[How I explore hémostatic abnormalities in pediatrics]. / Comment j'explore. Une anomalie du bilan d'hémostase en pédiatrie.

Hemostasis work-up is frequently requested in pediatric cares and can often seem complicated to interpret when certain results return to be abnormal. In addition, these biological tests are very sensitive and several pre-analytical conditions can influence them and skew the results, leading to erroneous analyzes and diagnoses. Indeed, systemic inflammation, anemia or even only the delay between blood sampling and analysis can make the results more difficult to be interpreted. However, when the tests have been carried out under good conditions, having in mind a few basic knowledge of hemostasis can easily help to first distinguish a pathology of primary hemostasis from a coagulopathy. Secondly, depending on the abnormal biological tests, complementary oriented assays may then be requested, ideally in a laboratory specialized in hemostasis, in order to confirm or rule out a true hemorrhagic pathology.

Le bilan d'hémostase standard, fréquemment demandé en pédiatrie, peut souvent sembler compliqué à interpréter lorsque certains résultats reviennent anormaux. De plus, l'influence des conditions pré-analytiques, parfois méconnues, sur ces tests biologiques extrêmement sensibles peut en fausser les résultats et entraîner des analyses et des diagnostics erronés. En effet, des paramètres tels que l'inflammation, un contexte d'anémie ou encore un délai trop important entre le prélèvement sanguin et l'analyse peuvent rendre les résultats ininterprétables. Lorsque les tests ont été réalisés dans de bonnes conditions, quelques bases de physiologie de l'hémostase ainsi que quelques spécificités liées à la pédiatrie permettent facilement de s'orienter vers une pathologie de l'hémostase primaire ou de la coagulation. Dans un second temps, en fonction des tests biologiques altérés, des dosages complémentaires orientés peuvent être demandés, idéalement dans un laboratoire spécialisé en hémostase, afin d'affirmer ou infirmer une véritable pathologie hémorragique.

[Case of refractory cardiogenic shock due to venlafaxine overdose : illustration of the support with veno-arterial extracorporeal membrane oxygenation]. / Choc cardiogénique réfractaire lié à une intoxication volontaire en venlafaxine : illustration de l'intérêt de l'ECMO veino-artérielle.

Venlafaxine is a widely prescribed antidepressant drug acting as a reuptake inhibitor of serotonin and noradrenaline. An overdose of venlafaxine can cause cardiovascular toxicity and cardiogenic shock can occur. A 32-year-old man ingested 12g of sustained-release venlafaxine in a suicidal attempt and developed within 24h acute heart failure with refractory cardiogenic shock requiring support by ECMO. The blood toxicology showed persistence of high levels of venlafaxine at day 10. The patient fully recovered and showed normal cardiac function at 3-months follow-up.

La venlafaxine est un antidépresseur largement prescrit agissant comme inhibiteur de recapture de la sérotonine et de la noradrénaline. Un surdosage en venlafaxine peut engendrer une toxicité cardiovasculaire allant jusqu'à l'état de choc cardiogénique. Un homme de 32 ans a ingéré 12 g de venlafaxine sous une forme à libération prolongée dans une tentative de suicide et a développé en 24 heures une insuffisance cardiaque aiguë avec choc cardiogénique réfractaire nécessitant un support hémodynamique par ECMO. La toxicologie sanguine a montré la persistance de niveaux élevés de venlafaxine au jour 10. Le patient s'est ensuite complètement rétabli et présentait une fonction cardiaque normale 3 mois après l'épisode.

[Implementation of prehospital transfusion in case of trauma shock]. / Instauration d'un protocole de transfusion préhospitalière dans le choc hémorragique traumatique.

Transfusion plays a major role in the management of hemorrhagic shock where every minute counts. A pre-hospital transfusion protocol is established in the medical vehicle within the emergency department of CHR hospital Liège. It is based on predefined clinical and biological severity criteria which allow us to start a massive transfusion protocol as early as possible and thus to optimize its effect during traumatic hemorrhagic shock.

La transfusion occupe une place majeure dans la prise en charge du choc hémorragique où chaque minute compte. Un protocole de transfusion préhospitalière est instauré via le véhicule SMUR (Service Mobile d'Urgence-Réanimation) au sein du service des urgences du CHR de Liège. Il est basé sur des critères de gravité cliniques et biologiques prédéfinis qui permettent de débuter, le plus précocement possible, un protocole de transfusion massive et, ainsi, d'optimaliser son effet lors de choc hémorragique traumatique.

[Multidisciplinary management of the pediatric sickle cell patient in 2019]. / Prise en charge multidisciplinaire du patient drépanocytaire pédiatrique en 2019.

Sickle cell disease is a common genetic disorder that affects haemoglobin. It is manifested by haemolytic anaemia and vaso-occlusive crisis. It can affect all organs and its evolution is unpredictable. The multidisciplinary management of pediatric patients who suffer from it is essential to adapt their treatment and optimize their evolution. One of the major challenges is to succeed the transition to adult medicine. New therapeutic perspectives are in development and look promising.

La drépanocytose est une maladie génétique fréquente qui affecte l'hémoglobine. Elle se manifeste par une anémie hémolytique et des phénomènes vaso-occlusifs. Elle peut toucher tous les organes et son évolution est imprévisible. La prise en charge multidisciplinaire des patients pédiatriques qui en souffrent est essentielle pour optimaliser leur évolution et adapter leur traitement. Un des défis majeurs est de réussir la transition vers la médecine adulte. De nouvelles perspectives thérapeutiques sont en développement.

Management of neonatal thrombocytopenia in a context of maternal antiplatelet alloimmunization: Expert opinion of the French-speaking working group.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, seen in 1/800-1000 neonates. FNAIT is the most common cause of early-onset isolated severe neonatal thrombocytopenia in maternity wards. The most feared complication of this disorder is intracranial hemorrhage, leading to death or neurological sequelae. There is no systematic screening of at-risk pregnancies and FNAIT is often discovered when fetal or neonatal bleeding is observed. A working group on fetomaternal platelet alloimmunization was created in 2017, under the auspices on the French Group of Thrombosis and Hemostasis (GFHT). The first objective of this group was to survey clinical practices for treatment of thrombocytopenic neonates in a context of suspected or confirmed FNAIT.

[Use of sFlt-1/PlGF ratio in preeclampsia : a monocentric retrospective analysis]. / L'utilisation du ratio sFlt-1/PlGF dans la prééclampsie : une analyse rétrospective monocentrique.

Soluble Fms-like tyrosine kinase 1 (sFlt-1) is an anti-angiogenic factor released in higher amounts in preeclampsia and implicated in endothelial dysfunction. sFlt-1/PlGF ratio is used in the prediction of preeclampsia. An sFlt-1/PlGF ratio inferior to 38 predicts the short-term absence of preeclampsia. A ratio ? 85 (early-onset PE) or ? 110 (late-onset of PE) could diagnose preeclampsia. In this study, sFlt-1/PlGF ratio has been measured in 183 patients. Sixty-seven preeclampsia have been diagnosed preeclamptic at delivery. The median sFlt-1/PlGF ratio was 100.3. The median ratio among women with preeclampsia (N=67) versus no preeclampsia (N=116) was 212.7 versus 35.4. In accordance with this analysis, an sFlt-1/PlGF ratio ? 38 has a sensibility of 95,5 % and a specificity of 73.3 %. The positive predictive value and the negative predictive value were 67.4 % and 96.6 %, respectively. These results suggest that sFlt-1/PlGF ratio is helpful in the diagnosis of preeclampsia.

La Fms-like tyrosine kinase 1 soluble (sFlt-1) est un facteur anti-angiogénique libéré en quantité excessive dans la prééclampsie (PE) et impliqué dans la dysfonction endothéliale. Il est comparé au facteur de croissance placentaire pro-angiogénique (PlGF) qui diminue dans la PE. Le ratio sFlt-1/PlGF est présenté dans la littérature comme outil dans la prédiction de la prééclampsie. Un ratio inf�rieur a 38 confirme l'absence de prééclampsie à court terme. Un ratio ? 85 dans la PE précoce (avant 34 semaines d'aménorrhée (SA)) et ? 110 dans la PE tardive (après 34 SA) peut poser le diagnostic de prééclampsie. Dans cette étude rétrospective monocentrique, le ratio sFlt-1/PlGF a été dosé chez 183 patientes à risque de PE dont 67 ont présenté une prééclampsie. Le ratio sFlt-1/PlGF médian pour toutes les patientes évaluées est 100,3. Le ratio médian pour les patientes ayant déclaré une prééclampsie (N=67) est 212,7 alors que celui des femmes sans prééclampsie (N=116) est de 35,4. En accord avec ces analyses, un ratio sFlt-1/PlGF ? 38 possède une sensibilité égale à 95,5 % et une spécificité égale à 73,3 % dans la mise au point de la PE. Les valeurs prédictives positive (VPP) et négative (VPN) sont, respectivement, 67,4 % et 96,6 %. Ces résultats suggèrent que le ratio sFlt-1/PlGF peut être une aide dans le diagnostic de la prééclampsie.

Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: I. Endocrine effects.

OBJECTIVES: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by 'co-administration' of dehydroepiandrosterone (DHEA). STUDY DESIGN: In this randomized, double-blind, placebo-controlled study in 99 new COC starters (18-35 years old with body mass index range 18-34 kg/m²), a COC containing 30mcg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) was used for 3cycles, followed by 6cycles of the same COC combined with either 50 mg/day DHEA or placebo. Total T, albumin, sex hormone-binding globulin (SHBG), DHEA-sulfate (DHEA-S), Δ4-androstenedione (AD), 3α-androstanediol glucuronide (ADG) and estradiol (E2) were measured, whereas free T and the free T index (FTI) were calculated. Assessments took place at baseline (no COC use), after the run-in period (COC use alone) and during the treatment period (DHEA or placebo). RESULTS: During COC use alone, androgen levels decreased, especially total T by 62% and free T by 86%, and SHBG increased by 243%. Total T increased with DHEA compared to placebo (change from end of run-in period to end of treatment period -- 1.3±1.2 nmol/L vs. 0.0±0.4 nmol/L; p<.0001) -- and was restored to baseline levels. Free T and the FTI increased significantly (p<.0001), but the free T level was still 53% below baseline levels. DHEA-S, AD and ADG increased significantly to levels above baseline (p<.0001 for each). DHEA had no effect on SHBG, albumin and E2. CONCLUSIONS: An EE/DRSP containing COC strongly suppressed endogenous androgen concentrations in all users. The addition of 50 mg DHEA to a COC regimen containing EE/DRSP restored total T to baseline levels, but free T levels were restored by only 47% as most of the T remains bound to SHBG. IMPLICATIONS: When using a COC that increases SHBG considerably, a daily dose of 50 mg DHEA is insufficient to normalize free T levels completely.

Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: II. Clinical effects.

OBJECTIVES: Combined oral contraceptives (COCs) decrease androgen levels, including testosterone (T), which may be associated with sexual dysfunction and mood complaints in some women. We have shown that 'co-administration' of dehydroepiandrosterone (DHEA) to a drospirenone (DRSP)-containing COC restored total T levels to baseline and free T levels by 47%. Here we describe the effects on sexual function, mood and quality of life of such an intervention. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled study in 99 healthy COC starters. A COC containing 30 mcg ethinylestradiol (EE) and 3 mg DRSP was used for three cycles, followed by six cycles of the same COC combined with 50 mg/day DHEA or placebo. Subjects completed the Moos Menstrual Distress Questionnaire (MDQ), the McCoy Female Sexuality Questionnaire and the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety and tolerability, including effects on skin, were evaluated. RESULTS: The addition of DHEA induced small but significant improvements compared to placebo in the MDQ score for autonomic reactions during the menstrual (-2.0 vs. 0.71; p=0.05) and the premenstrual phase (-3.1 vs. 2.9; p=0.01) and for behavior during the intermenstrual phase (-1.4 vs. 3.6; p=0.02). A significant difference was found in the MDQ score for arousal during the premenstrual phase in favor of placebo (-5.0 vs. 1.0; p=0.01). There were no statistically significant differences between groups for the MSFQ and Q-LES-Q scores. DHEA 'co-administration' resulted in an acceptable safety profile. DHEA negated the beneficial effect of the COC on acne according to the subjects' self-assessment. CONCLUSIONS: 'Co-administration' with DHEA did not result in consistent improvements in sexual function, mood and quality of life indicators in women taking EE/DRSP. Retrospectively, the 50 mg dose of DHEA may be too low for this COC. IMPLICATIONS: A well-balanced judgment of the clinical consequences of normalizing androgens during COC use may require complete normalization of free T.

Massive Transfusion Protocol: a local two years' experience.

Evidence supporting the implementation of a Massive Transfusion Protocol (MTP) and its effect on patients' outcome is still limited. However, we implemented in June 2013 a local MTP for trauma and nontrauma massively bleeding patients. Twenty months later, we propose here a short presentation of our MTP population and a critical analysis of the actual data supporting MTP implementation.

[Implementation of a massive transfusion protocol in an emergency department]. / Mise en place d'un protocole de transfusion massive dans un service d'urgences.

We present here the massive transfusion protocol implemented in our institution in 2013. It will improve our management of critical massive bleeding, a situation which is rare in in our hospital, but carries a high mortality risk.

[Clinical case of the month. Spontaneous hematoma and acquired hemophilia]. / Le cas clinique du mois. Hématomes spontanés et hémophilie acquise.

Acquired haemophilia is a rare disease, 50% of the cases are idiopathic. We report a case admitted in cardiology for spontaneous hematoma. Observation of isolated prolonged activated partial thromboplastin time (aPPT) without anticoagulation treatment and the absence of correction with normal plasma suggested diagnosis. Confirmation of inhibitors to FVIII allowed perfusions of activated prothrombin complex concentrates.

[Neonatal ABO incompatibility underlies a potentially severe hemolytic disease of the newborn and requires adequate care]. / L'allo-immunisation fœto-maternelle ABO peut être sévère.

ABO allo-immunization is the most frequent hemolytic disease of the newborn and ABO incompatibility is present in 15-25 % of pregnancies. True ABO alloimmunization occurs in approximately one out of 150 births. Intensity is generally lower than in RhD allo-immunization. We report on three cases showing that ABO allo-immunization can lead to severe hemolytic disease of the newborn with potentially threatening hyperbilirubinemia and complications. Early diagnosis and adequate care are necessary to prevent complications in ABO incompatibility. A direct antiglobulin test is the cornerstone of diagnosis and should be performed at birth on cord blood sampling in all group infants born to O mothers, especially if of African origin. Risk factor analysis and attentive clinical monitoring during the first days of life are essential. Vigilance is even more important for infants discharged before the age of 72 h. Every newborn should be assessed for the risk of developing severe hyperbilirubinemia and should be examined by a qualified healthcare professional in the first days of life. Treatment depends on the total serum bilirubin level, which may increase very rapidly in the first 48 h of life in cases of hemolytic disease of the newborn. Phototherapy and, in severe cases, exchange transfusion are used to prevent hyperbilirubinemia encephalopathy. Intravenous immunoglobulins are used to reduce exchange transfusion. Treatments of severe hemolytic disease of the newborn should be provided and performed by trained personnel in neonatal intensive care units.

Rh D foeto-maternal alloimmunization prophylaxis with anti-D immunoglobulins reviewed in the era of foetal RHD genotyping.

In Belgium, prevention of anti-D immunization is currently based on systematic postnatal prophylaxis associated with targeted antenatal injection in high-risk situations of foeto-maternal haemorrhage.The failures of prevention are mainly due to the non-respect of established guidelines for RhlG prophylaxis, and to spontaneous undetected foetal-maternal haemorrhages without any obvious cause during the third trimester of pregnancy. In order to reduce the rate of residual post-pregnancy anti-D immunization, several countries decided to associate the classical prophylaxis to a routine antenatal anti-D prophylaxis (RAADP) during the 28th or 29th week of gestation. Since a few years, the foetal RHD genotyping in maternal plasma enables us to limit the antenatal prophylaxis only to those D- women carrying a D+ foetus. This paper deals with: the advantages of an antenatal prevention in the light of non-invasive foetal RHD genotyping, the rules rendering prevention protocols efficient whatever the algorithm applied, and the recommended immuno-haematology follow-up of women who received RhlG.

Neonatal haemoglobinopathy screening in Belgium.

BACKGROUND: A neonatal haemoglobinopathy screening programme was implemented in Brussels more than a decade ago and in Liège 5 years ago; the programme was adapted to the local situation. METHODS: Neonatal screening for haemoglobinopathies was universal, performed using liquid cord blood and an isoelectric focusing technique. All samples with abnormalities underwent confirmatory testing. Major and minor haemoglobinopathies were reported. Affected children were referred to a specialist centre. A central database in which all screening results were stored was available and accessible to local care workers. A central clinical database to monitor follow-up is under construction. RESULTS: A total of 191,783 newborns were screened. One hundred and twenty-three (1:1559) newborns were diagnosed with sickle cell disease, seven (1:27,398) with beta thalassaemia major, five (1:38,357) with haemoglobin H disease, and seven (1:27,398) with haemoglobin C disease. All major haemoglobinopathies were confirmed, and follow-up of the infants was undertaken except for three infants who did not attend the first medical consultation despite all efforts. CONCLUSIONS: The universal neonatal screening programme was effective because no case of major haemoglobinopathy was identified after the neonatal period. The affected children received dedicated medical care from birth. The screening programme, and specifically the reporting of minor haemoglobinopathies, has been an excellent health education tool in Belgium for more than 12 years.

[New approaches to prenatal diagnosis of rhesus incompatibility]. / Nouvelles stratégies dans la prise en charge de l'allo-immunisation foeto-maternelle anti-RHD (Rhésus).

Despite generalisation of anti-D immunoprophylaxis, RhD allo-immunisation still remains the major cause of severe haemolytic disease of the fetus and of the newborn (HDFN). The routine follow up of pregnant women comprises: the ABO/D, Rh/Kell red cells typing and the search for irregular antibodies. In case of anti-D immunisation, the paternal Rh phenotype, when known, provides useful information regarding the probability for the fetus to have inherited the D antigen and thereby to be exposed to the risk of HDFN. The antibody titre, which is predictive of possible in vivo haemolysis, must be interpreted in the light of the previous obstetric history, and can lead to the decision of invasive amniocentesis. Then the measurement of the optical density (deltaOD450 nm) and the fetal RhD typing can be realised on amniotic fluid. New molecular techniques make it possible now to demonstrate the presence of fetal DNA in maternal plasma. These methods lying on non invasive procedures could advantageously be applied to the genotyping of fetal RHD during pregnancy. The present paper aims to discuss the predictive values of RHD fetal genotype in maternal plasma of RhD negative mothers. The ante-partum management of immunised pregnant women is reviewed in the light of this new molecular approach combined to Doppler ultrasonography of the fetal middle cerebral artery. This non invasive method for determining fetal RHD genotype could be systematically proposed to all RhD negative pregnant women for a better targeted prenatal follow-up and an increased efficacy of RhD prophylaxis.

[Fetal RHD in maternal plasma in prenatal follow-up]. / Le génotypage RHD foetal sur sang maternel dans le suivi prénatal des patientes Rh D négatif.

Since the beginning of RHD genotyping in maternal plasma, no Rh D positive baby was diagnosed RHD negative in our institution. Genotyping from circulating DNA in maternal plasma is as efficient as genotyping on amniocyts but without the associated risks. We propose a prophylactic injection based on fetal genotyping RHD in maternal blood with 300 microg anti-D immunoglobulin at 28 weeks of amenhorrea in all of Rh D negative pregnant women whitch fetuses positive RHD.

[Prenatal determination of fetal RHD in maternal plasma: two-years experience of routine clinical use]. / Utilisation en routine clinique du génotypage foetal RHD sur plasma maternel: bilan de deux ans d'activité

OBJECTIVES: To evaluate the predictive value of RHD fetal genotype in maternal plasma of Rh D negative mothers after 10 weeks of gestation in a clinical use. MATERIAL AND METHOD: Prospective, comparative study between fetal RHD genotyping in maternal plasma, with amplification of exons 4,5,10 of the RHD gene, by real-time multiplex PCR, and Rh D serology at birth, in 218 pregnancy and their 223 babies, between November 2002 and 2004. RESULTS: Combining the amplification of three exons, the concordance rate of fetal Rh D genotyping in maternal plasma and baby phenotyping at delivery was 100%. Four women whose the babies were Rh D negative were positive for RHD exon 10 during pregnancy. This positivity was, in three cases, correlated with the presence of RHDpsi pseudogene and in last case, with a haplotype Cdes (r's). RHD genotyping was performed for five twin pregnancies. CONCLUSION: Multiplex PCR using maternal plasma provides perfect prenatal prediction of fetal RHD gene. These results confirm that this non invasive procedure is the preferred method for assessing Rh D fetal status in Rh negative mothers. Using this method for two years in routine practice has led us to modify our management scheme for sensitized Rh D-negative pregnant women.

[Group B streptococcus in the antenatal clinic and in the delivery room: a matter of systematic attitude]. / Le streptocoque du groupe B en clinique anténatale et en salle de travail: un problème d'attitude systématique.

OBJECTIVES: We wanted to evaluate the compliance to the local recommendations, similar to the CDC (Centers for Disease Control and prevention) recommendations launched in 1996, for the prevention of perinatal group B streptococcal (GBS) disease in the clinical practice of a academic maternity and to identify the causes of missed screening and antibiotic prophylaxis. MATERIALS AND METHODS: Retrospective study of 1249 consecutive pregnancies between 1st January and 31th August 2002. The screening methods for GBS colonisation were the culture of rectovaginal swabs collected between 35 and 37 weeks and/or a rapid antigenic screening performed on a vaginal swab collected at the patient's admission for labor. RESULTS: Rate of global screening was very high (97.8%): 28.8% of antenatal screening versus 90.3% during labor. An appropriate antibiotic prophylaxis was administered to only one-third of positive women when the screening was performed at admission to the labor room, whereas two-thirds of GBS-positive women screened between 35 and 37 weeks received their antibiotic prophylaxis. 2.4%o of the newborns were infected and 2.9% were colonized. Among the different risk factors, intrapartum fever was more often associated with maternal GBS colonisation. The observed sensitivity of the rapide antigenic test was 20.4%. CONCLUSION: Compliance to guidelines is sometimes difficult in the clinical practice of an academic maternity. In our hands the rapid test for GBS screening had low sensitivity. The analysis of these data led to introducing a computerized algorithm in our maternity to improve the prevention of perinatal group B streptococcal disease.