(in Warkentin et al). Mechanism of lupus anticoagulant effect—role as surrogate marker.
(A) Anionic phospholipids, predominantly phosphatidylserine (negative charges), serve as potent cofactors for the assembly of 3 different coagulation complexes—the TF-VIIa complex, the IXa-VIIIa complex, and the Xa-Va complex—and thereby accelerate blood coagulation. The TF complex yields factors IXa or factor Xa; the IXa complex yields factor Xa; and the Xa formed from both of these reactions is the active enzyme in the prothrombinase complex that yields factor IIa (thrombin), which in turn cleaves fibrinogen to form fibrin.
(B) Lupus anticoagulant effect. aPL antibody-β2GPI complexes can prolong the coagulation times, compared with control antibodies, when there are limiting quantities of anionic phospholipid available. This effect occurs via antibody recognition of domains I or II on the β2GPI, which results in dimeric and pentameric IgG- and IgM-β2GPI complexes (such as the IgG antibody-β2GPI complexes shown) having high affinity for phospholipid via the cofactor’s domain V. These high-affinity complexes reduce the access of coagulation factors to anionic phospholipids, thereby resulting in a “lupus anticoagulant” effect in conditions where the antibody-cofactor complexes have sufficiently high affinity.
(C) Annexin A5, in the absence of aPL antibodies, serves as a potent anticoagulant by crystallizing over the anionic phospholipid surface, shielding it from availability to bind coagulation proteins.
(D) aPL antibody-mediated disruption of annexin A5 shield. aPL-β2GPI complexes with high affinity for phospholipid membranes disrupt the ability of annexin A5 to form ordered crystals on the phospholipid surface. This defective crystallization results in a net increase of the amount of anionic phospholipid available for promoting coagulation reactions.
Abbreviations: aPL, antiphospholipid; β2GPI, β2-glycoprotein I; TF, tissue factor.
