Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 x 10 9 /L. ABSTRACT antepartum intracranial hemorrhage. On this basis, it has been concluded that bBSS is associated with a very high risk of serious bleeding in the mother and the neonate. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopeniaSome information on pregnancy outcome is available also for MYH9-related disease (MYH9-RD), one of the most frequent forms of IT. A recent review of the literature examined 25 case reports and one case series describing a total of 75 pregnancies in 40 women.5 Postpartum hemorrhage in the mother occurred in 4 cases, while no obvious bleeding complications were reported among the newborns. Based on these data, MYH9-RD does not seem to increase bleeding risk either in mothers or neonates.Limited data on pregnancy outcomes have been provided for patients with mild to moderate thrombocytopenia due to monoallelic BSS (mBSS), in all cases induced by the p.Ala156Val substitution in GPIb alpha (Bolzano mutation). 6 Overall, 20 women delivered 34 children with no excessive maternal or neonatal bleeding. Although the authors did not provide information on management of pregnancies and childbirths, this study suggests that women with mBSS have gestational outcomes similar to healthy subjects.A moderate risk of bleeding during delivery has been reported in a series of subjects with thrombocytopenia induced by ANKRD26 mutations (ANKRD26-related thrombocytopenia, ANKRD26-RT).7 Thirteen patients gave birth, either vaginally or by caesarean section, with bleeding complications in 3 women. No information was provided o...

Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel FLI1 variants (c.1010G>A and c.1033A>G) responsible for macrothrombocytopenia. The FLI1 variant carriers’ platelets exhibited a defect in aggregation induced by low-dose adenosine diphosphate (ADP), collagen and thrombin receptor-activating peptide (TRAP), a defect in adenosine triphosphate (ATP) secretion, a reduced mepacrine uptake and release and a reduced CD63 expression upon TRAP stimulation. Precise ultrastructural analysis of platelet content was performed using transmission electron microscopy and focused ion beam scanning electron microscopy. Remarkably, dense granules were nearly absent in the carriers’ platelets, presumably due to a biogenesis defect. Additionally, 25–29% of the platelets displayed giant α-granules, while a smaller proportion displayed vacuoles (7–9%) and autophagosome-like structures (0–3%). In vitro study of megakaryocytes derived from circulating CD34+ cells of the carriers revealed a maturation defect and reduced proplatelet formation potential. The study of the FLI1 variants revealed a significant reduction in protein nuclear accumulation and transcriptional activity properties. Intraplatelet flow cytometry efficiently detected the biomarker MYH10 in FLI1 variant carriers. Overall, this study provides new insights into the phenotype, pathophysiology and diagnosis of FLI1 variant-associated thrombocytopenia.

ABSTRACTwith the PCR primers using the dye terminator sequencing kit from Applera Courtaboeuf, France. Informed consent was obtained from all patients. This work was approved by the local ethics committees (approvals DC 2008-214 and DC 2008-880).

Hereditary factor XI (FXI) deficiency is an autosomal bleeding disorder of variable severity but without a clear relationship between bleeding and FXI levels or mutation location or both. In the present study, the molecular basis of FXI deficiency in 16 patients from 12 families originating from the Marseilles area in the south of France was studied. FXI defect was evidenced by routine laboratory tests showing prolonged activated partial thromboplastin times and decreased factor XI activities. The promotor region, exons 1-15, and the exon-intron boundaries of the FXI gene were sequenced. Four novel mutations were found; three were missense mutations (Cys212Ser, Gly350Arg and Thr381Leu resulting from heterozygote mutation in exon 7, 10 and 11, respectively), and one was a one base deletion in exon 4 that induces a frameshift creating a stop codon four residues later (Thr57Ile fsX4). Eight previously reported mutations were also found. Contrarily to the Jewish, Basques or Briton populations, no recurrent mutation was identified. This cohort also illustrates that bleeding events occur not exclusively and not systematically in severe FXI deficiency but also in patients characterized by a mild FXI deficiency.

A congenital FXIII A subunit deficiency was diagnosed in a male child because of umbilical bleeding at birth. Venous infusion was difficult and prophylactic FXIII infusion was delayed. At age 1, he suffered a spontaneous intracranial haemorrhage. Substitutive FXIII was initiated, and at age 12, no other significant bleeding event had occurred. His 5 years younger brother also bears the same FXIII deficiency. The younger brother's treatment was initiated at birth and never discontinued, and no bleeding occurred. Mutation gene analysis found a homozygous four bases insertion predicting a stop codon seven residues after PRO675. Antigen assay indicated that the mutant molecule is secreted. This case highlights the importance of prophylactic FXIII infusion.