A high-risk laboratory profile of antiphospholipid antibodies and thrombosis is associated with a large number of extra-criteria manifestations in obstetric antiphospholipid syndrome.

Extra-criteria manifestations such as thrombocytopenia and livedo are described associated with antiphospholipid syndrome (APS) but are not included in the current classification criteria. Their clinical expression might be important, as they may be associated with a high-risk profile of antiphospholipid antibodies (aPL) and thrombosis. We evaluated the association between the presence of extra-criteria manifestations in primary obstetric-APS (POAPS) and aPL profiles. We also evaluated whether the presence of extra-criteria manifestations in POAPS patients increases the risk of developing thrombosis during the follow-up period (median follow-up 5 years; range 3-9 years). We selected 79 women who were included in our study only if they were first diagnosed with POAPS (with no history of previous thrombosis) and reevaluated for the presence of thrombosis after the follow-up period. We evaluated the association between the aPL profile and extra-criteria manifestations. We also evaluated the relationship of thrombosis during the follow-up period with extra-criteria manifestations and other risk factors. Patients with three or more extra-criteria manifestations presented high rates of triple positivity for the aPL profile (75%) (p < 0.001). We also found a relationship between the presence of extra-criteria manifestations and the presence of high titers of aPL: 91.7% of patients with three or more extra-criteria manifestations had high titers of aPL (p < 0.01). We further evaluated the group of POAPS patients according to thrombotic events during the follow-up. Among these patients, 6 (7.6%) presented thrombosis. Notably, 100% of patients with a thrombotic event during the follow-up had more than three extra-criteria manifestations. POAPS patients with extra-criteria manifestations might have a high-risk aPL profile and a major risk of developing thrombosis.

Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort. / Trombofilia hereditaria y pérdidas de embarazo. Estudio de una cohorte de Argentina.

BACKGROUND AND OBJECTIVES: Thrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, -675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies. PATIENTS AND METHODS: We performed a case-control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses, n = 107) and according to the type of vascular obstetric pathologies. RESULTS: No differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p >.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p >.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24-40.93], p = .03). CONCLUSIONS: Factor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE.

Maternal carriers of the ANXA5 M2 haplotype are exposed to a greater risk for placenta-mediated pregnancy complications.

PURPOSE: Annexin A5 (ANXA5) is a protein abundantly expressed in normal placenta where it contributes to the healthy outcome of a pregnancy. Lower ANXA5 levels have been observed in M2/ANXA5 haplotype carrying chorion. Consequently, this study aimed to assess the potential association of M2 maternal carrier status with the risk of recurrent pregnancy loss (RPL), the timing of miscarriages, and other obstetric complications, for the first time in a population from Latin America. METHODS: This study was designed as a prospective recruitment of RPL patients with post hoc analysis. The distribution of the M2/ANXA5 haplotype was compared between a group of 229 Argentine women with RPL and 100 parous controls, and was further analyzed in subgroups of patients stratified according to the timing of miscarriages and in relation to other obstetric complications. RESULTS: No significant differences were found in the distribution of M2 haplotype among either RPL patients or the subgroups with embryonic, early fetal, or late fetal losses compared to parous controls. Notwithstanding, maternal M2/ANXA5 was found to be independently associated with a higher risk of suffering intrauterine growth restriction (IUGR) and/or preeclampsia (PE). Simultaneously, the presence of inherited and/or acquired thrombophilia also proved to be an independent risk factor for these. CONCLUSIONS: The association found between the maternal carriage of the M2/ANXA5 haplotype and an elevated risk of IUGR and/or PE supports the hypothesis that carrier status of this haplotype and the consequently reduced placental ANXA5 expression might be responsible, at least partially, for the onset of these gestational vascular complications.

The -308 G/A polymorphism in the tumor necrosis factor-α gene is not associated with development and progression of rheumatoid arthritis in Argentinean patients.

AIM: A polymorphism in the tumor necrosis factor-alpha (TNF-α) promoter region has been associated with disease susceptibility and progression in rheumatoid arthritis (RA). The presence of an adenosine (TNF2 allele) instead of a guanine (TNF1 allele) at position -308 may be responsible for a general increase in the transcriptional activity of the TNF-α gene. Our aim was to evaluate the association of the TNF2 allele with the risk of disease development and/or progression of RA in an Argentine population cohort. METHODS: Two hundred and twenty-three consecutive patients with RA according to the 1987 criteria of the American College of Rheumatology were included in the study. Clinical variables, Disease Activity Score 28, Health Assessment Questionnaire and Rheumatoid Arthritis Quality of Life were recorded. The radiographic erosions were determined by the method of Sharp/van der Heijde. A group of 111 healthy subjects matched by sex and age was used as a control. All samples were genotyped for the -308 G/A TNF-α polymorphism. RESULTS: No significant differences were observed either in the frequency of the TNF2 allele or in the genotypic distributions of the -308 G/A TNF-α polymorphism (P > 0.05) between the control group and the RA patients. No association was found between the TNF2 allele and the variables related to the course and outcome of the disease (P > 0.05). CONCLUSION: In this cohort of Argentinean patients with RA, the TNF2 allele was neither associated with susceptibility to the disease nor was it associated with the variables related to the course and outcome of the disease.

4G/5G plasminogen activator inhibitor-1 and -308 A/G tumor necrosis factor-α promoter gene polymorphisms in Argentinean lupus patients: focus on lupus nephritis.

We investigated the relationship between the 4G/5G plasminogen activator inhibitor (PAI-1) and -308 A/G tumor necrosis factor-α (TNF-α) polymorphisms and the clinical and biochemical features of systemic lupus erythematosus (SLE) in an Argentinean patient cohort. A total of 402 patients were studied, including 179 SLE patients and 223 healthy individuals. PCR-RLFP was used to determine the genotypes of the 4G/5G PAI-1 and -308 A/G TNF-α polymorphisms. SLE patients with lupus nephritis (LN) (n = 86) were compared with patients without LN (n = 93). Additionally, LN patients were divided into proliferative LN and non-proliferative LN groups according to the results of the renal biopsies. No significant differences were noted in the genotype distributions or allele frequencies of these TNF-α and PAI-1 polymorphisms between SLE patients and controls. There were higher numbers of criteria for SLE, more lupus flares and higher damage scores in LN patients, but there were similar frequencies of anti-phospholipid antibody (APA) positivity and anti-phospholipid syndrome. No significant difference was noted for any studied variable between the proliferative LN and non-proliferative LN groups except for the presence of APA. We found no significant differences in the TNF-α and PAI-1 genotype distributions or allele frequencies between groups. We found that the -308 A/G TNF-α and 4G/5G PAI-1 polymorphisms are not associated with susceptibility to SLE in an Argentinean population. We also did not find any association between the presence of any specific allele or genotype and the development of LN in SLE patients. Finally, no association was noted between either of the two polymorphisms and the severity of renal disease.

Biomarkers in sepsis at time zero: intensive care unit scores, plasma measurements and polymorphisms in Argentina.

INTRODUCTION: A patient's response to sepsis is influenced by their genetic background. Our objective was to use plasma markers, such as protein C (PC), D-dimer, Plasminogen Activator Inhibitor-1 (PAI-1) levels, and the PAI-1 rs1799889 4G/5G and  Tumor Necrosis Factor-α rs1800629 G/A  polymorphisms to improve classical intensive care unit (ICU) scores. METHODOLOGY: We studied 380 subjects, 166 with sepsis. We performed coagulation tests: plasma PAI-1 and PC levels were evaluated by chromogenic methods; and D-dimer was evaluated by immunoturbidimetric assay. Polymorphisms were performed using for polymerase chain reactions followed by digest with specific restriction enzyme. We acquired the APACHE and SOFA scores (time zero), sex, age, body mass index, associated co-morbidities, length of ICU stay (days), the severity of sepsis (sepsis, severe sepsis or septic shock), the HIV status and the ICU outcome (survival or death). RESULTS: We found significant differences between patients who died (n=80) and those who survived (n=86) in terms of the ICU length of stay (6 vs. 10 days), septic shock (64 versus 24%), age (51 versus 38 years old), HIV+ condition (34 versus 16%), SOFA (7 versus 4), APACHE (19 versus 13), D-dimer (4.32 versus 2.88 mg/ml), PC (46.0 versus 63.5 %) and PAI-1 (33.0 versus 16.5 UA/l). When we used a regression analysis with dichotomized variables, only the SOFA4, PAI-116, HIV status and the PAI-1 4G allele proved to be predictors of death at time zero. CONCLUSIONS: In the future, ICU scores may be further improved by adding certain genomic or plasma data. 

Thrombophilia in human immunodeficiency virus-infected patients with osteonecrosis: Is there a real connection? The first case-control study.

Several reports have described an increased incidence of osteonecrosis in human immunodeficiency virus-infected patients (HIV+), but the cause has not been established. The association between thrombophilia and osteonecrosis in HIV+ was studied. A case-control study in HIV+, 19 cases and 38 controls, was designed. Magnetic resonance imaging was made in both groups to confirm or exclude hip osteonecrosis. The extensive tests of thrombophilia were measured, and the clinical data were recorded, nadir of CD4(+) cell count and well-known risk factors for osteonecrosis. Thrombophilia has been frequently found both in patients with and without osteonecrosis (thrombophilia, 68.4% vs 60.5%), but no specific thrombophilia tests were significantly associated with osteonecrosis. A low nadir of CD4(+) (<60 cells/microL) and corticoid use were significantly (P < .05) associated with osteonecrosis. In multivariate analysis, only nadir of CD4(+) <60 cells/microL remained a predictor of osteonecrosis (odds ratio = 7.33; 95% confidence interval, 1.80-29.82, P = .005). Thrombophilia might have a limited role in the development of osteonecrosis in HIV+. Nadir of CD4(+) <60 cells/microL and corticoid use were main factors.