Dabigatran in ibrutinib-treated patients with atrial fibrillation and chronic lymphocytic leukemia: experience of three cases.

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an essential enzyme for survival and proliferation of B cells by activating the B-cell receptor-signalling pathway. Ibrutinib has been shown to be highly effective in B-cell malignancies and is recommended in current international guidelines as a first-line and/or second-line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension). If atrial fibrillation is diagnosed, anticoagulant therapy may be required. Such patients receiving concomitant anticoagulation should be followed closely. DOAC is preferred over a VKA because of the lower risk of major bleeding events and because of the favorable stroke risk--benefit profile. Of all, Dabigatran offers the availability of an antidote and shows reduced potential for CYP3A4 interactions. We report the cases relating to three patients in concomitant therapy with Ibrutinib and Dabigatran.

Prevalence of IVS10nt-18G/A in Calabrian patients with moderate/mild hemophilia A and relation with Factor VIII inhibitor antibodies.

Hemophilia A is an X-linked bleeding disorder caused by widespread mutations in the factor VIII gene. In the course of a screening to research some hemophilia A mutations, our team has identified and posted a previously unreported nucleotide change in intron 10 in 20 patients with hemophilia A. We tried to identify a possible blood relationship between the people with this mutation, performing a backwards study of every family tree. First, we interviewed the patients and, if possible, parents and grandparents. When direct memory was no longer available, we consulted Registries of Births, Marriages and Deaths, and if these data were not sufficient, going backwards in time, we consulted registries of parish churches where newborns were baptized. The studied mutation was present in 33 hemophilic patients living in Calabria, 28 of them related. Three patients, carriers of this mutation, developed an FVIII inhibitor. In all the cases, the inhibitor development followed intensive treatments, after many days of exposure. Our study displayed the presence of a responsible moderate hemophilia A mutation, limited apparently to our country, probably because of a single ancestral event, and connected with FVIII inhibitor development.

Factor XI deficiency: a description of 34 cases and literature review.

Factor XI (FXI) deficiency is a rare bleeding disorder, resulting in a wide range of bleeding manifestations, from asymptomatic bleeding to injury-related bleeding. First in this review, we give an overview of the basic pathophysiology, clinical manifestations, and management of FXI deficiency. Finally, we describe 34 members of 16 FXI-deficient kindreds from south Italy, diagnosed and followed at the Haemophilia, Haemostasis and Thrombosis Centre of Pugliese-Ciaccio Hospital, Catanzaro, during the past 20 years. In our patients, bleeding tendency did not appear to be correlated with FXI levels. Furthermore, we describe 24 pregnancies in 11 patients with FXI deficiency. In all the pregnancies, no bleeding manifestations were reported.

Efficacy and safety of the long-term administration of low-molecular-weight heparins in pregnancy.

Pregnancy is associated with an increased risk of venous thromboembolism, which probably varies according to the presence of single or multiple thrombophilic defects. Acquired or inherited thrombophilia is moreover associated with adverse outcomes in pregnancy. For this reason, in the past, pregnant women at risk of venous thromboembolism or pregnancyes have been treated with oral anticoagulants or unfractionated heparin. Both of them are associated with fetal or maternal side effects. Low-molecular-weight heparins (LMWHs) offer several advantages, but they have no or only partial indication for use in pregnancy in many countries. We have prospectively evaluated 114 patients and overall 130 pregnancies treated with prophylactic or therapeutic LMWHs from January 2004 to February 2007. The occurrence of allergic reactions, hemorrhagic episodes, low platelet count, pathological fractures, thromboembolic events and adverse outcomes in pregnancy were considered. There was a significant difference in pregnancy outcome following prophylaxis with LMWHs (chi2 P < 0.0001) and the absolute and the relative risks were significantly decreased in the patients with treated pregnancy compared with those with previous untreated pregnancies. Moreover, in our series of patients, the long-term use of LMWH in pregnancy was confirmed well tolerated, with the rate of adverse effects, though very low, comparable with that in literature. Our experience confirms the safety and the efficacy of LMWH but suggests the need of randomized controlled trials.

Screening of mutations of hemophilia A in 40 Italian patients: a novel G-to-A mutation in intron 10 of the F8 gene as a putative cause of mild hemophilia A in southern Italy.

Hemophilia A is an X-linked bleeding disorder caused by widespread mutations in the human coagulation factor 8 gene. We have searched for mutations in factor 8 gene DNAs from 40 unrelated Italian patients with hemophilia A. All patients came from the same region (Calabria) and were followed-up at the same hemophilia center. Of the 40 patients, 20 (50%) had severe hemophilia A, 19 (47.5%) had moderate hemophilia A, and one (2.5%) had mild hemophilia A. All patients were first screened for the common intron 22 and intron 1 inversions. Inversion-negative samples were screened for point mutations by direct sequencing of all coding regions and intron-exon boundaries of the factor 8 gene. Mutations previously reported as causative of hemophilia A were identified in 14 of the 40 patients. These included five (12.5%) intron 22 inversions, one (2.5%) small deletion, one (2.5%) small insertion and seven (17.5%) point mutations. In all patients with moderate and mild hemophilia A, a nucleotide change in the c.1538 -18G>A in intron 10, not reported in the HAMSTeRS factor 8 mutation database (http://europium.csc.mrc.ac.uk/), was found. The G-to-A change predicts the appearance of a new acceptor splice site. We have also demonstrated that all patients share a common haplotype, suggesting that the mutation probably occurred in a single ancestor. In conclusion, we suggest that the c.1538-18G>A transition can be the putative mutation, which probably occurred in a common ancestor and then spread in neighbours, in patients with moderate-mild hemophilia A investigated in the present study.

Genetic prothrombotic risk factors in women with unexplained pregnancy loss.

INTRODUCTION: Inherited thrombophilia has been associated with unexplained recurrent pregnancy loss (RPL) and stillbirth. This thrombotic tendency can manifest as thrombotic lesions in the placenta, and may lead to abortion and stillbirth. The aim of our case-control study was to investigate the prevalence of FVL and FII G20210A in women with adverse pregnancy outcome, compared to the prevalence of the same mutations in our health control group. MATERIALS AND METHODS: 102 consecutive women with unexplained pregnancy loss (55 with history of RPL, and 47 with history of stillbirth) were studied for hereditary thrombophilia. The health control group consisted of 217 healthy women from the general population. RESULTS AND CONCLUSIONS: Of the 55 women with recurrent abortions, we found the same prevalence for the FVL and the FII G20210A(9.1%, 5 pts). (p=NS compared to control group). Of the 47 women with stillbirth, 11 (23.4%) had the FVL and 9 (19.1%) had the FII G20210A(p<0.0005 for both mutations). In our experience the prevalence of FVL and the FII G20210Amutations was significantly higher in women with unexplained stillbirth, instead the prevalence of genetic thrombophilia was high but not statistically significant in women with recurrent pregnancy loss.

Thrombosis in hemophiliacs with prothrombotic molecular defect.

Thrombosis in hemophiliacs is a very unusual event mostly reported in patients treated with concentrates containing large quantities of activated coagulation factors. A patient with hemophilia A is reported who had an acute myocardial infarction and in whom investigation for hereditary thrombophilia showed a prothrombotic molecular defect, the G20210A prothrombin mutation.