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Antiphospholipid antibody syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis and/or pregnancy morbidity in the presence of autoantibodies against phospholipid (PL)-binding plasma proteins, mainly a plasma apolipoprotein known as β2 glycoprotein I (β2GPI) and prothrombin (Table 320-1). Another group of antibodies termed lupus anticoagulant (LA) prolong clotting times in vitro; this prolongation is not corrected by adding normal plasma to the detection system. APS may occur alone (primary), or in association with any other autoimmune disease (secondary). Catastrophic APS (CAPS) is defined as a rapidly progressive thromboembolic disease involving simultaneously three or more organs, organ systems, or tissues leading to corresponding functional defects.

Table 320-1 Classification and Nomenclature of Antiphospholipid Antibodies

Anti-PL (aPL)-binding plasma protein antibodies occur in 1–5% of general population. Their prevalence increases with age; however, it is questionable whether they induce thrombotic events in elderly individuals. One-third of patients with systemic lupus erythematosus (SLE) (Chap. 319) possess these antibodies while their prevalence in other autoimmune connective tissue disorders such as systemic sclerosis (scleroderma), Sjögren's syndrome, dermatomyositis, rheumatoid arthritis, and early undifferentiated connective tissue disease, ranges from 6% to 15%. One-third of aPL positive individuals experience thrombotic events or pregnancy morbidity.

The trigger for the induction of antibodies to PL-binding proteins is not known. Preceding infections, however, have been proposed as the initiating event. These antibodies are pathogenic since anti-β2GPI/β2GPI complexes inactivate natural anticoagulants such as protein C, activate cells involved in the coagulation cascade to a prothrombotic phenotype, activate complement, and inhibit syncytium-trophoblast differentiation. Activated protein C (APC) binds the pro-coagulant factors Va and VIIIa and inactivates them. Anti-β2GPI/β2GPI complexes inhibit the APC activity in vivo by competing with the components of the APC/Va/VIIIa complexes for binding to a number of PL-binding sites, or by disrupting these complexes. Domain V of β2GPI can interact with apolipoprotein E receptor 2' (apoER2') and/or with the GPIbα subunit of the GPIb/IX/V receptor of platelets. Furthermore platelet factor 4 (PF4) tetramers dimerize β2GPI and the resulting complexes are recognized by anti-β2GPI antibodies, eventually activating the p38 mitogen-activated protein (p38 MAP) kinase phosphorylation, and leading to thromboxane B2 (TXB2) production in vitro. In fact, increased levels ...

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