Explaining Lupus Anticoagulant in Thrombotic Antiphospholipid Syndrome

The acquired thrombotic risk factor known as lupus anticoagulant (LA) is detected as a phospholipid-dependent prolongation of the clotting time and is the most clinically relevant antiphospholipid antibody within the antiphospholipid syndrome (APS). LA can be caused by autoantibodies against β2-glycoprotein I (β2GPI) or prothrombin. The association of LA with thrombosis represents a paradox, as prolonged clotting times are normally indicative for a bleeding tendency. The aim of this thesis was to gain more insight into the thrombotic mechanism of LA-causing antiphospholipid antibodies and to investigate how these antibodies interfere with coagulation assays. In Chapter 2, we described how anti-β2GPI and anti-prothrombin antibodies interfere in coagulation assays leading to the LA phenomenon. We showed that anti-β2GPI and anti-prothrombin antibodies cause LA through different mechanisms of action: while anti-β2GPI antibodies interfere with Factor V activation by Factor Xa through a direct interaction with FV, anti-prothrombin antibodies compete with FXa for phospholipid binding sites. In Chapter 3, we focused on the other part of the LA paradox by looking into the effect of anti-β2GPI and anti-prothrombin antibodies on the pro-thrombotic mechanism of activated protein C (APC) resistance. We showed that anti-β2GPI antibodies with LA-activity cause APC resistance via interference with the cofactor function of FV during Factor VIIIa inactivation. LA-causing anti-prothrombin antibodies interfere with the anticoagulant function of APC by preventing FV(a) cleavage. In Chapter 4, we further elaborated on the prothrombotic mechanisms of anti-β2GPI antibodies. We showed that these antibodies interfere with the anticoagulant function of tissue factor pathway inhibitor (TFPI) resulting in increased thrombin formation. In Chapter 5, we focused on LA in clinical settings. During the COVID-19 pandemic many patients with COVID-19 who were submitted to intensive care units (ICU) developed thrombosis. LA was frequently observed in these patients. We studied the association of LA with thrombosis in a cohort of COVID-19 patients admitted to ICU. We found high prevalence of LA and other antiphospholipid antibodies in these patients. And importantly, LA, as measured on admission to ICU, was strongly associated with thrombosis in critically ill COVID-19 patients, especially in patients <65 years of age. In Chapter 6, we discussed the interference of LA with international normalized ratio (INR). APS patients receive anticoagulant therapy with vitamin K antagonists (VKA) to prevent recurrent thrombosis. As the use of VKA imposes considerable bleeding risks, it requires strict monitoring with INR. It is known that LA can lead to elevated INR values with point-of-care-testing (POCT) devices which could result in inadequate adaptation of anticoagulant therapy. We found discrepancies between the standard POCT device used in the Netherlands (Coaguchek XS) and two laboratory-INR methods (Owren and Quick). We showed that elevated anti-β2GPI IgG antibodies are more frequently observed in patients with deviating POCT-INR results. In conclusion, we gained more insight into how anti-β2GPI and anti-prothrombin antibodies influence both procoagulant and anticoagulant pathways. The coming years will hopefully show more progress into the complete understanding of the thrombotic mechanism underlying APS together with the development of targeted therapy for patients with thrombotic APS.