Antiphospholipid Antibody Syndrome.

Antiphospholipid antibody syndrome (APS) is a recently defined autoimmune disorder characterized by recurrent vascular thromboses or recurrent pregnancy morbidity; these features are linked to the presence in blood of autoantibodies against negatively charged phospholipids or phospholipid-binding proteins. Thrombosis can occur in any tissue, in veins, arteries, or the microvasculature. Pregnancy morbidity in APS includes miscarriages or premature birth. Criteria that define the major clinical and laboratory features of APS were published in 1999. In patients with antiphospholipid antibodies and prior thrombosis or pregnancy morbidity, there is a high risk of recurrence that persists as long as antiphospholipid antibodies occur in blood. This risk for recurrence of thrombosis or pregnancy morbidity is greatly reduced by preventive anticoagulant therapy. Patients presenting with thrombosis in APS are initially managed in much the same way as are patients with vascular thrombosis owing to other causes. However, in patients with APS, high-intensity anticoagulation is usually needed to prevent recurrences of thrombosis. Thrombosis in APS is often multifactorial, as with non-APS thrombosis. Therefore, in all patients with APS, other reversible risk factors for thrombosis should be sought. The pregnancy outcome of women with APS who have had prior miscarriages is greatly improved by treatment during pregnancy with a combination of heparin and low-dose aspirin.

Viral origin of antiphospholipid antibodies: endothelial cell activation and thrombus enhancement by CMV peptide-induced APL antibodies.

Our observations and those from others, give further support to our hypothesis that "autoimmune aPL" may be generated by immunization with products from bacteria or viruses after incidental exposure or infection. We also were able to generate APS-like syndrome in a strain of mice susceptible to autoimmunity, indicating that other factors such as genetics are likely to be involved in the development of APS. Furthermore, not all aPL antibodies generated by immunization with bacterial or viral products are pathogenic. Based on the clinical experience and on the numerous reports indicating presence of aPL in a large number of infectious diseases, it may be expected that not all aPL antibodies produced during infection will be pathogenic. We hypothesize that a limited number aPL antibodies induced by certain viral/bacterial products would be pathogenic in certain groups of predisposed individuals. Identification of these bacterial and/ or viral agents may help to find strategies for the prevention of production of aPL "pathogenic" antibodies. Alternatively, free peptides may be used to induce tolerance against aPL production.

Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies.

Prothrombotic properties of antiphospholipid (aPL) antibodies may be explained in part by their ability to enhance the activation of platelets pre-treated with low doses of ADP or thrombin. The antimalarial drug hydroxychloroquine (HQ) has been used successfully in prevention of postoperative thrombosis and in treatment of patients with SLE or APS. In one study, administration of HQ reversed the thrombogenic properties of aPL in mice. However, the mechanism of action of HQ in preventing thrombosis is not clearly understood. In order to explore this further, the effects of HQ on activation of platelets by aPL in the presence of a thrombin agonist was studied. The changes in the expression of GPIIb/IIIa (CD41a) and GPIIIa (CD61) on platelet membrane by flow cytometry were used as indicators of platelet activation. Citrated whole blood from a healthy donor was treated at room temperature with suboptimal doses of a thrombin agonist receptor peptide (TRAP) and affinity-purified aPL antibodies, in the presence and in the absence of hydroxychloroquine (1 mM). TRAP increased the expression of GPIIb/IIIa and GPIIIa on platelet surface. The treatment of the platelets with the six aPL antibodies in the presence of 12 nMol/ml TRAP further increased the expression of GPIIb/IIIa by 42.3+/-12.3% and the expression of GPIIIa was further incremented by 46.8+/-13.5%. The effects of aPL and TRAP on expression of platelet surface markers of activation was completely abrogated by HQ in a dose-dependent fashion and was effective at concentrations of HQ as low as 25 microg/ml (0.0125 mM). This suggests at least one possible mechanism by which HQ may prevent thrombosis. This may have important implications in treatment of thrombosis in APS patients.

Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide cause thrombosis and activation of endothelial cells in vivo.

OBJECTIVE: To characterize the binding and functional properties of antiphospholipid antibodies (aPL) induced by immunization with a viral peptide and to determine whether aPL are pathogenic in vivo. METHODS: Ten murine monoclonal aPL were generated from spleen cells of PL/J mice immunized with TIFI, a phospholipid-binding peptide spanning Thr(101)-Thr(120) of ULB0-HCMVA from human cytomegalovirus (CMV), which shares structural similarity with the phospholipid-binding site of beta(2)-glycoprotein I (beta(2)GPI). RESULTS: The antibodies generated had aPL activity that was inhibited by cardiolipin liposomes, and this inhibition was enhanced in the presence of beta(2)GPI. Some of the antibodies exhibited binding to cultured endothelial cells in vitro, and some had lupus anticoagulant activity. Injection with 2 of the monoclonal aPL in mice resulted in a significant increase in the number of leukocytes adhering to endothelial cells and enhanced thrombus formation in vivo. CONCLUSION: These results indicate that aPL induced by immunization with a phospholipid-binding CMV peptide are pathogenic in vivo. The results also suggest a mechanism (molecular mimicry) by which pathogenic aPL may be generated in patients with antiphospholipid syndrome.

Viral infections and antiphospholipid antibodies.

OBJECTIVE: To study the relationship between viral infections and the induction of antiphospholipid (aPL) antibodies. METHODS: We reviewed the medical literature from 1968 until 2000 using MEDLINE and the key words virus, infection, antiphospholipid, and anticardiolipin. RESULTS: Anticardiolipin antibodies and/or lupus anticoagulant were associated with a number of viral infections, including hepatitis C virus, human immunodeficiency virus, cytomegalovirus, varicella zoster, Epstein-Barr virus, adenovirus, and parvovirus B. In many instances, the presence of these antibodies was associated with thrombosis. CONCLUSION: The clinical significance of finding aPL antibodies in patients with viral infections remains unknown. In some patients, these antibodies may be transient and disappear within 2 or 3 months. In other susceptible individuals, they may persist and raise the question of whether infections may trigger the development of aPL antibodies in autoimmune diseases.

Antibodies to cardiolipin and beta2-glycoprotein-1 in HTLV-1-associated myelopathy/tropical spastic paraparesis

Anticardiolipin and anti-beta2GP1 antibodies were measured in 50 patients with HTLV-1-associated Myelopathy-Tropical Spastic Paraparesis (HAM-TSP) and the results were compared with those obtained for 34 HTLV-1-positive and 35 HTLV-1-negative controls, as well as 128 SLE patients. aCL but not anti-beta2GP1 was associated with HTLV-I infection. aCL was more prevalent than anti-beta2GP1 (32 percent vs. 8 percent) and was not associated with anti-beta2GP1 in HAM-TSP. IgA was the dominant isotype of aCL and anti-beta2GP1. The data suggest that tin HAM-TSP, IgA aCL are frequent and are associated with HTLV-1 infection.(Au)

IGA antiphospholipid antibodies in HLTV-1-associated tropical spastic paraparesis

A retrovirus human T cell lymphotropic virus type I (HTLV-I), is an essential but not a sufficient aetiological factor for tropical spastic paraparesis (TSP). Because some TSP patients have biological false positive tests for trepomemal infections (BFP-STS), we used EISA to study BFP-STS and anticardiolipin antibodies in 42 Jamaican TSP patients. The data indicate that in TSP anticardiolipin antibodies accur in about 26 percent of patients, are associated with biological false positive treponemal serology, are relatively restricted to the IgA isotype and may be induced by HTLV-I or other non-treponemal infections. (Au)