Prediction of individual factor VIII or IX level for the correction of thrombin generation in haemophilic patients.

BACKGROUND: The thrombin generation (TG) assay can assess individual clotting potential. The thrombin generation potential is correlated with the patient's bleeding phenotype and varies from one patient to the other for the same degree of factor VIII or IX deficiency. OBJECTIVE: To define in vitro for individual haemophilic patients the target factor VIII or IX level required to normalize their TG. PATIENTS/METHODS: Plasmas from 20 haemophilic patients were spiked with increasing levels of the deficient coagulation factor and TG parameters were measured. The relationships between factor levels and TG parameters were determined by linear regression. The normal range of thrombin generation was defined in 39 healthy male volunteers. RESULTS: Despite inter-individual heterogeneity in basal TG and responses to spiking, a linear relationship was found between factor VIII or IX levels and TG parameters for individual patients. Based on the individual responses of patient plasmas to spiking, it is possible to define in vitro the target factor VIII or IX levels needed to normalize the TG parameters. For both haemophilic A and haemophilic B patients, significant correlations were found between basal peak values and their correction slopes. The correction slope was steeper in haemophilic B patients, so the factor IX level needed to normalize the TG parameters was lower than for haemophilic A patients. CONCLUSIONS: The TG assay could be used to determine in vitro the patient-specific factor VIII or IX level to be reached to effectively normalize their TG. These in vitro results should be confirmed by ex-vivo studies.

Neonatal outcome after fetal anemia managed by intrauterine transfusion.

UNLABELLED: In-utero transfusion is now well under control and improves the survival of foetuses monitored for fetal anemia with a survival rate of more than 80 %. The aim was to evaluate short-term neonatal outcome after fetal severe anemia managed by intrauterine transfusions. We did a retrospective study of all neonates born after management of severe fetal anemia (n = 93) between January 1999 and January 2013 in our regional center. The two main causes of anemia were maternal red blood cell alloimmunization (N = 81, 87 %) and Parvovirus B19 infection (N = 10, 10.8 %). In the alloimmunization group, phototherapy was implemented in 85.2 % of cases with a maximum level of bilirubin of 114.4 ± 60.7 (mg/dl). Transfusion and exchange transfusion were, respectively, required in 51.9 % and in 34.6 % of cases. One neonate presented a convulsive episode, and we observed three neonatal deaths. In the parvovirus group, none of the child had anemia at birth and no management was necessary. CONCLUSION: Contemporary management of Rhesus disease is associated with encouraging neonatal outcomes. In case of Parvovirus infection, no specific management is necessary at. But, in all cases of fetal anemia, children should be followed up with particular attention to neurologic development. WHAT IS KNOWN: • In-utero transfusion is now well under control and improves the survival of fetuses monitored for fetal anemia. • Limited studies are available on the effect of IUT on postnatal outcome in infants with a history of fetal anemia. What is New: • Contemporary management of severe Rhesus disease is associated with encouraging neonatal outcomes. • The majority of infants can be managed with phototherapy and a limited number of top-up transfusions and exchange transfusions. In case of Parvovirus infection, the short-term neonatal outcome is excellent.

Perioperative management and neuraxial analgesia in women with factor XI deficiency (<60 IU/dL): a French multicenter observational study of 314 pregnancies.

Background: Factor (F)XI deficiency is a rare bleeding disorder with a poor correlation between bleeding tendency and FXI level. Management of pregnant women with FXI deficiency is not clearly established, especially regarding neuraxial analgesia (NA). Objectives: A retrospective multicenter observational study was conducted in French hemostasis centers on pregnant women with FXI of <60 IU/dL. Methods: Data to report were (i) FXI levels before pregnancy and at time of delivery, (ii) type of NA and delivery management modalities, and (iii) possible complications related to NA and bleeding complications. Results: Three hundred fourteen pregnancies in patients with FXI deficiency of <60 IU/dL were reported (from 20 centers); among them, 199 NA procedures have been completed (137 epidurals and 61 spinals, 1 had both). The period of childbirth was mostly from 2014 to 2020 (281/314; 89.5%). Congenital FXI deficiency was established with certainty by investigators in 32.8% patients (n = 103). Previous bleedings were described in 20.4% of the patients (64/314; 45.3% cutaneous, 31.3% gynecologic, and 15.6% postsurgical). Thirteen deliveries had an NA procedure with FXI of <30 IU/dL, 42 with FXI of 30-40 IU/dL, and 118 with FXI of 40-60 IU/dL. Median FXI levels at delivery in the epidural and spinal groups were not significantly different but were significantly lower in the group without NA by medical staff contraindications. There were no complications related to NA. A 17.5% postpartum hemorrhage or excessive postpartum bleeding incidence was reported, which is consistent with previous data. Conclusion: Our data support the use of a 30 IU/dL FXI threshold for NA, as suggested by the French proposals published in August 2023.

[Blood transfusion in neonatology: Study of practical aspects in 2016 in France, excluding acute bleeding or surgical care]. / Réalisation d'une transfusion sanguine en néonatologie : état des lieux des pratiques en 2016 en France ; situations aiguës ou chirurgicales exclues.

BACKGROUND: Blood transfusion is common in neonatology, especially in preterm or low birth weight infants. Recommendations were proposed by the French National Authority of Health (HAS) in 2014 and 2015 for red blood cells and platelet transfusion respectively, but an heterogeneity of practical attitudes persist. The objective of this survey is to evaluate transfusion practices in neonatal intensive care units. METHODS: Investigation of practice of neonatal transfusion was organized among 68 neonatal intensive care unit (level 3) between September 2016 and May 2017, by mailing survey focused on systematic training of nurses, patient identification, immunohematology, information and technical aspects of blood components administration. RESULTS: Twenty-three neonatal intensive care units among the 68s answered the questionnaire. One thousand five hundred sixty seven neonates were transfused and 3382 blood products were administered. The results highlight a consensual attitude concerning the procedures of patient identification, immunohematology tests and blood products administration. However, heterogeneity remains concerning information of the parents or the person with parental authority, immediate and delayed follow-up and devices used for the transfusion. However HAS guidelines (2014 and 2015) appear to be well applied by clinicians for blood products, specifications and calcul of transfused volume based on gestational age and weight.

Management of red blood cell alloimmunization in pregnancy.

The main cause of fetal anemia is maternal red blood cell alloimmunization (AI). The search of maternal antibodies by indirect antiglobulin test allows screening for AI during pregnancy. In case of AI, fetal genotyping (for Rh-D, Rh-c, Rh-E and Kell), quantification (for anti-rhesus antibodies) and antibody titration, as well as ultrasound monitoring, are performed. This surveillance aims at screening for severe anemia before hydrops fetalis occurs. Management of severe anemia is based on intrauterine transfusion (IUT) or labor induction depending on gestational age. After intrauterine transfusion, follow-up will focus on detecting recurrence of anemia and detecting fetal brain injury. With IUT, survival of fetuses with alloimmunization is greater than 90% but 4.8% of children with at least one IUT have neurodevelopmental impairment.

[Is a non-invasive management allowed for maternofetal alloimmune thrombocytopenia? Experience over a 10-year period]. / Peut-on prendre en charge l'allo-immunisation plaquettaire foetomaternelle de manière non invasive? Expérience sur dix ans.

OBJECTIVES: Our purpose was to study a non-invasive management of fetomaternal alloimmune thrombocytopenia (FMAIT). PATIENTS AND METHODS: Between 1996 and 2005, 18 women were treated. The population was divided into 2 groups: patients with a history of intracranial haemorrhage (ICH) in the older sibling received weekly intravenous immunoglobulin (IVIG) therapy to the mother (1 g/kg per week) without initial cordocentesis whereas patients with a history of neonatal thrombocytopenia did not undergo any treatment. RESULTS: All pregnancies with a previous FMAIT were monitored with serial ultrasound scans without cordecentesis. 15 patients had HPA-1, 2 HPA-3 and 1 HPA-5 immunizations. Weekly intravenous immunoglobulin therapy was administered in 5 patients with a history of ICH in the older sibling. Two of these delivered thrombocytopenic children; one had a platelet count < 50 x 10(9)/l. For the 13 women (one twin) who had a sibling with neonatal thrombocytopenia, 11/14 newborns had a platelet count < 50 x 10(9)/l. Predelivery fetal blood sampling were performed in 8/18 pregnancies. The neonatal periods of the 19 children were uncomplicated and no ICHs were observed. DISCUSSION AND CONCLUSION: Our results suggest that a non-invasive strategy avoiding serial cordocentesis may be an effective therapy in patients who are at risk of fetal and neonatal alloimmune thrombocytopenia.

[Blood transfusion to pre-term neonates: What is new in the French guidelines since 2002?] / Transfusion de culot globulaire chez le nouveau-né grand prématuré : ce qui a changé dans les recommandations françaises depuis 2002.

This document updates the "Guidelines for the Administration of Blood Products: Transfusion of Infants and Neonates" published in 2002 by the French National Authority for Health (HAS). In doing so, it acknowledges changes in transfusion practices during the past decade, particularly with respect to safety issues and additional published transfusion-related guidelines. The major modifications concern irregular agglutinin screening indications before 4 months of age, a limitation of blood irradiation, and a non-recommendation for systematically checking for cytomegalovirus status. More precise thresholds for transfusion and an update of blood transfusion alternatives were also provided. Delayed cord clamping (>30s after birth) is recommended unless the neonate is asphyxiated and needs to be moved immediately for resuscitation.

[Platelet transfusion and allergic transfusion reactions: experiences at Lille Hospital over a four year period]. / Transfusion de plaquettes et incidents de type allergique: expérience du CHRU de Lille sur une période de quatre ans.

Among the immediate transfusion reactions caused by the utilization of blood products, those suggesting immuno-allergic mechanisms posed problems for frequency, gravity, laboratory diagnosis and safety. We report here the Lille Hospital's experience over a four-year period concerning these manifestations after platelet concentrate transfusion. Eight hundred and fifty-two immediate transfusion reactions have been declared, of which 230 were allergic, which appeared in 181 patients (27%). Among the most frequent clinical signs, rash was often described (158 cases: 68.7%); less frequent were respiratory problems such as dyspnea (34 cases: 14.8%) and hypotensive reactions (18 cases: 7.8%). Seven patients presented severe reactions (3%). Twenty percent of them presented multiple allergic reactions and in 43.2%, the recurrence was more serious than the initial problem in spite of preventive medication; the use of washed blood components was necessary. The age of platelet concentrates does not appear to play a part in provoking these events (67% of platelet concentrates had been collected within four days). These allergic transfusion reactions posed problems for those who prescribe medication, because they are frequent, sometimes serious, can recur and at present, the proposed medication prevention is not always efficient.

[Diagnostic difficulties of transfusion incidents due to bacterial contamination: report of two cases]. / Difficultés diagnostiques des incidents transfusionnels par contamination bactérienne: à propos de deux observations.

The French hemovigilance system has recently underlined the relative frequency of transfusion-associated bacterial sepsis and the necessity to remain constantly aware of this eventuality. We describe the experience of a hematology unit over a 18-month period: 189 acute transfusion reactions were registered and bacterial cultures of the implicated cellular blood products realized in 82 of them. A positive result was obtained in two cases. For both cases, clinical symptoms of transfusion reaction were limited to a lasting fever, and a skin rash occurred in aplastic patients with preexisting signs of sepsis. The causal relationship between this contamination and the transfusion reaction is difficult to establish. Clinical manifestations justifying a bacterial inquiry must therefore be more precisely defined, particularly in multitransfused patients.

[Immunohematologic surveillance of patients treated with ABO incompatible bone marrow allografts]. / Surveillance immunohématologique de patients traités par allogreffes de moelle osseuse ABO incompatibles.

Direct antiglobulin test (DAT), ABO typing and isoagglutinins titers were regularly performed in 26 patients who received a marrow transplant from a major ABO incompatible donor (M = 10 cases), from a minor ABO incompatible donor (m = 10 cases) or both (B = 6 cases). Erythrocyte or plasma depletion of bone marrow infusate was used in all major or certain minor ABO incompatibilities respectively. A positive DAT was recorded in 19/26 patients at various times, but only a few of them, belonging to groups M or B, exhibited a significant hemolysis. No serious complication was observed after bone marrow infusion. Five patients showed evidence of hemolysis after transplantation, 1 patient died with a graft rejection and 3 patients had a delayed erythropoietic engraftment. In all cases of major ABO incompatibility, the erythrocyte recovery was preceeded by a decrease of antibodies against the donor's blood group. These antibodies finally disappeared in all patients except one who had a persistence of isoagglutinins beyond day + 650. A transient appearance of isoagglutinins against the recipient blood group was sometimes detected in minor ABO incompatibility without any clinical complications.

[Impact of a quality approach for transfusion safety on prescription, circuit optimization, traceability]. / Impact d'une démarche qualité en sécurité transfusionnelle sur la prescription, l'optimisation des circuits, la traçabilité. Expérience du CHRU de Lille.

The Quality Assessment Program undertaken at the Regional University Hospital of Lille benefits from previous experience making management of this project possible: continuing education, preliminary initiation into the quality approach, and existing reference systems. The aims are to master the rates of outdated and no longer efficient red cell concentrates, to control red cell concentrate delivery time, to validate the refrigeration line integrity and to ensure a flawless marking out process. The process studied is transverse, with those taking part in it belonging to several professional categories. The method will consist in a process identification, its description and characterization according to FMECA (Failure Mode Effects and Criticality Analysis), the creation of a new process and its improvement. Thus failures should be identified and classified hierachically. The corrective actions will consist in communication aids, an education program, blood product transport and blood depot reorganization, data processing improvement and medical equipment acquisition. Quality indicators are developed according to the objectives of the study, and progress indicators are developed as a periodical assessment of blood transfusion practice. This ambitious project relies on the involvement of Hospital Management and referent network. These referents facilitate the improvement processes for those taking part in this process.

[Recurrent hematomas and normal standard hemostasis tests]. / Hématomes récidivants et bilan d'hémostase standard normal.

The authors report the case of a 22-month-old boy experiencing a voluminous subcutaneous haematoma, 72 hours after a head trauma. Two subsequent drainages of this haematoma were required because of its recurrence. The child, whose parents had blood relations, suffered from recurrent bleeding since his birth. A standard haemostasis assessment including prothrombin time, activated partial thrombopiastin time, bleeding time, concentration of fibrinogen and platelet count was unremarkable. Therefore, coagulation factors were explored. An inherited factor XIII deficiency (less than 2%) was recognized. A new drain was inserted, after administration of factor XIII concentrate. The time course of the haematoma was favourable. After discharge, the prophylactic therapy consisted of an injection of factor XIII concentrate (50 Ul.kg-1) every 5 weeks.

Is intrauterine exchange transfusion a safe procedure for management of fetal anaemia?

OBJECTIVE: To study modalities and complications of intrauterine exchange transfusion (IUET) for the management of severe fetal anaemia. STUDY DESIGN: Retrospective study of all IUET procedures performed between January 1999 and January 2012 at a regional centre. Characteristics of each procedure were studied to identify risk factors for complications. Survival rates according to the different aetiologies of anaemia were evaluated. RESULTS: In total, 225 IUET procedures were performed in 96 fetuses. Major indications were feto-maternal erythrocyte alloimmunization (n=80/96, 83.3%) and parvovirus B19 infection (n=13/96, 13.5%). Twenty-six percent of the fetuses (25/96) had hydrops fetalis before the first IUET. Intrauterine fetal death occurred after 2.7% (6/225) of procedures, premature rupture of the membranes occurred after 0.9% (2/225) of procedures, and emergency caesarean section was required after 3.6% (8/225) of procedures. Fetal bradycardia [odds ratio (OR) 37, 95% confidence interval (CI) 8.3-170; p<0.01] and gestational age up to 32 weeks (OR 3.67; 95% CI, 1.07-12.58; p=0.038] were significantly associated with complications after IUET. Complications occurred in 17.7% of pregnancies (17/96) and 7.5% of IUET procedures (17/225). The overall survival rate in the study cohort was 87.5% (84/96): 90% (72/80) in the alloimmunization group and 76.9% (10/13) in the parvovirus-infected group (NS). CONCLUSION: IUET has a higher complication rate than simple intrauterine transfusion, and should be performed by well-trained specialists.

[National survey of transfusion practices in the neonatal period for the development of recommendations based on the "Haute Autorité de Santé methodology"]. / Enquête nationale sur les pratiques transfusionnelles pendant la période néonatale en vue de l'élaboration de recommandations selon la méthodologie de la Haute Autorité de santé.

Although transfusion practices have changed these last years, the neonatal period remains one period when the transfusion of blood components (in particular in red blood cells concentrates) is frequent, particularly for low birth weight premature babies. It is thus important to know well the pathophysiological characteristics specific to this age of life in order to reduce the risks of transfusion and to allow an optimal effectiveness of this treatment. Various studies on neonatal transfusion show that transfusion practices during the neonatal period are very heterogeneous from a team to another, and even within the same team. Therefore, we wanted to know the practices in France, by addressing a questionnaire to neonatology centres, in collaboration with the French Society Vigilance and Transfusion Therapy and the French Society of Neonatology (SFN). The results obtained confirm the heterogeneity of practices. To follow up on this study, we constituted a working group, in partnership with the SFN, the SFVTT and the EFS, with an aim of proposing good practice recommendations according to the methodology of the French "High Authority for Health", in order to homogenize at the national level transfusion practices of the new-born baby.

[Two children with cerebral and retinal hemorrhages: do not diagnose shaken baby syndrome too rapidly]. / Association hémorragies cérébrales et rétiniennes chez 2 enfants : ne pas conclure trop vite au diagnostic d'enfant secoué.

We report on 2 cases associating retinal (RH) and cerebral hemorrhages (CH), which first suggested the diagnosis of shaken baby syndrome (SBS). After an etiologic search, the diagnosis was corrected: the first case was a late hemorrhagic disease of the newborn and the second case hemophilia A. RH is a major feature of SBS, although not pathognomonic. There is no specific RH of SBS but they usually affect the posterior retinal pole. Typically, RHs of SBS are present in both eyes, although unilateral RHs do not exclude the diagnosis of SBS. The relationship between RH and CH has been reported in SBS but also in other diseases. Thus, one must search for hemostasis abnormalities, even though the clinical presentation suggests SBS. Ignoring SBS as well as coming to the conclusion of SBS too quickly should be avoided. Diagnostic difficulties may be related to the number of physicians involved and their interpretation of the facts. These 2 cases underline the need for working as a team that includes hematologists able to interpret coagulation parameters.

[Pregnancy and essential thrombocytemia]. / Thrombocytémie essentielle et grossesse.

OBJECTIVE: To evaluate the management and outcome of pregnancy in women with essential thrombocytemia. PATIENTS AND METHODS: We conducted a retrospective study including all the pregnant women with essential thrombocytemia followed between January 2000 and January 2008 in a University Hospital (hôpital Jeanne-de-Flandre, Lille, France). We report our experience of 18 pregnancies in 13 women. The management and the complications of these pregnancies were reported. RESULTS: All the patients were treated with low dose aspirin during the pregnancy. We observed one intrauterine death, one premature delivery at 29 weeks of gestation and six maternal haemorrhages at delivery (33%). DISCUSSION AND CONCLUSION: It is essential to treat these patients with low dose aspirin as soon as the pregnancy begins. Aspirin will be continued in postpartum with anticoagulant treatment. This management appears to improve the obstetric outcome and decrease the thrombotic complications usually described. A national register seems to be necessary to evaluate the complications occurring during pregnancy and the optimum follow-up.

[Transfusion and postpartum haemorrhage]. / Transfusion et hémorragie du post-partum.

Postpartum haemorrhage is the leading cause of maternal death in France and worldwide. Guidelines help to conduct a timed management and to reduce maternal morbidity and mortality. Rescue and surgical care, transfusion and monitoring have to be previously organized.

Desmopressin is not always effective in mild haemophilia A patients undergoing urological surgery: the need of standardized protocols.

Desmopressin may be an efficient haemostatic treatment for mild A haemophiliacs because its infusion raises plasma factor VIII level. We report the use of desmopressin in five mild haemophilia A patients undergoing urological surgery. They all received a preoperative infusion (0.3 microg kg(-1), i.v.) 1 h before incision followed by repeated injections at 12- or 24-h intervals according to the severity of the procedure. Nevertheless, four patients presented a postoperative bleeding requiring again surgery performed for 3 of them under clotting factor concentrate instead of desmopressin. The occurrence of haemorrhage was not always correlated with particularly low plasma factor VIII level. Surgical management of urological procedures with desmopressin in mild haemophilia A patients requires standardized protocols.

Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia.

In pregnant women with antecedents of autoimmune thrombocytopenia (AITP), no predictive factor for severe fetal thrombocytopenia has been identified. We evaluated the relationships between the course of the maternal disease before and during pregnancy and the risk of severe fetal thrombocytopenia, in 64 pregnant women with known chronic AITP antecedents, over a 12-year period. 28 pregnant women had undergone splenectomy before pregnancy and 17 experienced severe thrombocytopenia (< 50 x 10(9)/l) during pregnancy (monthly determination). Eight infants presented with severe thrombocytopenia at birth (12.5%), and four in the following days (6.25%). No severe haemorrhage was observed. Severe thrombocytopenia at birth was present in 57% (CI 95% 18-90%) of the infants born to mothers with severe pregnancy-associated thrombocytopenia and splenectomy antecedents, and in 0% (CI 95% 0-15%) of the infants born to mothers who presented none of these antecedents (P=0.001). In thrombocytopenic mothers the infant platelet counts at birth were positively correlated to the nadir maternal platelet count during the index pregnancy (r=0.42, P=0.0075). These results suggest that severe autoimmune disease is a risk factor for severe fetal thrombocytopenia, and that pregnant women with no antecedent of splenectomy nor severe thrombocytopenia during pregnancy have a very low risk of severe fetal thrombocytopenia.