Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders

Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification of molecular causes and of clinical and biochemical phenotypes very challenging. However, the acknowledgement of the type of molecular defect is crucial for a safer therapy, which is going to improve the clinical management of these patients. In this review, some aspects concerning molecular and clinical findings available on congenital fibrinogen disorders will be discussed

Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders

Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification of molecular causes and of clinical and biochemical phenotypes very challenging. However, the acknowledgement of the type of molecular defect is crucial for a safer therapy, which is going to improve the clinical management of these patients. In this review, some aspects concerning molecular and clinical findings available on congenital fibrinogen disorders will be discussed

A novel congenital dysprothrombinemia leading to defective prothrombin maturation

Prothrombin deficiency is a very rare disorder caused by mutations in the F2 gene that generate hypoprothrombinemia or dysprothrombinemia and is characterized by bleeding manifestations that can vary from clinically irrelevant to life-threatening

Pregnancy-related venous thrombosis: Comparison between spontaneous and ART conception in an Italian cohort

10nononeObjective: To evaluate in an Italian cohort the incidence of venous thromboembolic events (VTE) in pregnancies after assisted reproductive technologies (ART). Setting: Thrombosis and Haemostasis Unit at I.R.C.C.S. 'Casa Sollievo della Sofferenza', S. Giovanni Rotondo. Participants: A prospective cohort of 998 women advised to undergo ART was referred by local fertility clinics from April 2002 to July 2011. Follow-up information was obtained during the check-up and/or by phone interviews. In a cohort of women who consecutively gave birth (n=3339) after spontaneous conception in our Institution, information on the diagnoses of pregnancy-related venous thromboses was obtained by linkage to a patient administrative register. Primary and secondary outcome measures: We calculated the incidence of VTE and superficial venous thrombosis in successful ART cycles and compared it with that of the general population conceiving spontaneously. Results: Overall, 684 ART cycles were carried out by 234 women, who achieved a clinical pregnancy; in case of more than one successful cycle, only the first pregnancy was considered. Three vein thromboses (two VTE and one superficial vein thrombosis) were recorded. An antithrombotic prophylaxis with LMWH alone or combined with low-dose aspirin was prescribed in 23/234 (9.8%) women. In the reference cohort of 3339 women, a total of 11 vein thromboses were observed: six VTE and five SVT. The two-tailed Fisher exact test showed a trend towards statistical significance (p: 0.06, OR: 3.9, 95% CI 0.87 to 15.3). After the exclusion of superficial thromboses in both the groups, we found that the incidence of VTE in our population of women who had undergone ART was 2/234 pregnancies (8.5 %), whereas that in our reference population was 6/3339 (1.8 %) (p: 0.09). Conclusions: Our data show a slightly higher incidence of vein thromboses in pregnancies after ART than in those after natural conception.noneVillani, Michela; Dentali, Francesco; Colaizzo, Donatella; Tiscia, Giovanni Luca; Vergura, Patrizia; Petruccelli, Tiziana; Petruzzelli, Francesco; Ageno, Walter; Margaglione, Maurizio; Grandone, ElviraVillani, Michela; Dentali, Francesco; Colaizzo, Donatella; Tiscia, Giovanni Luca; Vergura, Patrizia; Petruccelli, Tiziana; Petruzzelli, Francesco; Ageno, Walter; Margaglione, Maurizio; Grandone, Elvir

Pharmacogenetics of dabigatran etexilate interindividual variability

Introduction Dabigatran etexilate is given in fixed doses without coagulation monitoring for the prevention of blood clots in at risk adults. A high inter-individual variability in blood concentrations of the active metabolite of dabigatran has been reported. ABCB1 and CES1 exert an important effect in the metabolism of dabigatran etexilate and allele variants at these two loci are likely to play a pivotal role. To investigate whether screening for polymorphisms within the ABCB1 and the CES1 genes would explain a portion of the inter-individual variability in blood concentrations of the active metabolite of dabigatran. Material and methods In a cohort of patients who had atrial fibrillation and on anticoagulant prophylaxis with dabigatran etexilate, we investigated whether genotypes at rs4148738 (ABCB1), rs8192935 (CES1), and rs2244613 (CES1) loci would affect plasma dabigatran trough and peak concentrations. Results and discussion Among 92 patients (median age: 72.0 years, range: 52-92) analyzed, no clinical variable or genotype was associated with a significant difference in dabigatran peak concentrations. As for trough concentrations, in addition to creatinine clearance, and sex a significant association with the CES1 SNP rs8192935 (p = 0.023) was detected. The mean adjusted plasma levels were higher among patients with the CC genotype (86.3 ng/dl) than in those carrying the T allele (62.1 ng/dl). No significant effect was found for the ABCB1 SNP rs4148738. The CES1 SNP rs8192935 significantly influenced the dabigatran trough concentrations and carriers of the T allele showed significantly lower concentrations than did carriers of the CC genotype