Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? [see comments]

Abstract

Despite many studies on the pathophysiology of antiphospholipid antibodies (aPL), the mechanism by which aPL causes thrombosis has not been established. We have tried to elucidate the paradox between the prolongation of the clotting time of phospholipid-dependent coagulation tests in vitro and the occurrence of thrombosis in vivo. The effect on endothelial cell-mediated prothrombinase activity of 30 IgG fractions, of which 22 prolong the aPTT of normal plasma, was investigated. Only 4 of 22 fractions (18%) inhibited prothrombinase activity when tested on this more physiologic phospholipid surface, indicating that in most patients with aPL the prolongation of clotting tests is predominantly as in vitro phenomenon. It was recently reported that in detection methods for aPL, two plasma proteins, beta 2-glycoprotein I and prothrombin, enhance the binding of aPL to phospholipids. We have studied the specificity of the 4 IgG fractions that inhibit the prothrombinase activity and found that they were directed against a combination of phospholipids and prothrombin. However, the involvement of prothrombin in binding of aPL leading to impaired thrombin generation could still result in both a bleeding and a thrombotic tendency. Therefore, we proposed a new thrombogenic mechanism for aPL in which aPL bind to complexes of phospholipids and coagulation proteins, thereby interfering in different coagulation reactions. We tested this new hypothesis by investigating the effect of IgG from the same 30 patients on the activated protein C (APC)-mediated factor Va inactivation in the absence and presence of protein S. Three IgGs that inhibited APC-mediated factor Va inactivation independent of protein S and 4 additional IgGs that inhibited in the presence of protein S were found. Furthermore, we could specifically adsorb the inhibitory IgG with cardiolipin vesicles to which APC with or without protein S was bound. In conclusion, these results suggest that subpopulations of aPL exist that are directed to complexes of phospholipids and different plasma proteins. The identity of the plasma proteins involved in the binding of aPL might determine which pathogenic mechanism causes thrombosis.

Impaired endothelial function and increased carotid intima-media thickness in association with elevated von Willebrand antigen level in primary antiphospholipid syndrome

“…These results confirm a recent finding showing elevated vWF levels in subjects with primary APS. 41,42 Beyond that, we could associate the increased vW antigen level, which reflects endothelial activation with the deterioration of endothelial function; moreover we could identify the simultaneous thickening of IMT. Patients with APS require long-term anti-thrombotic therapy.…”

Anticardiolipin antibodies in various diseases in Taiwan: a retrospective analysis

“…10 Thus, inhibition of the protein C pathway is one of the major hypotheses explaining the prothrombotic state in APS. APLAs can inhibit the degradation of factor Va by activated protein C. 11 Therefore, protein C and protein S levels were examined in most of our patients with stroke and venous thrombosis.…”

State-of-the-Art Review: Antiphospholipid Thrombosis Syndromes

“…There is poor correlation between patients with thrombosis harboring anticardiolipin antibodies and those harboring lupus anticoagulants, and a stronger, but still not concordant, correlation between patients with thrombosis with anticardiolipin antibodies and these with antibodies to Jj-2-GP-I, or antibodies to phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, annexin-V, and phosphatidylcholine. Although there are similarities, there are, at times, dinical, laboratory, and biochemical differences, particularly regarding prevalence, etiology, possible mechanisms of thrombosis, clinical presentations, diag-nosis, and at times, management (4,5). The anticardiolipin antibody-thrombosis antiphospholipid syndrome is much more common than is the lupus anticoagulantthrombosis antiphospholipid syndrome, the ratio being about 5 to 1 (3,6,7).…”