003) documented the association of IgG anti-prothrombin antibodies with pregnancy loss and in particular early pregnancy loss in a large group of young female patients with APS. These researchers recommended routine testing for anti-prothrombin antibodies in young female patients with APS. However, they also stated that there is a need for further prospective studies to confirm the association between anti-prothrombin antibodies and pregnancy loss. Furthermore, Lopez et al (2004) reported weak predictive value and association with pregnancy morbidity of 4 anti-phospholipid antibodies (e.g., anti-prothrombin antibodies) in patients with systemic lupus erythematosus and patients with APS.
Guidelines on 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."
Tincani et al (2007) stated that prothrombin (PT) is a target for antibodies with LA activity, suggesting the possible application of anti-prothrombin antibody (aPT) assays in patients with APS. Different methods -- both homemade and commercial -- for the detection of aPT are available, but they seem to produce conflicting results. These researchers compared the performance of different assays on a set of well-characterized serum samples. Sera were gathered from 4 FIRMA institutions, and distributed to 15 participating centers. A total of 45 samples were from patients positive for LA and/or anti-cardiolipin antibodies (aCL) with or without APS, and 15 were from rheumatoid arthritis (RA) patients negative for anti-phospholipid antibodies. The samples were evaluated for IgG and IgM antibodies using a homemade direct aPT assay (method 1), a homemade phosphatidylserine-dependent aPT assay (aPS/PT, method 2), and 2 different commercial kits (methods 3 and 4). In addition, a commercial kit for the detection of IgG-A-M aPT (method 5) was used. Inter-laboratory results for the 5 methods were not always comparable when different methods were used. Good inter-assay concordance was found for IgG antibodies evaluated using methods 1, 3, and 4 (Cohen k greater than 0.4), while the IgM results were discordant between assays. In patients with thrombosis and pregnancy losses, method 5 performed better than the others. The authors concluded that while aPT and aPS/PT assays could be of interest from a clinical perspective, their routine performance can not yet be recommended because of problems connected with the reproducibility and interpretation of the results.
Oku et al (2008) stated that aCL, anti-beta2 glycoprotein I antibodies, and LA are the only laboratory tests considered within the revised criteria for the classification of the APS. Recently, antibodies against aPS/PT have been detected, and these antibodies, rather than antibodies against PT 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; aCL and aPS/PT have similar diagnostic value for APS, therefore aPS/PT should be further explored, not only for research purposes but also as a candidate for one of the laboratory criteria for the classification of the APS.
The Obstetric APS Task Force of the 13th International Congress (Branch, 2011) identified and discussed 5 general topics within "Obstetric" APS that contained areas of controversy or uncertainty: (i) recurrent early miscarriage (REM), (ii) fetal death, (iii) delivery less than 34 weeks for severe pre-eclampsia or placental insufficiency, (iv) post-partum care, and (v) long-term implications and care. The Task Force concluded that the frequency with which women with REM have a high titer of anti-phospholipid antibodies (aPL) or LA is somewhat controversial, especially with regard to the diagnostic titers required by the current international criteria for APS. Also, treatment trials involving heparin differ from one another with regard to the patients included and the outcomes achieved. Similarly, the frequency with which women with fetal death or delivery less than 34 weeks for severe pre-eclampsia or placental insufficiency have a high titer of aPL or LA is poorly defined, and there is no level I evidence to guide treatment in either group. Suggestions for future studies with regard to both REM and fetal death or delivery less than 34 weeks for severe pre-eclampsia or placental insufficiency were discussed. Post-partum and long-term care in women with APS diagnosed solely for obstetric criteria has been largely guided by expert opinion, and systematic evaluations of these populations would be welcome.
Sater et al (2012) examined the association of antibodies to β2-glycoprotein I (anti-β2GPI), cardiolipin (ACA), phosphatidylserine (anti-PS) and prothrombin (anti-PT) with recurrent spontaneous miscarriage (RSM). This was a case-control study involving 277 RSM cases and 288 controls. Autoantibody levels were measured by ELISA. Differences between cases and controls were analyzed by non-parametric Mann-Whitney test, and logistic regression was used in analyzing the association of autoantibodies with RSM. Anti-PS IgG, ACA IgM and IgG, and anti-PT IgM were significantly associated with RSM risk, and differential antibody association was noted according to BMI and primary and secondary RSM. Higher prevalence of elevated anti-PS IgG was seen in cases, with the strongest risk above the 99th percentile. For ACA IgM, 28 cases (10.1 %) and 5 controls (1.7 %) were positive, with increasing OR for increasing cut-off points, which was significant at antibody titers greater than 99th percentile. For ACA IgG, 101 cases (36.5 %) and 13 controls (4.5 %) were positive, with graded increase in OR for increasing cut-off points, which was significant at titers greate than 90th percentile (maximal at titers greater than 99th percentile). For anti-PT, 23 cases (12.0 %) and 9 controls (6.1 %) were positive, with increased OR at titers greater than 90th percentile. Regression analyses confirmed the independent association of anti-PS IgG, ACA IgM and IgG with RSM, and significant RSM risk was associated with high anti-PS IgG (p < 0.001) and ACA IgM (p < 0.001) titers, and a dose-dependent increase in RSM risk was seen with progressively increased ACA IgG titers. No significant association existed between anti-PT IgM and RSM.
Zigon et al (2013) stated that anti-prothrombin antibodies, measured with phosphatidylserine/prothrombin complex (aPS/PT) ELISA, have been reported to be associated with APS. They are currently being evaluated as a potential classification criterion for this autoimmune disease, characterized by thromboses and obstetric complications. Given the present lack of clinically useful tests for the accurate diagnosis of APS, these researchers evaluated in-house and commercial assays for determination of aPS/PT as a potential serological marker for APS. They screened 156 patients with systemic autoimmune diseases for antibodies against PS/PT, β₂-glycoprotein I, cardiolipin and for lupus anticoagulant activity. These investigators demonstrated a high degree of concordance between the concentrations of aPS/PT measured with the in-house and commercial assays. Both assays performed comparably relating to the clinical manifestations of APS, such as arterial and venous thromboses and obstetric complications. IgG aPS/PT represented the strongest independent risk factor for the presence of obstetric complications, among all tested aPL. Both IgG and IgM aPS/PT were associated with venous thrombosis, but not with arterial thrombosis. Most importantly, the association between the presence of IgG/IgM aPS/PT and lupus anticoagulant activity was highly significant. The authors concluded that aPS/PT antibodies detected with the in-house or commercial ELISA represent a promising serological marker for APS and its subsets.
Furthermore, an UpToDate review on “Pathogenesis of the antiphospholipid syndrome” (Bermas and Schnur, 2014) states that “Future studies and further refinement of APS assays are likely to clarify the role of antibodies to prothrombin, annexin V, phosphatidylserine, and other aPL targets”.
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