Co-Inheritance of FV Leiden and High Levels of FIX Results in Novel Models for Thrombophilia and Spontaneous Fetal Loss.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1946-1946
Author(s):  
Christian Furlan Freguia ◽  
Joerg Schuettrumpf ◽  
Stefano Baila ◽  
Jianhua Liu ◽  
Ralph Bunte ◽  
...  
Keyword(s):  
Gene Dosage ◽  
Fetal Loss ◽  
Placental Tissue ◽  
High Rate ◽  
Fibrin Deposition ◽  
Additional Risk ◽  
Maternal Genotype ◽  
Fv Leiden ◽  
Common Risk Factors ◽  
Risk For Thrombosis

Abstract High levels of FIX is emerging as a risk factor for spontaneous venous thrombosis, affecting ~20% of unselect patients and increasing rates of recurrent thromboembolic events. We have generated mice expressing supraphysiological levels of human FIX (up to 400% of normal) but these animals did not develop thrombosis. Therefore, we decided to test whether an additional risk for thrombosis would trigger a prothrombotic phenotype in these mice. Because the FVL mutation is also present in 20% of thrombophilia subjects, we chose FVL mice as model. Breedings included both parents being heterozygous FVL(+/−) but only one was transgenic for FIX (tFIX: 4–8μg/ml plus the endogenous murine FIX). All mice were on C57Bl/6 background. More than 200 newborns were obtained but surprisingly no animal of FVL(+/+)/tFIX genotype was identified. When pregnancies were interrupted at embryonic age of E9.5 to E16.5, no deviation from the expected/observed embryos genotypes was observed. However, the number of reabsorbed embryos increased significantly from 13% (E9.5) to 33% (E.16.5), p<0.02. All FVL(+/+)/tFIX embryos exhibited extensive bruises and hemorrhagic areas which colocalize with markedly fibrin deposition, findings consistent with disseminated intravascular coagulation. Placental analysis (n=18) of FVL(+/+)/tFIX embryos harvested at E12.5 or later demonstrated abnormalities such as excessive fibrin deposition and innumerous apoptotic cells, determined by TUNEL assay, mainly in the labyrinthine trophoblast zone. The maternal genotype clearly influenced the pregnancy outcome since the number of newborns per litter was 2-fold lower when the mother carried tFIX compared with father tFIX (average 4.3 vs. 8.3, respectively; p<0.02). No mice of other genotypes analyzed (n=112) presented similar abnormalities neither in embryos nor in placental tissue. Mice that achieve adulthood developed normally. However, FVL(+/−)tFIX mice (>7 months of age) presented high rate of thrombotic episodes (3/40; 7.5%) followed by 5.2% FVL(−/ −)/tFIX mice, whereas no other age-matched mice (n=74) developed such complication. Monitoring for coagulation activation by serial aPTT, PT, thrombin-antithrombin (TAT) and D-Dimers demonstrated genotype-dependent procoagulant activity. In FVL(+/−)/tFIX or FVL(−/ −)/tFIX mice, levels of TAT (70ng/ml, n=28/group) and D-dimers (230ng/ml, n=17/group) were ~ 2-fold higher (P<0.04), when compared to mice (TAT: 30ng/ml and D-Dimer: 100ng/ml) of other genotypes. Furthermore, FVL(+/−)/tFIX mice presented the highest fibrin deposition determined by Western blot analysis of tissues harvested, followed by FVL(−/ −)/tFIX mice when compared to the other animals (P<0.05). To exclude the possibility of abnormal interaction of human (h) FIX with murine antithrombin (AT), we compared the rate of inactivation of hFIXa by murine or human AT using purified proteins. The results showed that murine AT efficiently inactivated hFIXa in a similar fashion of that determined for human AT. Moreover, early work showed that hFIX efficiently corrected the phenotype of FIX-deficient mice. Therefore, these data revealed that gene-dosage dependent interaction of FVL and high levels of FIX in mice increase rates of spontaneous fetal loss and adulthood thrombosis. These models provide opportunities to better understand and to test therapeutics for thrombophilia-related complications due to common risk factors identified in humans.

Factor V Leiden Is Associated with Repeated and Recurrent Unexplained Fetal Losses

1997 ◽  
Vol 77 (05) ◽  
pp. 0822-0824 ◽  
Author(s):  
Elvira Grandone ◽  
Maurizio Margaglione ◽  
Donatella Colaizzo ◽  
Marina d'Addedda ◽  
Giuseppe Cappucci ◽  
...  
Keyword(s):  
Protein C ◽  
Strong Association ◽  
Activated Protein C ◽  
Fetal Loss ◽  
Factor V Leiden ◽  
Factor V ◽  
Significant Difference ◽  
History Of ◽  
Fv Leiden ◽  
Caucasian Women

SummaryActivated protein C resistance (APCR) is responsible for most cases of familial thrombosis. The factor V missense mutation Arg506>Gln (FV Leiden) has been recognized as the commonest cause of this condition. Recently, it has been suggested that APCR is associated with second trimester fetal loss. We investigated the distribution of FV Leiden in a sample (n = 43) of Caucasian women with a history of two or more unexplained fetal losses. A group (n = 118) of parous women with uneventful pregnancies from the same ethnical background served as control. We found the mutation in 7 cases (16.28%) and 5 controls (4.24%; p = 0.011). A statistically significant difference between women with only early fetal loss vs those with late events (p = 0.04) was observed. Our data demonstrate a strong association between FV Leiden and fetal loss. Furthermore, they indicate that late events are more common in these patients.

scholarly journals Role of Lectin-Like Oxidized Low Density Lipoprotein-1 in Fetoplacental Vascular Dysfunction in Preeclampsia

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Felipe A. Zuniga ◽  
Valeska Ormazabal ◽  
Nicolas Gutierrez ◽  
Valeria Aguilera ◽  
Claudia Radojkovic ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Pathological Condition ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Fetal Loss ◽  
Density Lipoprotein ◽  
Placental Tissue

The bioavailability of nitric oxide (NO) represents a key marker in vascular health. A decrease in NO induces a pathological condition denominated endothelial dysfunction, syndrome observed in different pathologies, such as obesity, diabetes, kidney disease, cardiovascular disease, and preeclampsia (PE). PE is one of the major risks for maternal death and fetal loss. Recent studies suggest that the placenta of pregnant women with PE express high levels of lectin-like oxidized LDL receptor-1 (LOX-1), which induces endothelial dysfunction by increasing reactive oxygen species (ROS) and decreasing intracellular NO. Besides LOX-1 activation induces changes in migration and apoptosis of syncytiotrophoblast cells. However, the role of this receptor in placental tissue is still unknown. In this review we will describes the physiological roles of LOX-1 in normal placenta development and the potential involvement of this receptor in the pathophysiology of PE.

Fractures and the increased risk of suicide

2018 ◽  
Vol 100-B (6) ◽  
pp. 780-786 ◽  
Author(s):  
C-F. Chang ◽  
E. C-C. Lai ◽  
M-K. Yeh
Keyword(s):  
Mental Health Problems ◽  
Conditional Logistic Regression ◽  
Spinal Fractures ◽  
High Rate ◽  
Physical And Mental Health ◽  
Additional Risk ◽  
Never Married ◽  
Increased Risk ◽  
Contextual Setting ◽  
Control Study

Aims A high rate of suicide has been reported in patients who sustain fractures, but the association remains uncertain in the context of other factors. The aim of this study was to examine the association between fractures and the risk of suicide in this contextual setting. Patients and Methods We performed a case-control study of patients aged 40 years or older who died by suicide between 2000 and 2011. We included patients’ demographics, physical and mental health problems, and socioeconomic factors. We performed conditional logistic regression to evaluate the associations between fractures and the risk of suicide. Results We included a total of 34 794 patients who died by suicide and 139 176 control patients. We found that fractures as a homogenous group (adjusted odds ratios (aOR), 1.48; 95% confidence interval (CI) 1.43 to 1.53), and specifically pelvic (aOR 2.04; 95% CI 1.68 to 2.47) and spinal fractures (aOR 1.53; 95% CI 1.43 to 1.64), were associated with a higher risk of suicide. In addition, we found that patients who had a lower income, had never married, had lower levels of educational attainment, or had coexistent physical and mental conditions such as anxiety, mood disorders, and psychosis-related disorders had a higher risk of suicide. Conclusion Fractures, specifically those of the hip and spine, were associated with an increased risk of suicide. The findings suggest that greater clinical attention should be given to this risk in patients with fractures, especially for those with additional risk factors. Cite this article: Bone Joint J 2018;100-B:780–6.

scholarly journals Placental Pathology in a COVID-19 Positive Patient with Abruptio Placentae- A Case Report

2021 ◽  
Author(s):  
Nishtha Jaiswal ◽  
Reena Yadav ◽  
Prerna Tayal ◽  
Lalita Jyotsna Prakhya
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Case Report ◽  
Pregnant Woman ◽  
Distress Syndrome ◽  
Histopathological Examination ◽  
Placental Tissue ◽  
Maternal Outcome ◽  
Placental Pathology ◽  
Fibrin Deposition ◽  
Abruptio Placentae

The effects of Severe Acute Respiratory Distress Syndrome-Associated Coronavirus-2 (SARS-CoV-2) on the placental tissue are still being explored. Whether these placental changes result in adverse foeto-maternal outcome is an aspect that needs to be understood. This is a report of 32-year-old pregnant woman who presented with Antepartum Haemorrhage (APH) and decreased foetal movements. She was also diagnosed to be positive for the SARS-CoV-2. The patient had abruptio placentae unrelated to pre-eclampsia. On histopathological examination, the umbilical cord showed funisitis with increased perivillous fibrin deposition on section from foetal and maternal surface of the placenta. Though the foetus was stillborn, with timely management the maternal outcome was not compromised.

Association of factor V gene polymorphisms (Leiden; Cambridge; Hong Kong and HR2 haplotype) with recurrent idiopathic pregnancy loss in Tunisia

2006 ◽  
Vol 95 (04) ◽  
pp. 612-617 ◽  
Author(s):  
Walid Zammiti ◽  
Nabil Mtiraoui ◽  
Eric Mercier ◽  
Nesrine Abboud ◽  
Sarra Saidi ◽  
...  
Keyword(s):  
Hong Kong ◽  
Pregnancy Loss ◽  
Fetal Loss ◽  
Factor V Leiden ◽  
Factor V ◽  
Inherited Thrombophilia ◽  
Factor V Gene ◽  
Fv Leiden ◽  
Clinical Risks ◽  
Control Study

SummaryInherited thrombophilia has been shown to be linked with fetal loss. We performed a case-control study on the association between thrombosis-related polymorphisms in the factor V (FV) gene (Leiden, Cambridge, Hong Kong; HR2 haplotype) and idiopathic recurrent pregnancy loss (RPL) in Tunisian women. A total of 348 women with RPL, and 203 control women were studied, corresponding to 1,250 pregnancy losses and 1,200 successful pregnancies. FV Leiden was seen in 19.4% of patients (4.3% in the homozygous state) and in 5.5% of controls. The prevalence of the FV HR2 haplotype was similar in patients and controls, but with 7 homozygous patients for 1 control. FV Cambridge and Hong Kong were absent from both patients and controls. The study of all pregnancy losses evidenced that the frequency of the factor V Leiden polymorphism was zero in women who had miscarried before7 weeks of gestation, and then sharply increased to a plateau. After categorization of pregnancy losses (before8 weeks of gestation; weeks 8 and 9; weeks 10 to 12; from the 13th week of gestation onwards), heterozygous and homozygous factor V Leiden polymorphisms, and homozygous FV HR2 haplotype, were associated with significant and independent risks of pregnancy loss during weeks 8 and 9, which increased during weeks 10 to 12, then culminated after week 12. In Tunisian women with idiopathic RPL, factor V Leiden polymorphism and homozygous FV HR2 haplotype are not a risk factor for very early pregnancy loss, before 8 weeks of gestation, but are thereafter associated with significant clinical risks, which gradually increase from the 8th week onwards.

scholarly journals Early transcription from the maternal genome controlling blastomere integrity in mouse two-cell-stage embryos

2010 ◽  
Vol 298 (5) ◽  
pp. C1235-C1244 ◽  
Author(s):  
Zhiming Han ◽  
Namdori R. Mtango ◽  
Zhisheng Zhong ◽  
Rita Vassena ◽  
Keith E. Latham
Keyword(s):  
Molecular Mechanisms ◽  
Severe Form ◽  
High Rate ◽  
Phosphatidylinositol 3 Kinase ◽  
Cell Stage ◽  
Maternal Genome ◽  
Maternal Genotype ◽  
Mammalian Embryos ◽  
High Level ◽  
Different Origins

Blastomere cytofragmentation in mammalian embryos poses a significant problem in applied and clinical embryology. Mouse two-cell-stage embryos display strain-dependent differences in the rate of cytofragmentation, with a high rate observed in C3H/HeJ embryos and a lower rate observed in C57BL/6 embryos. The maternally inherited genome exerts the strongest effect on the process, with lesser effects mediated by the paternally inherited genome and the ooplasm. The effect of the maternal genome is transcription dependent and independent of the mitochondrial strain of origin. To identify molecular mechanisms that underlie cytofragmentation, we evaluated transcriptional activities of embryos possessing maternal pronuclei (mPN) of different origins. The mPN from C57BL/6 and C3H/HeJ strains directed specific transcription at the two-cell stage of mRNAs corresponding to 935 and 864 Affymetrix probe set IDs, respectively. Comparing transcriptomes of two-cell-stage embryos with different mPN revealed 64 transcribed genes with differential expression (1.4-fold or greater). Some of these genes occupy molecular pathways that may regulate cytofragmentation via a combination of effects related to apoptosis and effects on the cytoskeleton. These results implicate specific molecular mechanisms that may regulate cytofragmentation in early mammalian embryos. The most striking effect of mPN strain of origin on gene expression was on adenylate cyclase 2 ( Adcy2). Treatment with dibutyryl cAMP (dbcAMP) elicits a high rate and severe form of cytofragmentation, and the effective dbcAMP concentration varies with maternal genotype. An activator of exchange proteins directly activated by cAMP (EPACs, or RAPGEF 3 and 4) 8-pCPT-2′- O-methyl-cAMP, elicits a high level of fragmentation while the PKA-specific activator N6-benzoyl-cAMP does not. Inhibition of A kinase anchor protein activities with st-Ht31 induces fragmentation. Inhibition of phosphatidylinositol 3-kinase signaling also induces fragmentation. These results reveal novel mechanisms by which maternal genotype affects cytofragmentation, including a system of opposing signaling pathways that most likely operate by controlling cytoskeletal function.

scholarly journals The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors

2014 ◽  
Vol 307 (10) ◽  
pp. E935-E943 ◽  
Author(s):  
Cara C. Rada ◽  
Grace Murray ◽  
Sarah K. England
Keyword(s):  
Growth Factor ◽  
Vascular Function ◽  
Fetal Loss ◽  
High Rate ◽  
Angiogenic Factor ◽  
Soluble Form ◽  
Vegf Receptor ◽  
Wild Type ◽  
Placental Perfusion ◽  
Sk3 Channel

Proper placental perfusion is essential for fetal exchange of oxygen, nutrients, and waste with the maternal circulation. Impairment of uteroplacental vascular function can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction (IUGR). Potassium channels have been recognized as regulators of vascular proliferation, angiogenesis, and secretion of vasoactive factors, and their dysfunction may underlie pregnancy-related vascular diseases. Overexpression of one channel in particular, the small-conductance calcium-activated potassium channel 3 (SK3), is known to increase vascularization in mice, and mice overexpressing the SK3 channel (SK3T/T mice) have a high rate of fetal demise and IUGR. Here, we show that overexpression of SK3 causes fetal loss through abnormal placental vascularization. We previously reported that, at pregnancy day 14, placentas isolated from SK3T/T mice are smaller than those obtained from wild-type mice. In this study, histological analysis reveals that SK3T/− placentas at this stage have abnormal placental morphology, and microcomputed tomography shows that these placentas have significantly larger and more blood vessels than those from wild-type mice. To identify the mechanism by which these vascularization defects occur, we measured levels of vascular endothelial growth factor (VEGF), placental growth factor, and the soluble form of VEGF receptor 1 (sFlt-1), which must be tightly regulated to ensure proper placental development. Our data reveal that overexpression of SK3 alters systemic and placental ratios of the angiogenic factor VEGF to antiangiogenic factor sFlt-1 throughout pregnancy. Additionally, we observe increased expression of hypoxia-inducing factor 2α in SK3T/− placentas. We conclude that the SK3 channel modulates placental vascular development and fetal health by altering VEGF signaling.

Immunological Studies of the Placenta in Maternal Connective Tissue Disease

1999 ◽  
Vol 2 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Jeanne Ackerman ◽  
Erick F. Gonzalez ◽  
Enid Gilbert-Barness
Keyword(s):  
Rheumatoid Arthritis ◽  
Connective Tissue ◽  
Connective Tissue Disease ◽  
Lupus Erythematosus ◽  
Fetal Loss ◽  
Second Trimester ◽  
Pathological Changes ◽  
Fibrin Deposition ◽  
Systemic Lupus ◽  
Immunofluorescence Studies

Maternal connective tissue disease is an important cause of second-trimester fetal loss. In order to assess the pathological changes in the placenta in maternal connective tissue disease, we reviewed the clinical histories and performed histologic and immunofluorescence studies on nine placentas: five from mothers with systemic lupus erythematosus (SLE), two from mothers with mixed connective tissue disease (MCTD), one from a mother with rheumatoid arthritis (RA), and one from a mother without prior known connective tissue disease. Excessive intervillous fibrin deposition and infarction were noted in all cases. Immunofluorescent and immunoperoxidase studies showed deposits of fibrinogen, IgG, IgM, IgA, and complement 3 (C3) localized to the trophoblast basement membrane (TBM). Electron microscopy documented thickening of the trophoblast basal lamina in three SLE placentas examined. The use of immunofluorescence may be enhanced further if antitrophoblast antibodies can be linked to placental compromise.

267. Interleukin-10 inhibits TNFα synthesis and protects against LPS-induced miscarriage and preterm labour

2005 ◽  
Vol 17 (9) ◽  
pp. 109
Author(s):  
S. A. Robertson ◽  
R. J. Skinner ◽  
A. S. Care
Keyword(s):  
Fetal Growth ◽  
Low Dose ◽  
Inflammatory Responses ◽  
Preterm Labour ◽  
Fetal Loss ◽  
Placental Tissue ◽  
Interleukin 10 ◽  
Null Mutant ◽  
Anti Inflammatory ◽  
In Pregnancy

The immune-deviating and anti-inflammatory cytokine interleukin-10 (IL-10) is expressed throughout pregnancy in the decidual and placental tissues. Mice with a null mutation in the IL-10 gene mice are fertile with no reduction in litter size, although fetal growth trajectories and placental structure are altered. IL-10 is known to terminate inflammatory responses and to limit inflammation-induced tissue pathology by inhibiting macrophage synthesis of tumor necrosis factor-α (TNFα). To investigate the anti-inflammatory role of IL-10 in pregnancy, the susceptibility of null mutant mice to low dose LPS-induced miscarriage and preterm labour has been evaluated. When IL-10 null mutant C57Bl/6 (IL-10–/–) and control (IL-10+/+) mice were given low dose E.coli LPS on d10 of pregnancy, IL-10 deficiency was associated with greater fetal loss with fewer mated IL-10–/– mice carrying viable fetuses at day 18 and increased rate of fetal resorption. In mice treated with LPS on day 17, preterm delivery within 24 h occurred in a higher proportion of IL-10–/– mice than IL-10+/+ mice. LPS induced very high and sustained TNFα and IL-6 content in serum, uterine and placental tissue in IL-10–/– mice, associated with upregulated mRNA expression of both cytokines in gestational tissues. These data show that IL-10 modulates placental resistance to inflammatory stimuli by down-regulating expression of the pro-inflammatory cytokines TNFα and IL-6. We conclude that IL-10 has a dual role in pregnancy, acting to regulate placental morphogenesis and fetal growth trajectory, and to protect against inflammation-induced miscarriage and preterm labour.

scholarly journals High Rate of Severe Fetal Outcomes Associated with Maternal Parvovirus B19 Infection in Pregnancy

2008 ◽  
Vol 2008 ◽  
pp. 1-4 ◽  
Author(s):  
Richard H. Beigi ◽  
Harold C. Wiesenfeld ◽  
Daniel V. Landers ◽  
Hyagriv N. Simhan
Keyword(s):  
Parvovirus B19 ◽  
Case Series ◽  
Fetal Loss ◽  
High Rate ◽  
Retrospective Case ◽  
Fetal Outcomes ◽  
Maternal Characteristics ◽  
Parvovirus B19 Infection ◽  
Trend Variation ◽  
In Pregnancy

Objective. To augment the understanding of parvovirus B19 infection in pregnancy with respect to maternal characteristics and their corresponding fetal outcomes.Study Design. Retrospective case-series of all women referred to Magee-Women_s Hospital with serologically-documented parvovirus B19 infection during pregnancy from 1998–2001.Results. All 25 cases that are available for analysis occurred from January through June. The frequency of cases varied substantially from year to year, with 14 cases in 1998, 0 cases in 1999 and 2000, and 11 cases in 2001. In contrast to previous reports, the minority of women [4/25(16%)] experienced symptoms attributable to parvovirus B-19 infection although 3 of 25 (12%) fetuses developed hydrops fetalis and 4/25 (16%) suffered an intrauterine of fetal death.Conclusions. These findings suggest that parvovirus B19 infection in pregnancy follows seasonal and annual trend variation, may produce a lower frequency of maternal symptoms and a higher fetal loss rate than previously reported.Synopsis. Maternal parvovirus B19 infection follows seasonal and annual variation is often asymptomatic and may have higher fetal loss rates than previously reported. Continued surveillance is warranted.

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