Hemophilia Center

Reggio Calabria, Italy

Hemophilia Center

Reggio Calabria, Italy
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Von Rappard S.,University of Bern | Hinnen C.,Intensive Care | Lussmann R.,Institute for Anesthesiology and Intensive Care | Rechsteiner M.,Center for Laboratory Medicine and Hemostasis | And 3 more authors.
Transfusion Medicine and Hemotherapy | Year: 2017

Objective: Fibrinogen and factor XIII (FXIII) have been shown to critically influence clot firmness in the intraoperative setting and thus likely influence intraoperative bleeding. We were interested to identify potential modulators of postoperative clot firmness in a tertiary care hospital surgical intensive care unit setting, independent of their clinical course during surgery. Methods: 272 day-shift consecutive patients were evaluated for whole blood clot firmness evaluated by the ROTEM® EXTEM thrombelastometric assay and various potential modulators of clot firmness upon arrival at the surgical intensive care unit (SICU). Results: Maximum clot firmness on the SICU was found to be independently influenced by the amount of colloids given during surgery as well as by platelet count, fibrinogen concentration, and FXIII activity at the time of SICU admission. In patients with lowest clot firmness, FXIII activity was the most important independent modulator of clot firmness; in patients with the highest clot firmness, platelet count and fibrinogen concentration were the most important modulators of clot firmness. Deficiencies (i.e., results below normal range) of these modulators of clot firmness were most prevalent for FXIII (activity < 70%: 45% of cases), which was significantly more frequent than thrombocytopenia (<150 × 109/l: 32%) or fibrinogen deficiency (<1.5 g/l: 6%). Conclusions: Postoperative clot firmness as evaluated by whole blood thrombelastometry (ROTEM EXTEM assay) is independently and frequently modulated though FXIII activity and the platelet count, while fibrinogen concentration is also an independent but much less frequent modulator. Different modulators show different influences, depending on the clot firmness being present. Colloids infused during surgery also independently modulate postoperative clot firmness. Based on our data, strategies can be developed to improving postoperative care of patients with bleedings or at risk for bleeding. © 2017 S. Karger GmbH, Freiburg. Copyright: All rights reserved.


Siboni S.M.,University of Milan | Zanon E.,Centro Emofilia Clinica Medica II | Sottilotta G.,Hemophilia Center | Consonni D.,University of Milan | And 7 more authors.
Haemophilia | Year: 2012

Central nervous system (CNS) bleeding is one of the most severe and debilitating manifestations occurring in patients with rare bleeding disorders (RBDs). The aim of this study was to retrospectively collect data on patients affected with RBDs who had CNS bleeding, to establish incidence of recurrence, death rate, neurological sequences, most frequent location, type of bleeding and efficacy of treatments. Results pertained to 36 CNS bleeding episodes in 24 patients with severe deficiency except one with moderate factor VII (FVII) deficiency. Six patients (25%) experienced a recurrence and two had more than one recurrence. Seven patients (29%) had an early onset of CNS bleeding before the first 2years of life, others (71%) later in life. In 76% of cases, CNS bleeding was spontaneous. CNS bleeding was intracerebral in 19 cases (53%), extracerebral in 10 (28%) and both intracerebral and extracerebral in two cases (6%). Neurosurgery was performed in 11 cases, in association with replacement therapy in seven cases. Seizures were noted in four patients. Residual psychomotor abnormalities were seen in two patients. No death was recorded. To prevent recurrence, 17/24 patients (71%) were put on secondary prophylaxis. In conclusion, recurrence of CNS bleeding was confirmed to be relatively frequent in patients with severe FV, FX, FVII and FXIII deficiencies. Most patients were managed with replacement therapy alone, surgery being reserved for those with worsening neurological conditions. Our results indicate that some RBDs require early prophylactic treatment to prevent CNS bleeding. Optimal dosage and frequency of treatment need further evaluation. © 2011 Blackwell Publishing Ltd.


PubMed | AO San Gerardo, Thrombosis Center, University of Insubria, Carlo Poma Hospital and 7 more.
Type: | Journal: Gastroenterology research and practice | Year: 2015

It is generally recommended that patients with splanchnic vein thrombosis (SVT) should receive a minimum of 3 months of anticoagulant treatment. However, little information is available on the long-term risk of recurrent thrombotic events. The aim of this study was to evaluate the risk of venous and arterial thrombosis after discontinuation of vitamin K antagonist (VKA) in SVT patients. Retrospective information from a cohort of SVT patients treated with VKA and followed by 37 Italian Anticoagulation Clinics, up to June 2013, was collected. Only patients who discontinued VKA and did not receive any other anticoagulant drug were enrolled in this study. Thrombotic events during follow-up were centrally adjudicated. Ninety patients were included: 33 unprovoked SVT, 27 SVT secondary to transient risk factors, and 30 with permanent risk factors. During a median follow-up of 1.6 years, 6 venous and 1 arterial thrombosis were documented, for an incidence of 3.3/100 patient-years (pt-y). The recurrence rate was highest in the first year after VKA discontinuation (8.2/100pt-y) and in patients with permanent risk factors (10.2/100pt-y). Liver cirrhosis significantly increased the risk of recurrence. In conclusion, the rate of recurrent vascular complications after SVT is not negligible, at least in some patient subgroups.


Carcao M.,University of Toronto | Zak M.,Novo Nordisk AS | Abdul Karim F.,Hemophilia Center | Hanabusa H.,Ogikubo Hospital | And 5 more authors.
Journal of Thrombosis and Haemostasis | Year: 2016

Essentials Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life. This phase 3 trial investigated its safety/efficacy in previously treated hemophilia B boys ≤ 12 years. A 40 IU kg−1 dose provided effective once-weekly prophylaxis and hemostasis when used to treat bleeds. Nonacog beta pegol was well tolerated in previously treated boys ≤ 12 years with hemophilia B. Summary: Background Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life, developed to improve care for patients with hemophilia B. Objectives To investigate the safety, efficacy and pharmacokinetics of nonacog beta pegol for the prophylaxis and treatment of bleeds in previously treated children with hemophilia B. Patients/Methods This phase 3 trial, paradigm™5, enrolled and treated 25 children (aged ≤ 12 years) with hemophilia B (FIX ≤ 2%). Patients were stratified by age (0–6 years and 7–12 years), and received once-weekly prophylaxis with 40 IU kg−1 nonacog beta pegol for 50 exposure days. Results No patient developed inhibitors, and no safety concerns were identified. Forty-two bleeds in 15 patients were reported to have been treated; the overall success rate was 92.9%, and most bleeds (85.7%) resolved after one dose. The median annualized bleeding rates (ABRs; bleeds per patient per year) were 1.0 in the total population, 0.0 in the 0–6-year group, and 2.0 in the 7–12-year group; the estimated mean ABRs were 1.44 in the total population, 0.87 in the 0–6-year group, and 1.88 in the 7–12-year group. For 22 patients who had previously been receiving prophylaxis, the estimated mean ABR was 1.38 versus a historical ABR of 2.51. Estimated mean steady-state FIX trough levels were 0.153 IU mL−1 (0–6 years) and 0.190 IU mL−1 (7–12 years). Conclusion Nonacog beta pegol was well tolerated in previously treated children with hemophilia B; a 40 IU kg−1 dose provided effective once-weekly prophylaxis and hemostasis when bleeds were treated. © 2016 International Society on Thrombosis and Haemostasis


Castaman G.,San Bortolo Hospital | Giacomelli S.H.,San Bortolo Hospital | Caccia S.,University of Milan | Riccardi F.,University of Parma | And 5 more authors.
Haemophilia | Year: 2013

Factor XI (FXI) deficiency is a rare inherited bleeding disorder invariably caused by mutations in the FXI gene. The disorder is rather frequent in Ashkenazi Jews, in whom around 98% of the abnormal alleles is represented by Glu117X and Phe283Leu mutations. A wide heterogeneity of causative mutations has been previously reported in a few FXI deficient patients from Italy. In this article, we enlarge the knowledge on the genetic background of FXI deficiency in Italy. Over 4 years, 22 index cases, eight with severe deficiency and 14 with partial deficiency, have been evaluated. A total of 21 different mutations in 30 disease-associated alleles were identified, 10 of which were novel. Among them, a novel Asp556Gly dysfunctional mutation was also identified. Glu117X was also detected, as previously reported from other patients in Italy, while again Phe283Leu was not identified. A total of 34 heterozygous relatives were also identified. Bleeding tendency was present in very few cases, being inconsistently related to the severity of FXI deficiency in plasma. In conclusion, at variance with other populations, no single major founder effect is present in Italian patients with FXI deficiency. © 2013 John Wiley & Sons Ltd.


PubMed | Hampshire Hospitals NHS Foundation Trust, Childrens Hospital and Clinics of Minnesota, Novo Nordisk AS, Ogikubo Hospital and 4 more.
Type: Journal Article | Journal: Journal of thrombosis and haemostasis : JTH | Year: 2016

Essentials Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life. This phase 3 trial investigated its safety/efficacy in previously treated hemophilia B boys 12 years. A 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when used to treat bleeds. Nonacog beta pegol was well tolerated in previously treated boys 12 years with hemophilia B.Background Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life, developed to improve care for patients with hemophilia B. Objectives To investigate the safety, efficacy and pharmacokinetics of nonacog beta pegol for the prophylaxis and treatment of bleeds in previously treated children with hemophilia B. Patients/Methods This phase 3 trial, paradigm() 5, enrolled and treated 25 children (aged 12 years) with hemophilia B (FIX 2%). Patients were stratified by age (0-6 years and 7-12 years), and received once-weekly prophylaxis with 40 IU kg(-1) nonacog beta pegol for 50 exposure days. Results No patient developed inhibitors, and no safety concerns were identified. Forty-two bleeds in 15 patients were reported to have been treated; the overall success rate was 92.9%, and most bleeds (85.7%) resolved after one dose. The median annualized bleeding rates (ABRs; bleeds per patient per year) were 1.0 in the total population, 0.0 in the 0-6-year group, and 2.0 in the 7-12-year group; the estimated mean ABRs were 1.44 in the total population, 0.87 in the 0-6-year group, and 1.88 in the 7-12-year group. For 22 patients who had previously been receiving prophylaxis, the estimated mean ABR was 1.38 versus a historical ABR of 2.51. Estimated mean steady-state FIX trough levels were 0.153 IU mL(-1) (0-6 years) and 0.190 IU mL(-1) (7-12 years). Conclusion Nonacog beta pegol was well tolerated in previously treated children with hemophilia B; a 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when bleeds were treated.


News Article | December 7, 2016
Site: www.eurekalert.org

PITTSBURGH, Dec. 7, 2016 - Researchers from the University of Pittsburgh School of Medicine and UPMC have engineered a protein that reverses carbon monoxide (CO) poisoning in mice, a discovery that could potentially lead to the creation of the first antidote in humans to the often deadly poisoning, according to research published today in the journal Science Translational Medicine. CO poisoning is responsible for more than 50,000 emergency room visits in the United States annually, and is one of the leading global causes of poisoning death. A colorless, odorless gas, CO is extremely effective at replacing oxygen molecules in hemoglobin, the oxygen carrying protein in blood. CO exposure also results in debilitating effects on the body and the brain, including cognitive deficits that in some cases can persist months or years after a poisoning event. "Despite being the most common poisoning worldwide, we still do not have an effective antidote for CO exposure," said Mark T. Gladwin, M.D., chair of medicine, Pitt School of Medicine, Dr. Jack D. Myers Professor of Internal Medicine, and director of the Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute. "Our protein is extraordinarily effective at scavenging CO from the blood, and could potentially prove to be a significant advance in the treatment of CO poisoning." Current treatment options for CO poisoning--administering 100 percent oxygen or using a pressurized hyperbaric chamber to administer oxygen at greater than normal air pressure--focus on trying to replace CO in blood with oxygen as quickly as possible. However, both these treatments are only moderately effective. Moreover, transporting patients to a hyperbaric chamber requires a significant amount of time, and many poisoned patients may not be stable enough for this therapy. When studying neuroglobin (Ngb), a hemoglobin-like protein present in the brain, Gladwin and his team discovered it could bind CO with an unusually high affinity. Based on prior knowledge of how the protein works, researchers engineered a mutant version of the protein, called Ngb H64Q, that was an even better scavenger of CO. In a purified sample of red blood cells infused with CO, they found that Ngb H64Q was 1,200 times faster at forcing CO to release itself from being bound to hemoglobin than just air alone. When tested in a mouse model of non-lethal CO poisoning, they found that Ngb H64Q was significantly better at removing CO from hemoglobin than 100-percent oxygen treatment. The normal half-life of CO in humans after poisoning (time it takes for half of the CO to be eliminated from the body) is 320 minutes, and even with 100-percent oxygen therapy, that time is 74 minutes. With the antidote therapy, the CO half-life was reduced to only 23 seconds. In a mouse model with lethal levels of CO poisoning, seven out of eight mice treated with Ngb H64Q (87.5 percent) survived the duration of the experiment, while 10 percent or less survived in the control groups. Additionally, the antidote restored blood pressure and improved the amount of oxygen that was present in tissues, suggesting that Ngb H64Q works by scavenging CO from hemoglobin and allowing oxygen to bind in its place, thus restoring normal oxygen delivery. Importantly, CO bound to Ngb H64Q was detected in the urine of mice shortly after treatment, which indicated that the rodents were able to excrete the antidote from the body without any major toxic effects. "If approved, this antidote could be rapidly administered to victims in the field, eliminating costly delays that occur with current treatment options," Gladwin said. "We still need extensive safety and efficacy testing before an antidote is available on the shelf, but our early results are very promising." Researchers plan to scale up their safety and efficacy testing in animal models and hope to advance to clinical trials within the next few years. Ivan Azarov, Ph.D., Ling Wang, M.D., Ph.D., and Jason J. Rose, M.D., all from Pitt, were the study's lead authors. Additional contributors included Qinzi Xu, M.D., Xueyin N. Huang, Ph.D., Ying Wang, Ph.D., Lanping Guo, Ph.D., Charles F. McTiernan, Ph.D., Christopher P. O'Donnell, Ph.D., Sruti Shiva, Ph.D., and Jesús Tejero, M.D., Ph.D., all of Pitt; and Chen Liu, Ph.D., Kamil B. Ucer, Ph.D., Andrea Belanger, Ph.D., and Daniel B. Kim-Shapiro, Ph.D., of Wake Forest University. The study was supported in part by the National Heart, Lung, and Blood Institute SMARTT (Science Moving towArd Research Translation and Therapy) Program, the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania; and National Institutes of Health grants F32 HL132418, R01 HL111706, R01 GM113816, R21 ES027390, R01 HL058091, R01 HL098032, R01 HL125886, P01 HL103455, T32 HL110849 and T32 HL007563. For access to a video interview with Gladwin, please contact Lawerence Synett at SynettL@upmc.edu or 412-302-4127. As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support. Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www. . A world-renowned health care provider and insurer, Pittsburgh-based UPMC is inventing new models of patient-centered, cost-effective, accountable care. It provides nearly $900 million a year in benefits to its communities, including more care to the region's most vulnerable citizens than any other health care institution. The largest nongovernmental employer in Pennsylvania, UPMC integrates 60,000 employees, more than 20 hospitals, more than 500 doctors' offices and outpatient sites, and a more than 3 million-member Insurance Services Division, the largest medical and behavioral health services insurer in western Pennsylvania. Affiliated with the University of Pittsburgh Schools of the Health Sciences, UPMC ranks No. 12 in the prestigious U.S. News & World Report annual Honor Roll of America's Best Hospitals. UPMC Enterprises functions as the innovation and commercialization arm of UPMC while UPMC International provides hands-on health care and management services with partners in 12 countries on four continents. For more information, go to UPMC.com.


Coppola A.,University of Naples Federico II | Santoro C.,University of Rome La Sapienza | Franchini M.,Carlo Poma Hospital | Mannucci C.,Bayer Italia | And 5 more authors.
Seminars in Thrombosis and Hemostasis | Year: 2013

Life expectancy for persons with hemophilia (PWH) has considerably increased in the last decades as a direct result of the availability of modern therapies to control the clotting defect. Because their life expectancy now matches that of the general population, PWH are experiencing age-related comorbidities, such as, cardiovascular diseases, metabolic syndrome, renal diseases, sexuality issues, malignancies, and neurologic problems, that until recently have been rarely seen in this group of patients. In this article, we present a summary of the current knowledge on the aging PWH along with the clinical approaches that may be integrated into the routine comprehensive care of these patients for preventing, diagnosing, and monitoring age-related comorbidities. In general, patients with and without hemophilia should receive similar care, with close collaboration between the physician treating PWH and the specialty expert treating the comorbid disease. © 2013 by Thieme Medical Publishers, Inc.


Collins P.,University of Cardiff | Baudo F.,Centro Emofilia | Knoebl P.,Medical University of Vienna | Levesque H.,University of Rouen | And 5 more authors.
Blood | Year: 2012

Acquired hemophilia A (AHA) is an auto-immune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. © 2012 by The American Society of Hematology.


Sottilotta G.,Hemophilia Center | Siboni S.M.,University of Milan | Latella C.,Hemophilia Center | Oriana V.,Hemophilia Center | And 4 more authors.
Clinical and Applied Thrombosis/Hemostasis | Year: 2010

Introduction: Elevated homocysteine (Hcy) is associated with the risk of deep vein thrombosis, pulmonary embolism, ischemic heart disease, and stroke. Several studies have suggested that hyperhomocysteinemia (HHcy) may predispose to retinal vein thrombosis (RVT) development. The aim of this study is to investigate the relationship between Hcy, C677T methylenetetrahydrofolate reductase (MTHFR) genotype, and RVT in patients compared with controls. Materials and Methods: We evaluated the Hcy plasma level of 3114 consecutive participants in 2 Italian centers during a 2-year period. Hyperhomocysteinemia was found in 99 patients and 136 healthy participants. Of the 99 patients, 20 had RVT with a high prevalence of HHcy in the RVT subgroup (20.2%). This result suggested a possible relationship between HHcy and RVT development. We investigated 105 consecutive patients with recent diagnosis of RVT, and we compared them with 226 healthy controls to evaluate whether HHcy may be a risk factor for RVT. Results: the prevalence of HHcy was higher in patients compared with controls (34.3% vs 14.2%; P <.001). The MTHFR C677T genotype was found in 69 of 105 (65.7%) patients with RVT (heterozygosity: 40 of 105 and homozygosity: 29 of 105). The control group showed the presence of MTHFR C677T genotype in 169 of 226 participants (74.8%; heterozygosity: 100 of 226 and homozygosity: 69 of 226) without difference between the 2 groups (P =.08). Conclusion: our study suggests that HHcy is a possible risk factor for RVT development, while no association was found between RVT and the C677T MTHFR genotype.

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