title: Correlation between the potency of a beta2-glycoprotein I-dependent lupus anticoagulant and the level of resistance to activated protein C.
abstract: The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies in plasma of patients. It has been published that antibeta2-glycoprotein I (beta2-GPI) antibodies, with lupus anticoagulant activity (LAC), highly correlate with thrombosis. Resistance related to antiphospholipid antibodies against activated protein C (APC) is one of the proposed mechanisms responsible for thrombosis. We investigated a possible correlation between a beta2-GPI-dependent LAC (titration of cardiolipin into an activated partial thromboplastin time-based assay) and increased APC resistance in a population of 22 plasma samples with LAC activity. Eleven plasma samples that displayed a beta2-GPI-dependent LAC also showed increased APC resistance. In contrast, only one of the 11 plasma samples with a beta2-GPI-independent LAC displayed increased APC resistance. In addition, a monoclonal antibeta2-GPI antibody and patient-purified immunoglobulin G (both with LAC activity) were diluted in plasma with/without protein C. Both antibodies only displayed a beta2-GPI-dependent LAC in plasma in the presence of protein C. This indicates that the principle of the beta2-GPI LAC-assay was based on increased resistance against protein C. Surface plasmon resonance analysis was used to investigate binding between APC and beta2-GPI. We observed that beta2-GPI was able to bind APC directly, especially in the presence of a monoclonal antibeta2-GPI antibody. In conclusion, our observations show a direct correlation between a major clinical symptom of antiphospholipid syndrome (thrombosis), a diagnostic assay (beta2-GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC resistance).
authors.affiliation: Department of Blood Coagulation, Diagnostic Services Sanquin, The Netherlands. b.delaat@sanquin.nl
authors.forename: Bas
authors.initials: B
authors.lastname: de Laat
authors.forename: Carel M
authors.initials: CM
authors.lastname: Eckmann
authors.forename: Marlies
authors.initials: M
authors.lastname: van Schagen
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Meijer
authors.forename: Koen
authors.initials: K
authors.lastname: Mertens
authors.forename: Jan A
authors.initials: JA
authors.lastname: van Mourik
mesh_terms: D020016:Activated Protein C Resistance / Q000150:complications* / Q000209:etiology* / Q000276:immunology; D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome / Q000150:complications*; D001777:Blood Coagulation; D006801:Humans; D016682:Lupus Coagulation Inhibitor / Q000502:physiology*; D011485:Protein Binding; D011486:Protein C / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology; D053482:beta 2-Glycoprotein I / Q000276:immunology* / Q000378:metabolism
chemical_list: D017152:Antibodies, Antiphospholipid; D016682:Lupus Coagulation Inhibitor; D011486:Protein C; D053482:beta 2-Glycoprotein I