The antiphospholipid syndrome (APS) is defined by the presence of anti-phospholipid antibodies (aPLs) and venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. The syndrome can be either primary or secondary to an underlying condition, most commonly systemic lupus erythematosus (SLE). Echocardiographic studies have disclosed heart valve abnormalities in about a third of patients with primary APS. SLE patients with aPLs have a higher prevalence of valvular involvement than those without these antibodies. Valvular lesions associated with aPLs occur as valve masses (nonbacterial vegetations) or thickening. These two morphological alterations can be combined and are thought to reflect the same pathological process. Both can be associated with valve dysfunction, although such association is much more common with the latter alteration. The predominant functional abnormality is regurgitation; stenosis is rare. The mitral valve is mainly affected, followed by the aortic valve. Valvular involvement usually does not cause clinical valvular disease. The presence of aPLs seems to further increase the risk for thromboembolic complications, mainly cerebrovascular, posed by valve lesions. Superadded bacterial endocarditis is rare but may be difficult to distinguish from pseudoinfective endocarditis. The current therapeutic guidelines are those for APS in general. Secondary antithrombotic prevention with long-term, high-intensity oral anticoagulation is advised. The efficacy of aspirin, either alone or in combination, is yet to be assessed. Corticosteroids are not beneficial and may even facilitate valve damage. Immunosuppressive agents should only be used for the treatment of an underlying condition. Current data suggest a role for aPLs in the pathogenesis of valvular lesions. aPLs may promote the formation of valve thrombi. These antibodies may also act by another mechanism, as indicated by the finding of subendothelial deposits of immunoglobulins, including anticardiolipin antibodies, and of colocalized complement components in deformed valves from patients with APS.

Accumulation of low-density lipoprotein (LDL)-derived cholesterol by macrophages in vessel walls is a pathogenomic feature of atherosclerotic lesions. Platelets contribute to lipid uptake by macrophages through mechanisms that are only partially understood. We have previously shown that platelet factor 4 (PF4) inhibits the binding and degradation of LDL through its receptor, a process that could promote the formation of oxidized LDL (ox-LDL). We have now characterized the effect of PF4 on the binding of ox-LDL to vascular cells and macrophages and on the accumulation of cholesterol esters. PF4 bound to ox-LDL directly and also increased ox-LDL binding to vascular cells and macrophages. PF4 did not stimulate ox-LDL binding to cells that do not synthesize glycosaminoglycans or after enzymatic cleavage of cell surface heparan and chondroitin sulfates. The effect of PF4 on binding ox-LDL was dependent on specific lysine residues in its C terminus. Addition of PF4 also caused an ϳ10-fold increase in the amount of ox-LDL esterified by macrophages. Furthermore, PF4 and ox-LDL co-localize in atherosclerotic lesion, especially in macrophage-derived foam cells. These observations offer a potential mechanism by which platelet activation at sites of vascular injury may promote the accumulation of deleterious lipoproteins and offer a new focus for pharmacological intervention in the development of atherosclerosis.

SUMMARYNucleated cells employ several strategies to evade killing by homologous complement. We studied complement resistance in the human carcinoma cell lines (CA) T47D (mammary), SKOV3 (ovarian), and PC-3 (prostate) with emphasis on the following mechanisms of defense: 1. Expression and shedding of the membrane complement regulatory proteins (mCRP) CD46, CD55 and CD59; 2. Resistance based on protein phosphorylation; 3. Cell surface expression of sialic acid residues; 4. Desensitization to complement upon exposure to sublytic complement doses. Anti-mCRP antibody blocking experiments demonstrated that CD59 is the main mCRP protecting these CA from complement. Soluble CD59 was also found in supernates of PC-3 > SKOV3 > T47D cells. Second, inhibitors of PKC, PKA and MEK sensitized the CA to lysis, thus implicating these protein kinases in CA complement resistance. Third, removal of sialic acid residues with neuraminidase also sensitized CA to lysis. Finally, exposure of CA to sublytic doses of complement conferred on them enhanced resistance to lytic complement doses in a PKC-dependent process. Combined treatment of CA with anti-CD59 antibodies, PD98059 (a MEK inhibitor) and neuraminidase produced a large enhancement in CA sensitivity to complement. Our results show that CD59 and sialic acid residues present on the cell surface, and intracellular processes involving protein phosphorylation act additively to secure CA resistance to complement-mediated lysis. Therefore, the effectiveness of antibody-and complement-based cancer immunotherapy will markedly improve by suppression of the various complement resistance mechanisms.

Antiphospholipid antibodies (aPL) have been associated with various neurological manifestations, but the underlying mechanism has not been elucidated. We assessed mice with induced experimental antiphospholipid syndrome (APS) for neurological and behavioral changes.

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Deposits of immunoglobulins including aCL, and of complement components, are common in affected valves of patients with primary and secondary APS. Such deposits may be involved in the pathogenesis of valvular lesions.

We studied the effect of beta 2-GPI on binding of antibodies in sera from patients with leprosy and patients with the antiphospholipid syndrome (APS) to CL in enzyme-linked immunosorbent assays (ELISAs). Increased levels of IgG aCL were detected in 59 of 61 leprosy patients' sera by the standard aCL-ELISA in the presence of bovine beta 2-GPI and in 60 of the 61 leprosy patients' sera by the modified aCL-ELISA without beta 2-GPI. When tested by both aCL-ELISAs on the same plate, 10/31 leprosy sera and 9/10 APS sera bound better in the standard aCL-ELISA, 16/31 leprosy sera bound better in the modified aCL-ELISA and in five leprosy and one APS sera the difference was not significant. A dose-dependent enhancing effect of beta 2-GPI on the leprosy and APS sera binding to CL was confirmed using purified human beta 2-GPI. Enhanced binding was seen if beta 2-GPI was added either before or together with the test serum. In 11/61 leprosy sera increased levels of IgG antibodies against beta 2-GPI were found by ELISA. Leprosy anti-beta 2-GPI antibodies appear to be a separate antibody population recognizing only beta 2-GPI adsorbed on the ELISA plate. These results demonstrate heterogeneity of leprosy aCL with respect to their beta 2-GPI requirement for binding to CL.

Heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin therapy. Antibodies to platelet factor 4 (PF4)/heparin complexes have been implicated in the pathogenesis of this disorder, but the antigenic epitope(s) on the protein have not been defined. To address this issue, we studied the binding of HIT antibodies to a series of recombinant proteins containing either point mutations in PF4 or chimeras containing various domains of PF4 and the related protein, neutrophil activating peptide-2 (NAP-2). Serum samples from 50 patients with a positive 14C-serotonin release assay (14C-SRA) and a clinical diagnosis of HIT and 20 normal controls were studied. HIT antibodies reacted strongly with wild-type (WT) PF4/heparin complexes, but reacted little, if at all, with NAP-2/heparin complexes (optical density [OD]405 = 2.5 and 0.2, respectively). Alanine substitutions at three of the four lysine residues implicated in heparin binding, K62, K65, and K66, had little effect on recognition by HIT antibodies (OD405 = 2.2, 2.8, and 2.0, respectively), whereas an alanine substitution at position K61 led to reduced, but still significant binding (OD405 = 1.0). Similar studies involving chimeras between PF4 and NAP-2 localized a major antigenic site to the region between the third and fourth cysteine residues for more than half of the sera tested. This site appears to involve a series of amino acids immediately after the third cysteine residue beginning with P37. Thus our studies suggest that whereas the C-terminal lysine residues of PF4 are important for heparin binding, they do not comprise a critical antigenic site for most HIT antibodies. Rather, we propose that maintaining a region near the third cysteine residue of PF4, distal from the proposed heparin-binding domain, is required to form the epitope recognized by many HIT antibodies. © 1998 by The American Society of Hematology.