Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study

Pharmacokinetic (PK) studies on recombinant FIX concentrate, Nonacog alpha, were conducted with different sampling time designs which gave rise to not complete and homogenous outcomes. In addition, patient's FIX genotype/PK relationship has never been investigated

Effect of splenectomy on type-1/type-2 cytokine gene expression in a patient with adult idiopathic thrombocytopenic purpura (ITP)

BACKGROUND: In view of clinical observations and laboratory results that support a central role of the spleen in idiopathic thrombocytopenic purpura (ITP) pathophysiology, we studied the effect of splenectomy on type-1 and type-2 cytokine gene expression in an adult ITP case, refractory to conservative treatment. CASE PRESENTATION: The patient was subjected to splenectomy 9 months after the diagnosis with complete response, attaining platelet counts over 150 × 10(6)/L within 10 days after the operation. Two consecutive blood samples were obtained from the patient, 3 and 7 months after the splenectomy for the purposes of this study. A control group consisted of 11 healthy adults. Peripheral blood mononuclear cells were prepared from each blood sample and cultured in vitro for 8 h with the addition of the mitogens phorbol myristate acetate and ionomycin. Total cellular RNA extracted from 10(6 )cells was submitted to semiquantitave reverse transcriptase-polymerase chain reaction (RT-PCR) for the amplification of IL-2, IFN-γ, IL-4, IL-5, and IL-10 metagraphs. The PCR products were run on ethidium-stained agarose gels, photographed and quantified by densitometry. A steep decrease of type-1 cytokine expression (IL-2, IFN-γ) and their calculated sum expressing Th1 activity was observed at 7 months post-splenectomy compared to 3 months post-splenectomy, in parallel with a rise of platelet count from 190 × 10(6)/L to 265 × 10(6)/L. The change of type-2 cytokine expression (IL-4, IL-5, IL-10) was slight and the Th2 activity (IL-4+IL-5) remained largely unchanged. The Th1/Th2 ratio, that reflects the pathogenic disease-specific T-cell immune deviation, was accordingly reduced 7 months post-splenectomy (Th1/Th2 = 1.3) compared to 3 months (Th1/Th2 = 3.5). CONCLUSIONS: The reduction of the Th1/Th2 cytokine ratio that was observed over time after splenectomy was accompanied by full clinical remission. Nevertheless, the persistence of a type-1 polarization, even after several months following spleen removal, is suggestive of a more basic abnormality of the immune function in these patients

Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey

A multicenter retrospective analysis was performed to estimate the frequency of thrombosis and hemorrhage after surgical procedures in patients with polycythemia vera (PV) and patients with essential thrombocythemia (ET). Data from 105 patients with PV and 150 patients with ET were analyzed, for a total of 311 surgical interventions. An emergency procedure was performed in 25 (8.1%) patients; 194 surgeries were done under general anesthesia, and 21 (23%) of 91 abdominal interventions were done under laparoscopy; 155 (50.1%) were major surgeries. Subcutaneous heparin was administered in 169 (54.3%) of 311 cases and antiplatelet therapy in 48 (15.4%) of 311 case interventions. One hundred eighty-eight (74%) of 255 patients were on cytoreductive therapy before surgery. No events were observed in 259 (83.2%) of 311 procedures during 3 months of follow-up; there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages, and 5 deaths. Arterial thromboses were more frequent in ET (5.3% vs 1.5%; P = .08), venous events were more frequent in PV (7.7% vs 1.1%; P = .002). There was not a correlation between bleeding episodes and the type of diagnosis, use of antithrombotic prophylaxis, or type of surgery. A high proportion of PV and ET surgeries was complicated by vascular occlusion (7.7%) or by a major hemorrhage (7.3%). Prospective investigations analyzing the optimal prophylaxis in these patients are suggested

Management of inherited von Willebrand disease in Italy : results from the retrospective study on 1234 patients

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD

Modeling the Subsurface Structure of Sunspots

While sunspots are easily observed at the solar surface, determining their subsurface structure is not trivial. There are two main hypotheses for the subsurface structure of sunspots: the monolithic model and the cluster model. Local helioseismology is the only means by which we can investigate subphotospheric structure. However, as current linear inversion techniques do not yet allow helioseismology to probe the internal structure with sufficient confidence to distinguish between the monolith and cluster models, the development of physically realistic sunspot models are a priority for helioseismologists. This is because they are not only important indicators of the variety of physical effects that may influence helioseismic inferences in active regions, but they also enable detailed assessments of the validity of helioseismic interpretations through numerical forward modeling. In this paper, we provide a critical review of the existing sunspot models and an overview of numerical methods employed to model wave propagation through model sunspots. We then carry out an helioseismic analysis of the sunspot in Active Region 9787 and address the serious inconsistencies uncovered by \citeauthor{gizonetal2009}~(\citeyear{gizonetal2009,gizonetal2009a}). We find that this sunspot is most probably associated with a shallow, positive wave-speed perturbation (unlike the traditional two-layer model) and that travel-time measurements are consistent with a horizontal outflow in the surrounding moat.Comment: 73 pages, 19 figures, accepted by Solar Physic

Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease : Results from 3WINTERS-IPS, an international and collaborative cross-sectional study

Background Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. Aims To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. Methods We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. Results In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels <20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. Conclusions In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.Peer reviewe

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: a case-control study

Background Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). Objectives This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. Patients/Methods Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. Results Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. Conclusions Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.Clinical epidemiolog