Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is defined as the presence of venous or arterial thromboses, and/or recurrent miscarriage, with evidence of antiphospholipid antibodies (aPL). Central to the disease, is the development of the antibodies to phospholipid molecules themselves, or to their binding proteins. The production of these antibodies may depend upon the unusual exposure of cytoplasmic molecules seen during the process of apoptosis. The exact pathogenesis of antiphospholipid syndrome remains unclear, but various putative models exist. These include the up-regulation of endothelial cell adhesion molecules, membrane disruption during lipid peroxidation, a dysfunction of endogenous anticoagulants, or abnormal platelet aggregation. The mainstay of treatment is with aspirin or warfarin, and more research is required to discover novel, and safer, therapies.     

Antiphospholipid syndrome

Antiphospholipid syndrome is diagnosed when arterial or venous thrombosis or recurrent miscarriages occur in a person in whom laboratory tests for antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant and/or anti-beta 2-glycoprotein I) are positive. Despite the strong association between antiphospho-lipid antibodies and thrombosis, their pathogenic role in the development of thrombosis has not been fully elucidated. Novel mechanisms involving both the complement pathway and micro-particles have been described. The knowledge of these new pathogenic approaches might identify novel therapeutic targets and therefore may improve the management of these patients.     

Antiphospholipid antibody‐activated NETs exacerbate trophoblast and endothelial cell injury in obstetric antiphospholipid syndrome

Despite the widespread use of antiplatelets and anticoagulants, women with antiphospholipid syndrome (APS) may face pregnancy complications associated with placental dysplasia. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many autoimmune diseases, including vascular APS; however, their role in obstetric APS is unclear. Herein, we investigated the role of NETs by quantifying cell‐free DNA and NET marker levels. Live‐cell imaging was used to visualize NET formation, and MAPK signalling pathway proteins were analysed. Cell migration, invasion and tube formation assays were performed to observe the effects of NETs on trophoblasts and human umbilical vein endothelial cells (HUVECs). The concentrations of cell‐free DNA and NETs in sera of pregnant patients with APS were elevated compared with that of healthy controls (HCs) matched to gestational week. APS neutrophils were predisposed to spontaneous NET release and IgG purified from the patients (APS‐IgG) induced neutrophils from HCs to release NETs. Additionally, APS‐IgG NET induction was abolished with inhibitors of reactive oxygen species, AKT, p38 MAPK and ERK1/2. Moreover, NETs were detrimental to trophoblasts and HUVECs. In summary, APS‐IgG‐induced NET formation deserves further investigation as a potential novel therapeutic target in obstetrical APS.     

Antiphospholipid antibodies and acute-phase response in non-metastatic colorectal cancer patients.

AIM: To investigate the plasma levels and prevalence of the most common antiphospholipid antibodies, as well as their relationships with several plasma markers of inflammation, in order to characterize some aspects of cancer thrombophilia. MATERIALS AND METHODS: Eighty-three cancer patients with non-metastatic colorectal solid tumors and 94 control subjects were tested for the presence of IgG/IgM/IgA anti-cardiolipin and anti-Beta2-glycoprotein I antibodies and of several acute-phase reactants, i.e., fibrinogen, factor VIII:C and C4b-binding protein. RESULTS: In cancer patients the plasma levels of the acute-phase reactants and the IgA/IgG anti-cardiolipin and IgA anti-Beta2- glycoprotein I antibodies were significantly higher; the acute-phase reactants were significantly correlated with anti-cardiolipin antibodies; the prevalence of antiphospholipid antibodies was not significantly higher. CONCLUSIONS: In patients with non-metastatic colorectal cancer the acute-phase response is associated with antiphospholipid generation. This could represent a further pathogenetic mechanism for the short-term post-surgery thrombotic complications of patients with colorectal cancer.     

Antiphospholipid antibodies in young myocardial infarction patients

Myocardial infarction (MI) is a multi-factorial disease which claims many young lives. There are very few Indian studies that have investigated antiphospholipid antibodies (APLs) in MI patients. APLs have been implicated in arterial thrombosis including premature coronary artery and cerebrovascular thrombosis. In the present study, the prevalence of two clinically significant APLs--anticardiolipin antibody (ACA) and lupus anticoagulants (LA) in young MI patients was studied and compared with age- and sex-matched controls. Fifty healthy blood donors and 40 young MI patients (less than 45 yrs) diagnosed according to the American Heart Association guidelines were recruited for the study. The criteria for diagnosis were presence of atleast two of three classical findings including: clinical symptoms, diagnostic ECG, and presence of one or more cardiac biomarkers out of raised CK-MB isoform and T-troponin on serial measurement. LA and ACA were tested by lupus-sensitive activated partial thromboplastin time (aPTT) and ELISA respectively. Elevation of ACA was observed in 9 patients, while 6 were positive for LA. ACA of IgG isotype was detected in 8 patients. One patient had LA and raised ACA of IgG and IgM isotypes. Antiphospholipid antibodies were found to be significantly associated with MI in young patients, when considered together (p < 0.05) and in coronary thrombosis, mild elevation of ACA may be considered significant.     

Antiphospholipid antibodies: discovery,definitions, detection and disease

Antiphospholipid antibodies (aPL) are immunoglobulins of IgG, IgM and IgA isotypes that target phospholipid (PL) and/or PL-binding plasma proteins. Detection of aPL in the laboratory is done currently by both immunoassays and functional coagulation tests. Convention defines aPL specificity in immunoassays according to the particular PL substrate present, for example aPS represents antiphosphatidylserine antibodies. This may be technically incorrect inasmuch as a particular PL may be responsible for binding and highly concentrating a specific plasma protein, the latter then becomes the target for the aPL. The binding of beta(2)GP-I (apolipoprotein H) to the negatively charged PL, cardiolipin (CL) provides a good example of this circumstance. In contrast, aPL which specifically prolong coagulation times in in vitro are called lupus anticoagulants (LA). The precise PL target(s) of the aPL responsible for LA activities are unknown and often debated. The persistent finding of aPL in patients in association with abnormal blood clotting and a myriad of neurological, obstetrical and rheumatic disorders often compounded by autoimmune diseases has led to an established clinical diagnosis termed antiphospholipid syndrome (APS). The common denominator for these APS patients is the presence of circulating aPL on two or more occasions and the observation of events attributable to abnormal or accelerated blood clotting somewhere in vivo. The purpose of this review is to collect, collate, and consolidate information concerning aPL.     

Antiphospholipid antibodies in healthy Serbian middle-aged subjects: Preliminary data

BackgroundThe investigation of the prevalence of the IgG and the IgM isotypes of anticardiolipin (aCL) and antib2glycoprotein I (ab2gpI) Abs in healthy Serbian middleaged subjects was the main goal of our study. In addition, we analyzed the potential associations of above-mentioned Abs with serum proteins and lipids/lipoproteins.MethodsForty healthy subjects were included in our study. Obesity (BMI 30 kg/m2) was present in 8/40 (20%) subjects. Titers of analyzed Abs were measured by ELISA.ResultsThe prevalence of IgG and IgM ab2gpI Abs was 5% and 12.5%, respectively, while the prevalence of IgM aCL was 10%. The IgG ab2gpI Abs were significantly different between subjects with normal triglycerides levels and those with hypertriglyceridemia (Mann-Whitney, P = 0.014). The significant difference in hsCRP concentrations was observed between subjects with the increased levels of the IgM isotype of aCL Abs and those with normal IgM aCL values (Mann-Whitney, P = 0.028).ConclusionsDyslipidemia and BMI ≥30 were associated with aPL Abs and therefore, the correction of BMI and lipid status might be beneficial in reduction or elimination of predisposing factors that might trigger thrombotic events in otherwise healthy middle-aged subjects. Larger national study is necessary to confirm our findings.     

Antiphospholipid antibodies induce monocyte chemoattractant protein-1 in endothelial cells

The presence of antiphospholipid Ab is associated with increased risk of thrombosis. The monocyte-endothelial cell interaction has been suggested to play a key role at the site of vascular injury during thrombosis. Therefore, we tested the effect of anticardiolipin Abs (aCL) on the production of monocyte chemoattractant protein-1 (MCP-1) in HUVEC. We found that monoclonal aCL as well as IgG fractions from patients with antiphospholipid syndrome (APS-IgG) could induce the production of MCP-1 in HUVEC. The ability of IgG aCL to induce MCP-1 production could be abrogated by preabsorption with cardiolipin liposomes. Simultaneous addition of either monoclonal aCL or APS-IgG with IL-1beta resulted in synergistic increase in MCP-1 production, whereas the addition of control IgG lacking aCL activity did not alter IL-1beta-induced levels of MCP-1. MCP-1 mRNA expression was also up-regulated when HUVEC were incubated with either APS-IgG or monoclonal aCL, and down-regulated by the treatment of dexamethasone. In addition, we found that serum levels of MCP-1 in 76 systemic lupus erythematosus patients correlated well with the titers of IgG aCL. Collectively, these results indicate that aCL could promote endothelial cell-monocyte cross-talk by enhancing the endothelial production of MCP-1, thereby shifting the hemostatic balance toward the prothrombotic state of APS.     

Trousseau's syndrome.

We report 4 cases of Trousseau''s syndrome, in which spontaneous recurrent or migratory venous thromboses, arterial emboli caused by nonbacterial thrombotic endocarditis, or both, develop in a patient with a recognized or occult malignant tumor. The clinical course of 3 of the patients emphasizes a key point: The occurrence for no known reason of thromboses preventable by anticoagulation therapy with heparin but not with warfarin sodium should alert a physician to focus diagnostic efforts on uncovering an underlying malignant lesion. Thromboses may occur months to years before the tumor is discovered, and a thorough negative initial examination does not obviate the need for a continuing search. Patients with Trousseau''s syndrome have persistent low-grade intravascular coagulation, and therapy with heparin should be continued indefinitely. Stopping heparin therapy for even a day may permit a new thrombosis to develop. Immunostaining a biopsy specimen from 1 patient provided evidence that 2 properties of a neoplastic lesion are required for the syndrome to develop: The malignant cells express surface membrane tissue factor, and structural features of the tumor permit the malignant cells or vesicles it sheds to be exposed to circulating blood.