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This study was carried out to explore hemostasis modifications occurring in pregnant women and thromboelastography profiles in those taking antithrombotic drugs. An exploratory study was carried out in the period from March 2017 to May 2018. Caucasian women from Southern Italy were recruited during a routine obstetric assessment. Participants were divided into four groups: T1 (gestational week <14 weeks), T2 (14-28 weeks), T3 (29-42 weeks) and T4 in the postpartum period. We investigated thromboelastography profile in 19 and 5 women administered with low-molecular-weight heparin or low-dose aspirin, respectively. "MA" value observed in the T1 group was significantly greater than that observed in the T3 and the T4 groups, while "K" in the T1 group was significantly longer than that in the T3 and the T4 groups, indicating a gradual development of a prothrombotic state (in all cases Mann-Whitney U test, p<0.05). Significant differences within "R" were observed between the T2 and the T3 and between the T3 and the T4 ("R" parameter) (Mann-Whitney U test, p<0.05). "LY30" parameter resulted to be significantly higher in the T1 group (Mann-Whitney U test, p=0.01) compared with the T4 one, indicating fibrinolysis decreases throughout pregnancy and until post partum. No significant variations were found in women administered with prophylactic doses of low-molecular-weight heparin. Significantly higher fibrinolysis (p<0.01) was observed for "LY30" parameter in women taking low-dose aspirin versus women not taking any treatments. Our data contribute to better interpret thromboelastography profile in the context of peripartum complications, which are often unpredictable and need prompt therapies. [ABSTRACT FROM AUTHOR]

Immune-mediated thrombotic thrombocytopenic purpura is a rare and challenging hematological disease caused by the antibody anti-ADAMTS13. Though the mortality rate has decreased considerably in recent years, fatalities still remain unacceptable. This study aimed at further adding to the existing knowledge of this medical challenge. We enrolled 89 consecutive patients observed in six Italian centers (from 8 August 2013 to 28 May 2021) with a diagnosis of immune-mediated thrombotic thrombocytopenic purpura. Clinical information and blood parameters were collected for all patients. We describe clinical manifestations and laboratory data, possible risk factors and the therapeutic management of first episodes or relapses. A total of 74 first episodes and 19 relapses (median 3 years (interquartile range (IQR): 2–7)) were recorded. Seventy percent of patients enrolled at the first episode showed neurological signs and/or symptoms. All the patients enrolled at the first episode were treated with plasma exchange (median = 12; IQR: 8–19.5) and methylprednisolone (1 mg/kg/day). Rituximab (375 mg/m2 weekly for four weeks) and caplacizumab were given to 15 (20.2%) and 2 patients (2.6%), respectively. We observed an overall mortality of 5.4% in the follow-up (median 60 months; IQR: 36.0–103.5). All fatalities occurred after a diagnostic delay. Present data point to the importance of the early detection of factors mostly associated with poor outcomes. It is likely that use of caplacizumab could improve the prognosis in those patients. [ABSTRACT FROM AUTHOR]

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This study was carried out to explore hemostasis modifications occurring in pregnant women and thromboelastography profiles in those taking antithrombotic drugs. An exploratory study was carried out in the period from March 2017 to May 2018. Caucasian women from Southern Italy were recruited during a routine obstetric assessment. Participants were divided into four groups: T1 (gestational week <14 weeks), T2 (14-28 weeks), T3 (29-42 weeks) and T4 in the postpartum period. We investigated thromboelastography profile in 19 and 5 women administered with low-molecular-weight heparin or low-dose aspirin, respectively. "MA" value observed in the T1 group was significantly greater than that observed in the T3 and the T4 groups, while "K" in the T1 group was significantly longer than that in the T3 and the T4 groups, indicating a gradual development of a prothrombotic state (in all cases Mann-Whitney U test, p<0.05). Significant differences within "R" were observed between the T2 and the T3 and between the T3 and the T4 ("R" parameter) (Mann-Whitney U test, p<0.05). "LY30" parameter resulted to be significantly higher in the T1 group (Mann-Whitney U test, p=0.01) compared with the T4 one, indicating fibrinolysis decreases throughout pregnancy and until post partum. No significant variations were found in women administered with prophylactic doses of low-molecular-weight heparin. Significantly higher fibrinolysis (p<0.01) was observed for "LY30" parameter in women taking low-dose aspirin versus women not taking any treatments. Our data contribute to better interpret thromboelastography profile in the context of peripartum complications, which are often unpredictable and need prompt therapies., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Congenital fibrinogen disorders are caused by variants occurring within the fibrinogen gene cluster. We describe ten subjects with disease-causative variants, adding information on such disorders., Materials and Methods: Ten subjects were referred to our Centre because of likely hypo/dysfibrinogenaemia. We evaluated the function and quantity of fibrinogen, using Clauss and immunoreactive assays, and performed genetic investigations by direct sequencing of alpha, beta and gamma chain-encoding genes. Mutations were analysed using SIFT and Polyphen-2 algorithms., Results: We identified one afibrinogenaemic patient (alpha p.Arg178* homozygote) with bleeding/thrombotic events, three heterozygous patients with hypo/dysfibrinogenaemia (gamma p.Thr47ILeu combined with beta IVS7+1G>T; beta p.Cys95Ser; beta p.Arg196Cys) referred for bleeding or thrombotic episodes and six heterozygous subjects with hypofibrinogenaemia (alpha p.Glu41Lys; gamma p.Gly191Val; beta p.Gly288Ser; gamma p.His333Arg; gamma p.Asp342Glu and p.343-344 duplication; gamma p.Asp356Val), of whom four were symptomatic. Five novel missense changes and one novel duplication variant were found, all in hypofibrinogenaemic subjects: p.Glu41Lys (SIFT score 0, Polyphen-2 score 0.986) was identified in a woman with bleeding after major orthopaedic surgery; p.Gly191Val (SIFT score 0.02, Polyphen-2 score 1) in an asymptomatic woman; p.His333Arg (SIFT score 0, Polyphen-2 score 1) in a woman with a post-partum haemorrhage; and p.Asp342Glu (SIFT score 0.23, Polyphen-2 score 0.931); and an Asn-343 and Asp-344 duplication in a child who developed a haematoma following a fall., Discussion: All but one of the novel mutations were in symptomatic subjects and are predicted to be deleterious. Our findings shed more light on genotype-phenotype relationships in congenital fibrinogen disorders.

Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype-phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency., Competing Interests: The authors declare no conflict of interest.

This study aimed at attempting to correlate genotype and phenotype in factor VII deficiency. Here, we present molecular and clinical findings of 10 patients with factor VII deficiency. From 2013 to 2016, 10 subjects were referred to our center because of a prolonged prothrombin time identified during routine or presurgery examinations or after a laboratory assessment of a bleeding episode. Mutation characterization was performed using the bioinformatics applications PROMO, SIFT, and Polyphen-2. Structural changes in the factor VII protein were analyzed using the SPDB viewer tool. Of the 10 variants we identified, 1 was responsible for a novel missense change (c.1199G>C, p.Cys400Ser); in 2 cases we identified the c.-54G>A and c.509G>A (p.Arg170His) polymorphic variants in the 5'-upstream region of the factor VII gene and exon 6, respectively. To our knowledge, neither of these polymorphic variants has been described previously in factor VII-deficient patients. In silico predictions showed differences in binding sites for transcription factors caused by the c.-54G>A variant and a probable damaging effect of the p.Cys400Ser missense change on factor VII active conformation, leading to breaking of the Cys400-Cys428 disulfide bridge. Our findings further suggest that, independently of factor VII levels and of variants potentially affecting factor VII levels, environmental factors, e.g., trauma, could heavily influence the clinical phenotype of factor VII-deficient patients., Competing Interests: The authors declare no conflict of interest.