This application addresses Challenge Topic 03-HL-101* to identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood and vascular dysfunction - specifically, the antiphospholipid syndrome (APS) an autoimmune thrombotic condition that is reported to be responsible for ~10% of patients with venous thromboembolic disease, one of the leading causes of mortality and morbidity that results in ~ 300,000 hospitalizations and 50,000 fatalities annually APS is currently diagnosed through empirical tests for antiphospholipid (aPL) antibodies that were developed over 25 years ago - the aPL immunoassays which were derived from the """"""""biologic false positive syphilis"""""""" test and a coagulation inhibitor known as the lupus anticoagulant (LA). These assays do not test disease mechanisms and have poor specificities and sensitivities and predictive values. Moreover, because of their limitations, the current tests do not permit diagnosis until after patients have already had at least one adverse clinical event. However, there have been significant recent advances in knowledge of the pathophysiology of APS that are likely to have a major impact on diagnosis. These include: 1) Identification of a mechanism - the antibody-mediated disruption of the potent vascular and placental anticoagulant protein, annexin A5 - has been defined, for which we developed a robust functional assay, the annexin A5 resistance (A5R) assay, validated in several blinded studies of small well defined groups, wherein this mechanism is consistently identified in at least half of all patients currently defined as having APS. 2) Identification of a specific target epitope for the autoantibodies - domain I (D1) of beta-2-glycoprotein I - that also correlates with significantly increased risks of thrombosis and pregnancy losses. The assay for anti-D1 IgG has been shown to correlate with A5R. This grant application is therefore focused on validating these 2 new and related biomarkers for a thrombogenic APS mechanism: 1) the annexin A5 resistance (A5R) assay and 2) an immunoassay for antibodies to domain I of beta-2-glycoprotein I (anti-D1), an epitope that correlates with Annexin A5 resistance. Montefiore Medical Center (MMC) is the major academic medical center in Bronx, NY that serves the 1.5 million residents of one of the poorest urban counties in the US. MMC has the patient base and resources for successful completion of these studies within the 2 year Challenge Grant time frame. We currently perform over 2,700 diagnostic aPL panels annually on patients suspected of having APS. MMC's computerized health record system, access to anonymized samples, laboratory facilities, and our research base on APS, ideally position us to complete this project over the 2 year time frame. This project is likely to result in validation of significant new mechanistic biomarkers that are likely to have a direct impact on improving the diagnosis and treatment of patients with APS and also fulfill the economic intents of the ARRA.
This application addresses Challenge Topic 03-HL-101* to identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood and vascular dysfunction - specifically, the antiphospholipid syndrome (APS). This grant application is therefore focused on validating these 2 new and related biomarkers for a thrombogenic APS mechanism: 1) the annexin A5 resistance (A5R) assay and 2) an immunoassay for antibodies to domain I of beta-2-glycoprotein I (anti-D1), an epitope that correlates with Annexin A5 resistance.
