Bleeding complications during pregnancy and delivery in haemophilia carriers and their neonates in Western France: An observational study.

BACKGROUND: Pregnancy, delivery and the postpartum period expose haemophilia carriers, as well as their potentially affected neonates to a high risk of haemorrhagic complications. OBJECTIVES: To describe bleeding complications in haemophilia carriers and their newborns throughout pregnancy and postpartum and to identify potential factors increasing the risk of bleeding in this population. PATIENTS/METHODS: The ECHANGE multicentre observational cohort study was conducted between January 2014 and February 2019 using the BERHLINGO database comprised of patients from seven French haemophilia centres. RESULTS: During the 5 years study period, a total of 104 haemophilia carriers and 119 neonates were included, representing 124 pregnancies and 117 deliveries. Thirty-five (30%) bleeding events were observed, most of them (83%) occurred during the postpartum period, and 37% were reported during the secondary postpartum. Neuraxial anaesthesia was not complicated by spinal haematoma. Three (2.5%) neonates experienced cerebral bleeding. Caesarean section was associated with an increased risk of maternal bleeding in primary and secondary postpartum periods. Basal factor level <0.4 IU/mL was also found to be associated with an increased risk of bleeding during secondary postpartum. CONCLUSION: In our cohort, bleeding events occurred in more than a third of haemophilia carriers mainly in the postpartum period, and a significant portion of this bleeding occurred during the secondary postpartum. Haemophilia carriers warrant specific attention during primary and secondary postpartum, in particular in case of caesarean section and low basal factor level. The ECHANGE study is registered at clinicaltrials.gov identifier: NCT03360149.

Direct Rivaroxaban-Induced Factor XA Inhibition Proves to be Cardioprotective in Rats.

BACKGROUND: Acute myocardial infarction is a leading cause of death worldwide. Though highly beneficial, reperfusion of myocardium is associated with reperfusion injury. While indirect inhibition of Factor Xa has been shown to attenuate myocardial ischemia-reperfusion (I/R) injury, the underlying mechanism remains unclear. Our study sought to evaluate the effect of rivaroxaban (RIV), a direct inhibitor of Factor Xa, on myocardial I/R injury and determine its cellular targets. EXPERIMENTAL APPROACH: We used a rat model of 40-min coronary ligation followed by reperfusion. RIV (3 mg/kg) was given per os 1 h before reperfusion. Infarct size and myocardial proteic expression of survival pathways were assessed at 120 and 30 min of reperfusion, respectively. Plasmatic levels of P-selectin and von Willebrand factor were measured at 60 min of reperfusion. Cellular RIV effects were assessed using hypoxia-reoxygenation (H/R) models on human umbilical vein endothelial cells and on rat cardiomyoblasts (H9c2 cell line). KEY RESULTS: RIV decreased infarct size by 21% (42.9% vs. 54.2% in RIV-treated rats and controls respectively, P < 0.05) at blood concentrations similar to human therapeutic (387.7 ±â€Š152.3 ng/mL) levels. RIV had no effect on H/R-induced modulation of endothelial phenotype, nor did it alter myocardial activation of reperfusion injury salvage kinase and survivor activating factor enhancement pathways at 30 min after reperfusion. However, RIV exerted a cytoprotective effect on H9c2 cells submitted to H/R. CONCLUSIONS: RIV decreased myocardial I/R injury in rats at concentrations similar to human therapeutic ones. This protection was not associated with endothelial phenotype modulation but rather with potential direct cytoprotection on cardiomyocytes.

REMOTE ISCHEMIC CONDITIONING INFLUENCES MITOCHONDRIAL DYNAMICS.

Remote ischemic preconditioning (RIPC) has emerged as an attractive strategy to protect the heart against ischemia-reperfusion (I/R) injury. The mechanisms by which remote ischemic conditioning (RIC) is protective are to date unknown, yet a well-accepted theory holds that the mitochondria play a central role. Mitochondria are dynamic organelles that undergo fusion and fission. Interventions that decrease mitochondrial fission or increase mitochondrial fusion have been associated with reduced I/R injury. However, whether RIPC influences mitochondrial dynamics or not has yet to be ascertained.We sought to determine the role played by mitochondrial dynamics in RIPC-induced cardioprotection. Male adult rats exposed in vivo to myocardial I/R were assigned to one of two groups, either undergoing 40 min of myocardial ischemia followed by 120 min of reperfusion (MI group) or four 5-min cycles of limb ischemia interspersed by 5 min of limb reperfusion, immediately prior to myocardial ischemia and 120 min of reperfusion (MI+RIPC group). After reperfusion, infarct size was assessed and myocardial tissue was analyzed by Western blot and electron microscopy. RIPC induced smaller infarct size (-28%), increased mitochondrial fusion protein OPA1, and preserved mitochondrial morphology. These findings suggest that mitochondrial dynamics play a role in the mechanisms of RIPC-induced cardioprotection.

The synthetic pentasaccharide fondaparinux attenuates myocardial ischemia-reperfusion injury in rats via STAT-3.

Acute myocardial infarction is a leading cause of mortality and morbidity worldwide. Although essential for successful recovery, myocardium reperfusion is associated with reperfusion injury. Two major cell survival signaling cascades are known to be protective against ischemia-reperfusion (I/R) injury: the reperfusion injury salvage kinase, including Akt, extracellular signal-regulated kinase 1/2, and the downstream target GSK-3ß, and the survivor activating factor enhancement, which involves STAT-3. Pharmacologic inhibition of factor Xa has been shown to attenuate I/R injury, but the cellular mechanism is poorly understood. Our aim was to determine the role of whole blood in fondaparinux (FDX)-induced cardioprotection and the involvement of reperfusion injury salvage kinase and survivor activating factor enhancement pathways. We investigated FDX ability to prevent in vivo I/R injury using a transient coronary ligation rat model and ex vivo using a model of crystalloid-perfused isolated rat heart. In both models, infarct size was assessed after 120 min of reperfusion. Myocardial tissues were collected after 15 and 30 min of reperfusion for Western blot analysis. In vivo, FDX decreased infarct size by 29% and induced significant STAT-3 and GSK-3ß phosphorylation in comparison to controls. Adding AG490, an inhibitor of JAK/STAT pathway, before I/R, prevented STAT-3 phosphorylation and abolished FDX-induced cardioprotection. On the contrary, FDX did not have an effect on infarct size or hemodynamic parameters in the isolated-heart model. Fondaparinux decreased I/R injury in vivo, but not in a crystalloid-perfused isolated heart. Under our experimental conditions, FDX required whole blood to be protective, and this beneficial effect was mediated through STAT-3 phosphorylation.

Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.

A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.