Lupus anticoagulant: a never-ending story. New insights from anti prothrombin antibodies

Until recently, the lupus anticoagulant (LA) phenomenon was largely attributed to antibodies directed against β2-glycoprotein I (β2GPI). However, this explanation does not account for LA activity in patients with isolated LA, in whom anti-β2GPI antibodies are absent. Increasing evidence indicates that anti-prothrombin (aPT) antibodies play a key role in these cases. aPT antibodies detected with the anti-phosphatidyl-serine/prothrombin (aPS/PT) test appear to explain the coagulation inhibition observed in most patients with isolated LA. They also represent a major determinant of LA activity in triple-positive patients (LA, aCL, and aβ2GPI). Because false-positive LA results frequently occur in patients receiving oral anticoagulants, detection of aPT antibodies may represent a useful surrogate marker of LA. In vitro, some aPT antibodies can induce activated protein C resistance, contributing to the hypercoagulable state promoted by aβ2GPI antibodies. However, aPT antibodies are also involved in LA/hypoprothrombinemia syndrome, which is a bleeding disorder. In this case, aPT antibodies contribute to causing severe hypoprothrombinemia by promoting rapid prothrombin clearance. These observations suggest three biological patterns of LA: i) procoagulant LA in triple-positive patients at high thrombotic risk, typically associated with high-titer IgG aPT antibodies detected by aPS/PT test. ii) Mildly procoagulant LA in patients with isolated LA, generally associated with moderate-to-high-titer IgM aPT antibodies detected by aPS/PT test. iii) Anticoagulant LA, characterized by very high titers of aPT antibodies detected by aPS/PT test associated with hypoprothrombinemia and bleeding. Recognition of these mechanisms is refining the interpretation of LA and providing new insights into the pathophysiology of antiphospholipid syndrome.