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OBJECTIVES: (I) To identify and measure the clinical consequences of a delayed diagnosis in patients with primary obstetric antiphospholipid syndrome (POAPS), in terms of time and events associated to antiphospholipid syndrome (APS), and (II) to evaluate the impact of their treatment status on perinatal outcomes, before and after diagnosis. METHODS: This retrospective multicentre study included 99 POAPS women who were separated in two groups of timelines based on their diagnostic status: group 1: women who met the clinical criteria for POAPS; group 2: included the same patients from group 1 since they meet the laboratory criteria for APS. In group 1, we assessed the following variables: obstetric events, thrombotic events and time (years) to diagnosis of APS. We also compared perinatal outcomes between patients in group 1 vs. group 2. Women in group 2 were treated with standard of care for POAPS. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding the impact of the delay on diagnosis, a total of 87 APS-related events were recorded: 46 miscarriages, 32 foetal losses and 9 premature deliveries before the 34th week due to preeclampsia, and one thrombosis. The estimated rate of preventable events was 20.58 per year/100 patients. The mean diagnostic delay time was 4.27 years. When we compared both groups during pregnancy, we found that patients in group 1 (no treatment) had a higher association with pregnancy losses [OR = 6.71 (95% CI: 3.59-12.55), p < 0.0001]. CONCLUSION: Our findings emphasize the negative impact of POAPS underdiagnosis on patient health and the critical importance of a timely intervention to improve pregnancy outcomes. Key Points •Our study shows the relevance of underdiagnosis on primary obstetric antiphospholipid syndrome (POAPS). •These patients presented a high risk of APS-related events with each passing year. •Shorter diagnostic delay time was observed in the reference centres.

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OBJECTIVES: (1) To assess the clinical utility of the adjusted global antiphospholipid syndrome score (aGAPSS) to predict new obstetric events during follow-up in primary obstetric antiphospholipid syndrome (POAPS) patients under standard-of-care treatment (SC) based on the use of low-dose aspirin (LDA) + heparin and (2) to study the risk of a first thrombotic event and to evaluate whether stratification according to this score could help to identify POAPS patients who would benefit from long-term thromboprophylaxis. METHODS: This is a retrospective, multicentre study. 169 women with POAPS were evaluated for the presence of a new obstetric event and/or a first thrombotic event during follow-up [time period: 2008-2020, median: 7 years (6-12 years)]. The outcomes of 107 pregnancies from these POAPS patients with SC were studied to evaluate relapses. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding obstetric morbidity, only triple positivity for antiphospholipid antibodies (aPLs) [OR = 8.462 (95% CI: 2.732-26.210); p < 0.0001] was found to be a strong risk factor independently associated with treatment failure. On the other hand, triple positivity for aPLs [OR=10.44 (95% CI: 2.161-50.469), p = 0.004] and an aGAPSS ≥7 [OR = 1.621 (95% CI: 1.198-2.193), p = 0.002] were independent risk factors associated with a first thrombotic event. LDA was marginally associated with a decrease in the risk of thrombosis only in patients with aGAPSS ≥ 7 (p = 0.048). CONCLUSION: aGAPSS appears to be useful in predicting the occurrence of a first thrombotic event in POAPS patients, and these stratification of patients could be helpful in selecting patients who would benefit from thromboprophylaxis with LDA.

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Over time, the knowledge on the role of histones has significantly changed. Initially, histones were only known as DNA packaging proteins but later, it was discovered that they act extracellularly as powerful antimicrobial agents and also as potentially self-detrimental agents. Indeed, histones were found to be the most abundant proteins within neutrophil extracellular traps what ultimately highlighted their microbicidal function. In addition, extracellular histones proved to be involved in triggering exacerbated inflammatory and coagulation responses, depending on the cell type affected. Consequently, several investigations were conducted towards studying the potential of histones and their derivatives as either biomarkers or therapeutic target candidates in different diseases in which inflammation and thrombosis have a key pathophysiological role, such as sepsis, thrombosis and different types of cancer. The main objective of this review is to summarize and discuss the current state of the art with regard to both beneficial and harmful roles of histones and also their possible use as biomarkers and therapeutic targets.

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Resumen El tratamiento de un paciente anticoagulado con antagonistas de la vitamina K (AVK) sigue siendo un desafío, especialmente en regiones donde, por el costo, los dicumarínicos son todavía la alternativa más buscada a la hora de elegir un anticoagulante oral. Las clínicas de anticoagulación han demostrado ser la forma más eficiente y segura de evitar complicaciones trombóticas y hemorrágicas y de mantener al paciente en rango óptimo de tratamiento. Sin embargo, requieren de una adecuada infraestructura y personal capacitado para que funcionen eficientemente. En este consenso argentino se propone una serie de parámetros para la gestión efectiva de una clínica de anticoagulación. El objetivo es lograr una elevada calidad desde el punto de vista clínico-asistencial a través de un laboratorio de hemostasia de excelencia. Los criterios desarrollados en el documento fueron consensuados por un amplio grupo de expertos especialistas en hematología y en bioquímica de todo el país. Estos criterios deben adaptarse a la irregular disponibilidad de recursos de cada centro, pero siempre se los debe tener en cuenta a la hora de indicar el tratamiento anticoagulante con estas drogas. Tener en consideración estas premisas nos permitirá optimizar la atención del enfermo anticoagulado con AVK y de esta forma minimizar las intercurrencias trombóticas y hemorrágicas a las que está expuesto, para así honrar nuestra promesa de no dañar al paciente.

Abstract Treating an anticoagulated patient with vitamin K antagonists (VKA) remains a challenge, especially in areas where dicoumarins are still the first drug of choice due to the cost of other oral anticoagulants. Anticoagulation clinics have proven to be the most efficient and safe way to avoid thrombotic and hemorrhagic complications and to keep patients in optimal treatment range. However, they require adequate infrastructure and trained personnel to work properly. In this Argentine consensus we propose a series of guidelines for the effective management of the anticoagulation clinics. The goal is to achieve the excellence in both the clinical healthcare and the hemostasis laboratory for the anticoagulated patient. The criteria developed in the document were agreed upon by a large group of expert specialists in hematology and biochemistry from all over the country. The criteria presented here must always be considered when indicating VKA although they had to be adapted to the unequal reality of each center. Taking these premises into consideration will allow us to optimize the management of the anticoagulated patient with VKA and thus minimize thrombotic and hemorrhagic intercurrences, in order to honor our promise not to harm the patient.

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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.

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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.

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Serological risk factors are the most important determinant in predicting unsuccessful pregnancy in obstetric antiphospholipid antibodies syndrome (OAPS) despite conventional treatment. It is not clear if changes in the profile of antiphospholipid antibodies (aPL) during pregnancy modify the risk associated with a poor response to conventional treatment. The aim of our study was to compare the value of a serological tag for aPL obtained before and during the first trimester of pregnancy to predict the response to conventional treatment. We carefully selected 97 pregnancies in women who were included in our study only if they were diagnosed with OAPS prior to a new pregnancy (basal serological risk), retested for aPL during the first trimester of pregnancy (serological risk during pregnancy), and treated with conventional therapy. High baseline serological risk was associated with pregnancy failure in 62.1% of cases (18/29) and predicted 82.5% of pregnancy outcomes with conventional treatment: OR = 16.9, CI = 5.5-52.1, p < 0.001. High serological risk during pregnancy was associated with pregnancy failure in 86.3% of cases (19/22) and predicted 91.8% of pregnancy outcomes with conventional treatment: OR = 88.7, CI = 19.4-404.8, p < 0.001. According to these results, we found that risk categorization performed during pregnancy was better in predicting pregnancy outcome (82.5 vs. 91.8%). Moreover, risk categorization during pregnancy had an increased specificity regarding the prediction: 84.9% at baseline and 95.9% during pregnancy (p = 0.024). Our findings suggest that it is important to perform aPL during the first trimester of pregnancy since that is the best time to establish the serological risk factors.

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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.

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La Enfermedad Tromboembólica Venosa (ETV) es una patología de etiología multifactorial. Entre sus factores de riesgo se encuentran factores tanto genéticos como circunstanciales. La identificación de variantes genéticas protrombóticas y su combinación con otros factores de riesgo para desarrollar "scores predictivos" podrían ser herramientas muy útiles para identificar grupos de riesgo para ETV en los cuales implementar estrategias de prevención. El objetivo general del estudio es analizar si diferentes variantes genéticas están asociadas a una mayor susceptibilidad a desarrollar ETV. A partir de los resultados obtenidos, intentaremos establecer un "score de riesgo", incluyendo factores genéticos y circunstanciales, que mejore la capacidad de predecir la susceptibilidad a sufrir ETV. El estudio que estamos desarrollando es de tipo observacional, descriptivo, de casos y controles. A su finalización, esperamos contar con 400 pacientes con ETV (casos) y 400 controles. Hasta el momento, se han reclutado 149 casos y 146 controles. Los resultados preliminares del estudio indicarían que ser portador del Factor V Leiden aumentaría más de 10 veces el riesgo de sufrir ETV (p=0,015), independientemente de otras variables genéticas. Asimismo, mediante el armado de un "score genético de riesgo" aproximativo, hemos visto que los pacientes con ETV tendrían sumas de genotipos de riesgo significativamente mayores (p=0,002) que los controles. Pese a ciertas limitaciones de nuestros análisis preliminares, algunos resultados serían promisorios al evidenciar superficialmente que la combinación de variantes genéticas de riesgo podría mejorar el valor predictivo de modelos de susceptibilidad a ETV. Al finalizar el estudio, esperamos poder determinar con mayor certeza si, al combinarlos con factores de riesgo circunstanciales, logramos establecer un "score de riesgo" para la predicción de ETV. Los resultados presentados son los primeros en Argentina acerca de la prevalencia y de la asociación con ETV de algunas de las variantes genéticas estudiadas

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The aim of this study was to analyze the influence of nucleotide transition (G/A) in position -2518 of the MCP-1 gene related to the susceptibility of developing RA. Two hundred twenty-three consecutive RA patients according to 2010 ACR/EULAR criteria were included; 120 healthy subjects were used as controls. MCP-1 -2518 A/G polymorphism (AG + GG) was present in 162 (72.6 %) RA patients and in 63 (52.5 %) healthy subjects [OR 2.44 (IC95% 1.53-3.88, p = 0.0002)]; associations for heterozygotes and homozygotes were OR 1.92 (IC95% 1.19-3.15, p = 0.001) and OR 5.19 (IC95% 2.34-11.51, p = 0.001), respectively. In Argentine patients, MCP-1 gene polymorphism confers susceptibility for developing RA.

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