Antibodies to tissue-type plasminogen activator (tPA) in patients with antiphospholipid syndrome: evidence of interaction between the antibodies and the catalytic domain of tPA in 2 patients

Abstract

The causes of thrombosis and pregnancy loss in antiphospholipid syndrome (APS) are still unknown, although several hypotheses have been proposed and hypofibrinolysis has been implicated. Anti-tissue-type plasminogen activator (tPA) antibodies may induce fibrinolytic defects and preliminary data indicate an association with thrombosis in APS. We measured plasma anti-tPA antibody levels in 91 consecutive patients with APS, 91 healthy controls, 40 patients with antiphospholipid antibodies without APS symptoms, and 23 patients with systemic lupus erythematosus (SLE) without antiphospholipid antibodies and APS symptoms. Patients with APS had anti-tPA antibody levels higher than controls (P ‫؍‬ .0001), patients with SLE (P ‫؍‬ .0001), and asymptomatic antiphospholipid patients (P ‫؍‬ .05). A subgroup of 53 patients had plasma levels of tPA antigen higher (P ‫؍‬ .0001) and tPA activity lower (P ‫؍‬ .05) than controls, with an inverse correlation (r ‫؍‬ ؊0.454; P ‫؍‬ .003) between anti-tPA antibody levels and tPA activity and no correlation with tPA antigen. The 2 patients with the highest antibody levels had tPA activity below the normal range. Their antibodies were, respectively, IgG1 and IgG3; both recognized human tPA, recombinant tPA, and the catalytic domain of tPA, but not ␤ 2 -glycoprotein I, prothrombin, or plasminogen. Our data indicate that anti-tPA antibodies specifically interacting with the catalytic domain of tPA can be found in patients with APS, representing a possible cause of hypofibrinolysis. (Blood.

Anti-Plasminogen Antibodies Compromise Fibrinolysis and Associate with Renal Histology in ANCA-Associated Vasculitis

“…Anti-tPA antibodies characterized in two APS patients bound to its protease domain but did not cross-react with plasminogen or thrombin. 15 AAV-IgG that display dual reactivity against plasminogen and tPA may comprise distinct immunoglobulins that bind exclusively to one or other serine protease or, alternatively, cross-reactive immunoglobulins recognizing common epitopes. The cross-inhibition studies favor the existence of cross-reactive immunoglobulins in at least some AAV patients.…”

Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment

“…Another popular hypothesis is that antibodies directed against b 2 GPI disturb fibrinolysis [49][50][51]. However, this is unlikely because deficiencies of plasminogen, the pro-enzyme of the fibrinolytic system, is only a weak risk factor, if it all, for thrombotic complications [52], and there are no indications that plasminogen defects can result in foetal loss.…”

Antiphospholipid Antibodies and APS Nephropathy

“…Isolated aPL antibodies with activity against plasmin as well as whole IgG from APS patients, have been found to impair plasmin-mediated fibrinolysis [41,42]. A subsequent study of the reactivity of aPL with tissue plasminogen activator (tPA), another fibrinolytic factor sharing homology with plasmin, showed that several of these aPL were able to reduce tPA activity in converting plasminogen to plasmin [43,44]. Elevated plasminogen activator inhibitor type 1 (PAI-1) levels and decreased tPA release after venous occlusion in APS patients has also been reported [45].…”