Prediction and prevention of venous thrombosis in pregnancy

Venous thromboembolism (VTE) remains the leading cause of maternal mortality. Reports identified further research is required in obese and women post caesarean section (CS). Risk factors for VTE during pregnancy are periodically absent indicating the need for a simple and effective screening tool for pregnancy. Perturbation of the uteroplacental haemostasis has been implicated in placenta mediated pregnancy complications. This thesis had 4 main aims: 1) To investigate anticoagulant effects following a fixed thromboprophylaxis dose in healthy women post elective CS. 2) To evaluate the calibrated automated thrombogram (CAT) assay as a potential predictive tool for thrombosis in pregnancy. 3) To compare the anticoagulant effects of fixed versus weight adjusted thromboprophylaxis dose in morbidly obese pregnant women. 4) To investigate the LMWH effects on human haemostatic gene and antigen expression in placentae and plasma from the uteroplacental , maternal and fetal circulation. Tissue factor pathway inhibitor (TFPI), thrombin antithrombin (TAT), CAT and anti-Xa levels were analysed. Real-time PCR and ELISA were used to quantify mRNA and protein expression of TFPI and TF in placental tissue. In women post CS, anti-Xa levels do not reflect the full anticoagulant effects of LMWH. LMWH thromboprophylaxis in this healthy cohort of patients appears to have a sustained effect in reducing excess thrombin production post elective CS. The results of this study suggest that predicting VTE in pregnant women using CAT assay is not possible at present time. The prothrombotic state in pregnant morbidly obese women was substantially attenuated by weight adjusted but not at fixed LMWH doses. LMWH may be effective in reducing in- vivo thrombin production in the uteroplacental circulation of thrombophilic women. All these results collectively suggest that at appropriate dosage, LMWH is effective in attenuating excess thrombin generation, in low risk pregnant women post caesarean section or moderate to high risk pregnant women who are morbidly obese or tested positive for thrombophilia. The results of the studies provided data to inform evidence-based practice to improve the outcome for pregnant women at risk of thrombosis.

Poor quality specimens delay detection of blood disorders in newborns

This sheet describes the right way to take a blood sample from a newborn infant.

Prediction of hypertensive disorders in pregnancy by combined uterine artery Doppler, serum biomarkers and maternal characteristics

Objectif: Évaluer l'efficacité du dépistage de l’hypertension gestationnelle par les caractéristiques démographiques maternelles, les biomarqueurs sériques et le Doppler de l'artère utérine au premier et au deuxième trimestre de grossesse. Élaborer des modèles prédictifs de l’hypertension gestationnelle fondées sur ces paramètres. Methods: Il s'agit d'une étude prospective de cohorte incluant 598 femmes nullipares. Le Doppler utérin a été étudié par échographie transabdominale entre 11 +0 à 13 +6 semaines (1er trimestre) et entre 17 +0 à 21 +6 semaines (2e trimestre). Tous les échantillons de sérum pour la mesure de plusieurs biomarqueurs placentaires ont été recueillis au 1er trimestre. Les caractéristiques démographiques maternelles ont été enregistrées en même temps. Des courbes ROC et les valeurs prédictives ont été utilisés pour analyser la puissance prédictive des paramètres ci-dessus. Différentes combinaisons et leurs modèles de régression logistique ont été également analysés. Résultats: Parmi 598 femmes, on a observé 20 pré-éclampsies (3,3%), 7 pré-éclampsies précoces (1,2%), 52 cas d’hypertension gestationnelle (8,7%) , 10 cas d’hypertension gestationnelle avant 37 semaines (1,7%). L’index de pulsatilité des artères utérines au 2e trimestre est le meilleur prédicteur. En analyse de régression logistique multivariée, la meilleure valeur prédictive au 1er et au 2e trimestre a été obtenue pour la prévision de la pré-éclampsie précoce. Le dépistage combiné a montré des résultats nettement meilleurs comparés avec les paramètres maternels ou Doppler seuls. Conclusion: Comme seul marqueur, le Doppler utérin du deuxième trimestre a la meilleure prédictive pour l'hypertension, la naissance prématurée et la restriction de croissance. La combinaison des caractéristiques démographiques maternelles, des biomarqueurs sériques maternels et du Doppler utérin améliore l'efficacité du dépistage, en particulier pour la pré-éclampsie nécessitant un accouchement prématuré.

Correlations among antiangiogenic factors and trace elements in hypertensive disorders of pregnancy

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Trombose da veia porta em crianças e adolescentes : deficiência das proteínas C, S e Antitrombina e pesquisa das mutações fator V Leiden, G20210A da Protrombina e C677T da Metileno-tetraidrofolato redutase

Objetivo: A trombose da veia porta é uma causa importante de hiper-tensão porta em crianças e adolescentes, porém, em uma proporção importante dos casos, não apresenta fator etiológico definido. O objetivo desse estudo é determinar a freqüência de deficiência das proteínas inibidoras da coagulação – proteínas C, S e antitrombina − e das mutações fator V Leiden, G20210A no gene da protrombina e C677T da metileno-tetraidrofolato redutase em crianças e adolescentes com trom-bose da veia porta, definir o padrão hereditário de uma eventual deficiência das pro-teínas inibidoras da coagulação nesses pacientes e avaliar a freqüência da deficiên-cia dessas proteínas em crianças e adolescentes com cirrose. Casuística e Métodos: Foi realizado um estudo prospectivo com 14 crianças e adolescentes com trombose da veia porta, seus pais (n = 25) e dois gru-pos controles pareados por idade, constituídos por um grupo controle sem hepato-patia (n = 28) e um com cirrose (n = 24). A trombose da veia porta foi diagnosticada por ultra-sonografia abdominal com Doppler e/ou fase venosa do angiograma celíaco seletivo. A dosagem da atividade das proteínas C, S e antitrombina foi determinada em todos os indivíduos e a pesquisa das mutações fator V Leiden, G20210A da pro-trombina e C677T da metileno-tetraidrofolato redutase, nas crianças e adolescentes com trombose da veia porta, nos pais, quando identificada a mutação na criança, e nos controles sem hepatopatia. Resultados: Foram avaliados 14 pacientes caucasóides, com uma média e desvio padrão de idade de 8 anos e 8 meses ± 4 anos e 5 meses e do diagnóstico de 3 anos e 8 meses ± 3 anos e seis meses. Metade dos pacientes pertenciam ao gênero masculino. O motivo da investigação da trombose da veia porta foi hemorra-gia digestiva alta em 9/14 (64,3%) e achado de esplenomegalia ao exame físico em 5/14 (35,7%). Anomalias congênitas extra-hepáticas foram identificadas em 3/14 (21,4%) e fatores de risco adquiridos em 5/14 (35,7%) dos pacientes. Nenhum pa-ciente tinha história familiar de consangüinidade ou trombose venosa. A deficiência das proteínas C, S e antitrombina foi constatada em 6/14 (42,9%) (p < 0,05 vs con-troles sem hepatopatia), 3/14 (21,4%) (p > 0,05) e 1/14 (7,1%) (p > 0,05) pacientes com trombose da veia porta, respectivamente. A deficiência dessas proteínas não foi identificada em nenhum dos pais ou controles sem hepatopatia. A mutação G20210A no gene da protrombina foi identificada em um paciente com trombose da veia porta e em um controle sem hepatopatia (p = 0,999), mas em nenhum desses foi identificado a mutação fator V Leiden. A mutação C677T da metileno-tetraidrofo-lato redutase foi observada na forma homozigota, em 3/14 (21,4%) dos pacientes com trombose da veia porta e em 5/28 (17,9%) controles sem hepatopatia (p = 0,356). A freqüência da deficiência das proteínas C, S e antitrombina nos pacientes com cir-rose foi de 14/24 (58,3%), 7/24 (29,2%) e 11/24 (45,8%), respectivamente (p < 0,05 vs controles sem hepatopatia), sendo mais freqüente nos pacientes do subgrupo Child-Pugh B ou C, que foi de 11/12 (91,7%), 5/12 (41,7%) e 9/12 (75%), respectivamente (p < 0,05 vs controles sem hepatopatia). Conclusões: A deficiência de proteína C foi freqüente nas crianças e adolescentes com trombose da veia porta e não parece ser de origem genética. A deficiência de proteína S, antitrombina e as presenças das mutações G20210A da protrombina e C677T da metileno-tetraidrofolato redutase foram observadas mas não apresentaram diferença estatística significativa em relação ao grupo controle sem hepatopatia. O fator V Leiden não foi identificado. Os resultados deste estudo sugerem que a deficiência da proteína C pode ocorre como conseqüência da hiper-tensão porta. Os distúrbios pró-trombóticos hereditários não parecem apresentar um papel importante em relação à trombose nas crianças e adolescentes estudadas.

International registry on factor XIII deficiency: a basis formed mostly on European data

FXIII deficiency is known as one of the rarest blood coagulation disorders. In this study, the phenotypic and in part genotypic data of 104 FXIII-deficient patients recorded from 1993 - 2005 are presented. The most common bleeding symptoms were subcutaneous bleeding (57%) followed by delayed umbilical cord bleeding (56%), muscle hematoma (49%), hemorrhage after surgery (40%), hemarthrosis (36%), and intracerebral bleeding (34%). Prophylactic treatment was initiated in about 70% of all patients. FXIII-B subunit-deficient patients had a milder phenotype than patients with FXIII-A subunit deficiency. The most frequent mutation affecting the F13A gene was a splice site mutation in intron 5 (IVS5-1G>A). This mutation was found in eight (17%) of 46 analyzed families. The haplotype analysis of patients carrying the IVS5-1A allele was consistent with a founder effect. The international registry (http://www.f13-database.de) will provide clinicians and scientists working on FXIII deficiency with a helpful tool to improve patient care and direct future studies towards better understanding and treatment of the disease.

Association between matrix metalloproteinase (MMP)-2 polymorphisms and MMP-2 levels in hypertensive disorders of pregnancy

We examined whether two functional polymorphisms (g.-1306 C> T and g.-735 C>T) in matrix metalloproteinase (MMP)-2 gene are associated with preeclampsia (PE) or gestational hypertension (GH), and whether they modify MMP-2 or tissue inhibitor of metalloproteinase (TIMP)-2 plasma concentrations in these hypertensive disorders of pregnancy. We studied 130 healthy pregnant (HP), 130 pregnant with GH, and 133 pregnant with PE. Genomic DNA was extracted from whole blood and genotypes for g.-1306 C>T and g.-735 C>T polymorphisms were determined by Real Time-PCR, using Taqman allele discrimination assays. Haplotypes were inferred using the PHASE program. Plasma MMP-2 and TIMP-2 concentrations were measured by ELISA. The main findings were that pregnant with PE have higher plasma MMP-2 and TIMP-2 concentrations than HP (P<0.05), although the MMP-2/TIMP-2 ratios were similar (P>0.05). Moreover, pregnant with GH have elevated plasma MMP-2 levels and MMP-2/TIMP-2 ratios compared to HP (P<0.05). While MMP-2 genotypes and haplotypes are not linked with hypertensive disorders of pregnancy, MMP-2 genotypes and haplotypes are associated with significant alterations in plasma MMP-2 and TIMP-2 concentrations in preeclampsia (P<0.05). Our findings may help to understand the relevance of MMP-2 and its genetic polymorphisms to the pathophysiology of hypertensive disorders of pregnancy. It is possible that patients with PE and the MMP-2 haplotype combining the C and T alleles for the g.-1306 C>T and g.-735 C>T polymorphisms may benefit from the use of MMPs inhibitors such as doxycycline. However, this possibility remains to be determined. (C) 2012 Elsevier Inc. All rights reserved.

Human blood coagulation and its disorders,

Bibliography: p. 369-398.

Pregnancy loss and psychiatric disorders in young women : an Australian birth cohort study

Background Recent evidence has linked induced abortion with later adverse psychiatric outcomes in young women. Aims To examine whether abortion or miscarriage are associated with subsequent psychiatric and substance use disorders. Method A sample (n=1223) of women from a cohort born between 1981 and 1984 in Australia were assessed at 21 years for psychiatric and substance use disorders and lifetime pregnancy histories. Results Young women reporting a pregnancy loss had nearly three times the odds of experiencing a lifetime illicit drug disorder (excluding cannabis): abortion odds ratio (OR)=3.6 (95% CI 2.0–6.7) and miscarriage OR=2.6 (95% CI 1.2–5.4). Abortion was associated with alcohol use disorder (OR=2.1, 95% CI 1.3–3.5) and 12-month depression (OR=1.9, 95% CI 1.1–3.1). Conclusions These findings add to the growing body of evidence suggesting that pregnancy loss per se, whether abortion or miscarriage, increases the risk of a range of substance use disorders and affective disorders in young women.

FP01-5 Pregnancy loss and psychiatric disorders in young men and women : results from Australian longitudinal cohort study

Recent evidence has linked induced abortion with later adverse psychiatric outcomes in young women. Little is known about later adverse psychiatric outcomes in young men whose partners have fallen pregnant and either go on to have a child, have an abortion or miscarry. 1223 women and 1159 men, from an Austrailan cohort born between 1981 and 1984, were assessed at 21 years for psychiatric and substance misuse and lifetime pregnancy histories. Young women reporting a pregnancy loss (either miscarriage or abortion) had nearly three times the odds of experiencing a illicit drug disorder (excluding cannabis), and nearly twice the odds of an alcohol misuse compared to never pregnant women. Young men whose partner had an abortion, but not a miscarriage, had nearly twice the odds of cannabis disorder, illicit drug disorder, and mood disorder compared to men that had never fathered a pregnancy. Young women who have lost a pregnancy have an increased risk of developing alcohol or substance abuse in later life. Young men whose partner aborted a pregnancy only had an increased of substance abuse and mood disorder in later life. These findings add to the growing body of evidence suggesting that pregnancy loss per se increases the risk of a range of substance use disorders in young women. The findings for young men are novel and raise the possibility that the associations measured may be due to common unmeasured factors associated with early pregnancy in young people rather than pregnancy loss.