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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., (© 2024 The Authors.)

Background: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a congenital disorder of glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and those responsible for life-threatening bleeding events have never been investigated., Objectives: To assess platelet functions in patients with XMEN disease., Methods: Two unrelated young boys, including one before and after hematopoietic stem cell transplantation, were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans., Results: Platelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin α IIb β 3 activation, calcium mobilization, and protein kinase C activity were impaired between both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide were absent at both low and high concentrations. These defects were also associated with decreased molecular weights of glycoprotein Ibα, glycoprotein VI, and integrin α IIb due to partial impairment of N-glycosylation. All these defects were corrected after hematopoietic stem cell transplantation., Conclusion: Our results highlight prominent platelet dysfunction related to MAGT1 deficiency and defective N-glycosylation in several platelet proteins that could explain the hemorrhages reported in patients with XMEN disease., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Heparin-induced thrombocytopenia (HIT) is a rare, difficult-to-diagnose, and potentially serious adverse drug reaction with thrombotic complications. Even though the immune system is still immature during the neonatal period, HIT has been described in newborns with reporting rates ranging from 0% to 2.3%. Therefore, it is important to clarify the risk of HIT in newborns because it can affect the management and monitoring of heparin treatment., Objectives: The objectives of the present study were to review the literature and determine the incidence of HIT after cardiac surgery in newborns in our pediatric hospital., Methods: We searched the literature from 1992 to 2021 for reports of HIT in newborns. Four raters then analyzed all the literature reports on HIT and classified them as "likely," "uncertain," or "unlikely." We also determined the incidence of HIT among newborns having undergone cardiac surgery in our pediatric hospital., Results: Eleven population-based studies and 12 case reports on suspected HIT in 17 newborns were reviewed. One study reported HIT in 14 out of 930 (1.5%) heparin-treated newborns, but the other studies ( n  = 467 newborns) did not mention HIT at all. None of the cases described in the literature was classified as "likely" by the raters. In our center, none of the 2997 newborns that had undergone cardiac surgery in the previous 16 years was diagnosed with HIT., Conclusion: We conclude that the incidence of HIT in newborns has been overestimated in the literature., (© 2023 The Authors.)

Background: Light transmission aggregation (LTA) is used widely by the clinical and research communities. Although it is a gold standard, there is a lack of interlaboratory harmonization., Objectives: The primary objective was to assess whether sources of activators (mainly adenosine diphosphate [ADP], collagen, arachidonic acid, epinephrine, and thrombin receptor activating peptide6) and ristocetin contribute to poor LTA reproducibility. The secondary objective was to evaluate interindividual variability of results to appreciate the distribution of normal values and consequently better interpret pathologic results., Methods: An international multicenter study involving 28 laboratories in which we compared LTA results obtained with center-specific activators and a comparator that we supplied., Results: We report variability in the potency (P) of activators in comparison with the comparator. Thrombin receptor activating peptide 6 (P, 1.32-2.68), arachidonic acid (P, 0.87-1.43), and epinephrine (P, 0.97-1.34) showed the greatest variability. ADP (P, 1.04-1.20) and ristocetin (P, 0.98-1.07) were the most consistent. The data highlighted clear interindividual variability, notably for ADP and epinephrine. Four profiles of responses were observed with ADP from high-responders, intermediate-responders, and low-responders. A fifth profile corresponding to nonresponders (5% of the individuals) was observed with epinephrine., Conclusion: Based on these data, the establishment and adoption of simple standardization principles should mitigate variability due to activator sources. The observation of huge interindividual variability for certain concentrations of activators should lead to a cautious interpretation before reporting a result as abnormal. Confidence can be taken from the fact that difference between sources is not exacerbated in patients treated with antiplatelet agents., Competing Interests: Declaration of competing interests M.L. has received speaker fees from Bayer, participated in industry-funded trials from Idorsia, served on advisory boards for Servier and JAMP/Orimed Pharma, and received in-kind support for investigator-initiated grants from Fujimori Kogyo. M.C.A. has received fees from Novo Nordisk, participated in industry-funded trials from Agrobio, participated in PIA-funded project in collaboration with Stago and Agrobio, and served on advisory boards for Novo Nordisk. U.J.S. has received research grants from Octapharma; consulting fees from Bayer, SOBI, CSL Behring, and Pfizer; and travel support from Bayer, SOBI, CSL Behring, Biotest, Takeda, and Leo Pharma. D.F. has received honorarium and travel support from Viatris. S.V. has received travel support from Stago. F.M. has received speaker fees from Fresenius, Technoclone, and Werfen. P.F. has received travel support from SOBI and Novo Nordisk. A.G. reports personal fees from Aspen, Bayer Vital, Chromatec, Instrumentation Laboratory, Portola, Sanofi-Aventis, Roche, and GTH e.V.; grants from Ergomed, Boehringer Ingelheim, Rovi, Sagent, Biokit, Fa. Blau Farmaceutics, Prosensa/Biomarin, DRK-BSD Baden-Würtemberg/Hessen, Deutsche Forschungsgemeinschaft, Robert-Koch-Institut, Dilaflor, and GIZ Else-Körner-Stiftung; grants and personal fees from Macopharma; grants and other fee from DRK-BSD NSTOB; and nonfinancial support from Veralox, Vakzine Projekt Management GmbH, AstraZeneca, and Janssen Vaccines & Prevention B.V. outside the submitted work. In addition, A.G. has a patent—screening methods for transfusion-related acute lung injury (TRALI)—with royalties paid to EP2321644, 18.05.2011. M.C. has received research grant from Agios Pharmaceuticals, Genentech Inc, and Novartis Inc; consulting fees from Novo Nordisk; and honoraria for board participation with Novo Nordisk, Takeda Inc, Genentech Inc, BPL Inc, CSL Behring Inc, and Genzyme Corp Agios Pharmaceuticals. C.P. has received research grant from Stago. I.D. has received travel support from Sobi, Takeda, and Novonordisk and speaker fees from Novonordisk. A.B. has received fees from Aguettant, Alexion, and Viatris. J.R. has received support from Instituto de Salud Carlos (PI20/00926 [ISCIII&Feder], PMP21/00052 [ISCIII&NG EU], and CB15/00055) and Sociedad Española de Trombosis y Hemostasia (Ayuda a Grupo Español de Alteraciones Plaquetarias Congénitas). P.G. has received speaker’s fees from Sanofi and Roche, and honoraria for board participation with Viatris. M.R.C., M.C., C.L.-B., M.I.K., L.G., B.H., A.S., C.C., A.N.S., M.B., M.F., K.D., W.H., M.F.H., A.N.M., J.P.F., P.S., F.P., A.C., N.B., J.R., and D.L. have no conflict of interest to declare., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pretest probability assessment and dedicated laboratory assays., Objective: To develop a pretest score for HIT., Design: Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839)., Setting: Thirty-one tertiary hospitals in France, Switzerland, and Belgium., Patients: Patients tested for HIT antibodies (2280 evaluable), randomly allocated to derivation and validation cohorts., Measurements: Independent adjudicators diagnosed HIT based on the prospectively collected data and serotonin release assay results., Results: Heparin-induced thrombocytopenia was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); ≥40% decrease in platelet count over ≤6 days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 (95% CI, 0.76-0.82). In the validation cohort, the area under the receiver operating characteristic curve was 0.77 (95% CI, 0.74-0.80). Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group., Limitation: The performance of the score may depend on settings and practices., Conclusion: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pretest score, which may guide clinical decisions regarding diagnostic testing and anticoagulation., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Correct diagnosis of the cause of thrombocytopenia is crucial for the appropriate management of patients. Hyposialylation/desialylation (characterized by abnormally high β-galactose exposure) accelerates platelet clearance and can lead to thrombocytopenia. However, the reference range for β-galactose exposure in healthy individuals has not been defined previously., Objective: The objective of the present study was to develop a standardized assay of platelet β-galactose exposure for implementation in a clinical laboratory., Methods: β-Galactose exposure was measured in platelet-rich plasma by using flow cytometry and Ricinus communis agglutinin (RCA). A population of 120 healthy adults was recruited to study variability., Results: We determined an optimal RCA concentration of 12.5 μg/mL. The measure was stable for up to 4 hours (mean fluorescence intensity [MFI]-RCA: 1233 ± 329 at 0 hour and 1480 ± 410 at 4 hours). The platelet count did not induce a variation of RCA and the measure of RCA was stable when tested up to 24 hours after blood collection (MFI-RCA: 1252 ± 434 at day 0 and 1140 ± 297 24 hours after blood sampling). To take into account the platelet size, results should be expressed as RCA/forward scatter ratio. We used the assay to study variability in 120 healthy adults, and we found that the ratio is independent of sex and blood group., Conclusion: We defined a normal range in a healthy population and several preanalytical and analytical variables were evaluated, together with positive and negative controls. This assay may assist in the diagnosis of thrombocytopenic diseases linked to changes in β-galactose exposure., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors., Objective: To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay., Method: We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin., Results: A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke-like episodes or thrombosis displayed this hypercoagulant phenotype., Conclusion: A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events., (© 2019 French National Institute of Health and Medical Research. © 2019 International Society on Thrombosis and Haemostasis.)

Background: Extracorporeal circuit coating has been shown to improve coagulation derangements during pediatric cardiopulmonary bypass (CPB). This study compared platelet function and hemostasis activation in pediatric cardiac surgery conducted with nonheparin coating (Balance; Medtronic, Minneapolis, MN) versus heparin-based coating (Carmeda; Medtronic) circuits., Methods: A prospective, randomized, double-center trial was conducted in children older than 1 month undergoing congenital heart disease treatment. Blood samples were collected at baseline (T0), 15 minutes after the start of CPB (T1), and 15 minutes (T2) and 1 hour after the conclusion of CPB (T3). The primary end point of the study was to detect potential differences in β-thromboglobulin levels between the two groups at T2. Other coagulation and platelet function indicators were analyzed as secondary end points., Results: The concentration of β-thromboglobulin increased significantly at T2 in both groups. However, there was no significant difference between the groups across all time points. There was no difference in the secondary end points between the groups., Conclusions: The two circuits showed similar biological effects on platelet function and coagulation. This observation may be useful in optimizing the conduct of CPB and in rationalizing its cost for the treatment of congenital heart disease., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: The complex hemostatic changes associated with Berlin Heart (BH) implantation in children require a challenging antithrombotic treatment. The aim of this retrospective analysis was to evaluate the thromboelastography (TEG)-platelet mapping (PM) assay to monitor antiplatelet therapy in children implanted with a BH., Methods: TEG-PM was performed in 4 BH-implanted patients receiving dipyridamole and aspirin, and 9 healthy volunteers. Patients' antiplatelet therapy was adjusted to TEG-PM results. Light transmission aggregometry (LTA) was also available for 2 of these patients., Results: Between 2009 and 2014, 4 BH-implanted patients received a dual antiplatelet therapy monitored by TEG-PM. In 2 patients, 18 of 34 tracings were atypical, because the maximum amplitude due to fibrin never stabilized, which made difficult antiplatelet therapy adjustment as recommended by BH's guidelines. To overcome this difficulty, TEG-PM and LTA were next performed in parallel. However, both methods led to different decisions to adjust antiplatelet therapy in 57% of the cases. In order to better understand this atypical tracing, TEG-PM was also performed in 9 volunteers and surprisingly 3 of them had the same atypical tracing. This atypical tracing was corrected by adding apyrase, suggesting that adenosine diphosphate (ADP) participates to spontaneous platelet activation in heparinized samples. In addition, we evidenced a high variability in the responses of TEG-PM with ADP in volunteers., Conclusions: Antiplatelet therapy monitoring in BH-implanted children remains challenging, as TEG-PM is sensitive to several preanalytical and analytical conditions.

Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

The glycoprotein VI (GPVI)/FcRgamma complex is a key receptor for platelet activation by collagen. We describe, for the first time, 2 genetic abnormalities in one patient. This 10-year-old girl presented ecchymoses since infancy, a prolonged bleeding time despite a normal platelet count and no antiplatelet antibodies. Collagen-induced platelet activation was null, whereas GPVI quantification by flow cytometry evidenced an incomplete deficiency. Immunoblotting showed an abnormal migration of residual GPVI, and no FcRgamma defect. GPVI DNA sequencing revealed (1) an R38C mutation in exon 3 of one allele and (2) an insertion of 5 nucleotides in exon 4 of the other allele, leading to a premature nonsense codon and absence of the corresponding mRNA. Introduction of the R38C mutation into recombinant GPVI-Fc resulted in abnormal protein migration and a loss of collagen binding. Thus, this composite genetic GPVI deficiency and dysfunction cause absence of platelet responses to collagen and a mild bleeding phenotype.

We hypothesized that Fcgamma receptor IIIa (FcgammaRIIIa), a polymorphic receptor for the Fc portion of immunoglobulin G (IgG) other than FcgammaRIIa, was involved in heparin-induced thrombocytopenia (HIT). FcgammaRIIa-131 and FcgammaRIIIa-158 genotypes were determined in 102 patients with definite HIT and in 2 control groups of patients treated by heparin (86 subjects without detectable antibodies [Abs] to heparin-platelet factor 4 [H/PF4], Ab(-) group; 84 patients with Abs to H/PF4 without HIT, Ab(+) group). There were no significant differences in genotype distribution or allele frequencies between the 3 groups for FcgammaRIIa-131H/R polymorphism. In contrast, FcgammaRIIIa-158V homozygotes were more frequent in the HIT group than in the Ab(+) group (P = .02), a difference that was more pronounced in patients with high levels of anti-H/PF4 Abs (P = .01). Since anti-H/PF4 Abs are mainly IgG1 and IgG3, clearance of sensitized platelets may be increased in patients homozygous for the FcgammaRIIIa-158V allotype, thus contributing to the development of thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) occurs in nearly 3% of patients treated with heparin after cardiopulmonary bypass (CPB). HIT carries a risk of severe thrombotic complications, and must be diagnosed rapidly. To identify simple criteria for estimating the probability of HIT after CPB, we retrospectively analyzed the files of 84 patients with suspected HIT after CPB and we analyzed the usefulness of several variables collected at the time of HIT suspicion to estimate HIT probability. HIT was confirmed in 35 cases and ruled out in 49 cases, on the basis of a platelet increment after heparin withdrawal, detection of heparin-dependent antibodies, and absence of other clear cause of thrombocytopenia. A biphasic platelet count from CPB to the first day of suspected HIT, an interval of >/= 5 days from CPB to the first day of suspected HIT, and a CPB duration of

Cardiac surgery with extracorporeal circulation induces major alterations of haemostasis and requires high level of anticoagulation, usually achieved by unfractionated heparin infusion. Optimization of anticoagulant regimen, through adapted biological monitoring, can probably improve postoperative course, at least for postoperative haemostatic status. Despite increasing knowledge on extracorporeal circulation-induced haemostatic abnormalities and the development of new biological devices for heparin monitoring, the optimal level of anticoagulation remains matter of debate, as well as the monitoring procedures. This critical review presents the current available data on heparin anticoagulation and monitoring in this specific context, and underlines the pending issues about anticoagulation management during extracorporeal bypass.