Angelo Bianchi Bonomi Hemophilia and Thrombosis Center

Milano, Italy

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center

Milano, Italy

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Gouw S.C.,Wilhelmina Childrens Hospital | Gouw S.C.,University Utrecht | Van Der Bom J.G.,Leiden University | Van Der Bom J.G.,Center for Clinical Transfusion Research | And 13 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS: We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS: Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS: Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience). Copyright © 2013 Massachusetts Medical Society.

Oldenburg J.,University of Bonn | Jimenez-Yuste V.,Hospital Universitario La Paz | Peiro-Jordan R.,Grifols | Aledort L.M.,Mount Sinai Medical Center | Santagostino E.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Haemophilia | Year: 2013

Most studies on immune tolerance induction (ITI) therapy in haemophilia A patients are focused on primary ITI in children. Here we report on the ITI outcome in a large retrospective cohort, including adults and patients with rescue ITI, treated with a pdFVIII/VWF concentrate. Retrospective data from haemophilic patients (FVIII< 2%) with inhibitors from 22 centres in Spain, Italy and Germany, who underwent primary or rescue ITI with pdFVIII/VWF concentrate, were collected. Complete success (CS), partial success (PS) and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. A total of 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults) were evaluated. Success (CS+PS) rate of 87% was achieved in primary ITI and 74% in the higher risk profile of rescue ITI. Eight of nine (85%) patients with poorest prognosis (three or more of the known risk factors of poor response to ITI) achieved success (CS+PS). CS of 100% was observed in eight primary ITI patients with titre at start of ITI ≤2.5 BU and inhibitor peak ≤25 BU. The favourable response rates in primary and rescue ITI in children and in adult patients, even in the presence of poor prognostic factors, should be encouraged for broadening the indication of immune tolerance therapy in haemophilia A patients with inhibitors. © 2013 John Wiley & Sons Ltd.

Becattini C.,University of Perugia | Agnelli G.,University of Perugia | Schenone A.,Galliera Hospital | Eichinger S.,Medical University of Vienna | And 8 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: About 20% of patients with unprovoked venous thromboembolism have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy. Extending anticoagulation prevents recurrences but is associated with increased bleeding. The benefit of aspirin for the prevention of recurrent venous thromboembolism is unknown. METHODS:In this multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked venous thromboembolism who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment. The primary efficacy outcome was recurrence of venous thromboembolism, and major bleeding was the primary safety outcome. RESULTS:Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 taking placebo had a recurrence (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups. CONCLUSIONS: Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. (Funded by the University of Perugia and others; WARFASA number, NCT00222677.) Copyright © 2012 Massachusetts Medical Society.

Mancuso M.E.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center | Mannucci P.M.,University of Milan | Rocino A.,San Giovanni Bosco Hospital | Garagiola I.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center | And 2 more authors.
Journal of Thrombosis and Haemostasis | Year: 2012

Background: Inhibitor development is influenced by several factors and the type of factor VIII (FVIII) products may play a role. Objectives: In order to explore such a role, we designed a cohort study whose novelty resides in the classification of products not only according to the source of FVIII (plasmatic, pd, or recombinant, r) but also to their degree of purity (expressed as specific activity). Patients/Methods: Treatment data up to inhibitor development or 150 exposure days were collected in 377 patients with hemophilia A. Results: Inhibitors developed in 111 patients (29%; 96 high-responders, 25%). The cumulative incidence was progressively higher from patients treated with low/intermediate-purity pdFVIII compared with those treated with high-purity pd and rFVIII. The adjusted hazard ratio of inhibitor development was 4.9 with rFVIII and 2.0 with high-purity pdFVIII (95% CI, 2.9-8.3 and 1.1-4.0), taking as reference low/intermediate-purity pdFVIII. There was no difference in the frequency of inhibitor testing between treatment groups. Sensitivity analyses (in patients who never switched product type, previously untreated patients, those treated on-demand and those with high-risk F8 mutations) confirmed an increased inhibitor risk with rFVIII and high-purity pdFVIII. Conclusions: This study shows that the degree of purity of FVIII products influences inhibitor development independently from other risk factors, and emphasizes that differences exist within pdFVIII products. © 2012 International Society on Thrombosis and Haemostasis.

Mancuso M.E.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center | Berardinelli L.,University of Milan
Haemophilia | Year: 2010

Treatment for children with severe haemophilia is based on prophylaxis and, if inhibitors occur, on immune tolerance induction (ITI). Both regimens require frequent infusions at early ages and therefore an adequate venous access is essential. Peripheral veins represent the best option; however, central venous catheters (CVCs) have been used to facilitate regular treatment. Unfortunately, survival of CVCs is affected by infectious and/or thrombotic complications that often lead to premature removal and consequent treatment discontinuation. This aspect may have an impact on treatment outcome, especially in the case of ITI. In light of this, internal arteriovenous fistula (AVF) has been proposed as an alternative option because of a lower rate of infectious complications. Moreover, AVF is easy to use in the home setting and is well accepted by children and parents. The possible complications are postoperative haematoma and transient symptoms of distal ischaemia; one case of symptomatic thrombosis has been reported to date. Other complications include loss of patency, aneurysmatic dilatation and limb dysmetria. A regular follow-up is mandatory to allow early remedial interventions. Surgical AVF dismantlement is recommended as soon as transition to peripheral vein access is possible. © 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.

Santagostino E.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Haemophilia | Year: 2013

Approximately 20-30% of patients with severe haemophilia A develop alloantibodies ('inhibitors') to infused FVIII rendering use of such replacement therapy ineffective. Once an inhibitor emerges, immune tolerance induction (ITI) is the standard treatment. ITI involves giving regular doses of FVIII concentrate to eradicate the inhibitor and achieve immunogenic acceptance of administered FVIII. In the early 2000s, a retrospective analysis of inhibitor patients treated at a single centre in Germany indicated that success rates were higher when patients were treated with von Willebrand factor (VWF)-containing plasma-derived FVIII (pdFVIII/VWF) concentrate compared with recombinant or non-VWF-containing pdFVIII products. Importantly, pdFVIII/VWF as rescue therapy was able to convert 8 of 10 patients who had failed primary ITI with recombinant or non-VWF-containing pdFVIII product. A subsequent study from Italy in patients with poor prognostic factors for ITI success also reported good success rates with pdFVIII/VWF as rescue therapy (53% success; 41% partial success). The Grifols-Immune Tolerance Induction (G-ITI) Study represents the largest group of haemophilia A inhibitor patients treated with a single pdFVIII/VWF concentrate (Alphanate®/Fanhdi®) to be reported to date. Data have been collected for 95 patients who underwent primary or rescue ITI at 46 centres in Europe and the US. Currently, published data are available for 33 patients in the US cohort (11 centres), and data from the European cohort are being analysed. Both groups contained patients with poor prognostic factors and most patients received a high-dose regimen (≥100 IU pdFVIII/VWF kg-1 daily). As expected, the success rate was better for primary vs. rescue ITI and for patients with good vs. poor prognostic factors. However, more than half the patients in the US cohort receiving rescue ITI achieved success (33% complete success; 20% partial success). These results should encourage clinicians to consider the use of pdFVIII/VWF concentrates for rescue ITI. Published outcomes data from the total global G-ITI cohort (95 patients) are awaited with anticipation. © 2012 Blackwell Publishing Ltd.

De Stefano V.,Catholic University | Martinelli I.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Best Practice and Research: Clinical Haematology | Year: 2012

Thromboses of abdominal veins outside the iliac-caval axis are rare but clinically relevant. Early deaths after splanchnic vein thrombosis occur in 5-30% of cases. Sequelae can be liver failure or bowel infarction after splanchnic vein thrombosis, renal insufficiency after renal vein thrombosis, ovarian infarction after ovarian vein thrombosis. Local cancer or infections are rare in Budd-Chiari syndrome, and common for other sites. Inherited thrombophilia is detected in 30-50% of patients. Myeloproliferative neoplasms are the main cause of splanchnic vein thrombosis: 20-50% of patients have an overt myeloproliferative neoplasm and/or carry the molecular marker JAK2 V617F. Renal vein thrombosis is closely related to nephrotic syndrome; finally, ovarian vein thrombosis can complicate puerperium. Heparin is used for acute treatment, sometimes in conjunction with systemic or local thrombolysis. Vitamin K-antagonists are recommended for 3-6 months, and long-term in patients with Budd-Chiari syndrome, unprovoked splanchnic vein thrombosis, or renal vein thrombosis with a permanent prothrombotic state such as nephrotic syndrome. © 2012 Published by Elsevier Ltd.

Martinelli I.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center | De Stefano V.,Catholic University
Best Practice and Research: Clinical Haematology | Year: 2012

Venous thrombosis typically involves the lower extremities. Rarely, it can occur in cerebral, splanchnic, or renal veins, with a frightening clinical impact. Other rare manifestations are upper-extremity deep vein thrombosis, that can complicate with pulmonary embolism and post-thrombotic syndrome, and retinal vein occlusion, significantly affecting the quality of life. This review is focused on venous thromboses at unusual extra-abdominal sites. Local infections or cancer are frequent in cerebral sinus-venous thrombosis. Upper-extremity deep vein thrombosis is mostly due to catheters or effort-related factors. Common risk factors are inherited thrombophilia and oral contraceptive use. Acute treatment is based on heparin; in cerebral sinus-venous thrombosis, local or systemic fibrinolysis should be considered in case of clinical deterioration. Vitamin-K antagonists are recommended for 3-6 months; indefinite anticoagulation is suggested for recurrent thrombosis or unprovoked thrombosis and permanent risk factors. However, such recommendations mainly derive from observational studies; there are no data about long-term treatment of retinal vein occlusion. © 2012 Published by Elsevier Ltd.

Mancuso M.E.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center | Mannucci P.M.,Scientific Direction
Drug Design, Development and Therapy | Year: 2014

Prophylaxis with regular infusions of factor VIII (FVIII)- or factor IX (FIX)- containing products is the mainstay of modern hemophilia care. However, this therapeutic regimen is inconvenient, requiring repeated intravenous injections from childhood. Approaches meant to prolong the half-life of FVIII and FIX in plasma have been developed in order to improve the feasibility and acceptability of replacement therapy, extending protection from bleeding, reducing infusion frequency and hence the need for venous access devices in young children. Several strategies have been implemented to enhance the pharmacokinetics of clotting factors, including conjugation with polyethylene glycol and the production by genetic engineering of fusion proteins containing the coagulation factors linked to a long-lived plasma protein such as albumin or the Fc fragment of immunoglobulin (Ig)G. The latter technology is one of the most promising, since the prolongation of FVIII and FIX half-life is obtained by exploiting the physiological binding of the Fc domain to the neonatal Fc receptor. Fc fusion monomers have been obtained with both recombinant FVIII (rFVIIIFc) and FIX (rFIXFc), and data from preclinical and clinical studies showed improved pharmacokinetics for both factors, which are produced in human embryonic kidney (HEK) 293 cells, thus ensuring full human post-translational modifications. In Phase I/IIa studies, rFVIIIFc and rFIXFc showed 1.5-1.7 fold and 3.0-4.0 fold longer elimination half-life, respectively. Similar data have been obtained in the Phase III clinical studies with rFVIIIFc and rFIX-Fc published recently. Both drugs were satisfactorily safe, particularly with respect to immunogenicity, and no serious adverse event was observed. © 2014 Mancuso and Mannucci. This work is published by Dove Medical Press Limited.

Martinelli I.,Angelo Bianchi Bonomi Hemophilia and Thrombosis Center | De Stefano V.,Catholic University | Mannucci P.M.,Scientific Direction
Nature Reviews Cardiology | Year: 2014

Venous thromboembolism (VTE) has important heritable components. In the past 20 years, knowledge in this field has greatly increased with the identification of a number of gene variants causing hypercoagulability. The two main mechanisms are loss-of-function of anticoagulant proteins and gain-of-function of procoagulants, the latter owing to increased synthesis or impaired downregulation of a normal protein or, more rarely, to synthesis of a functionally hyperactive molecule. Diagnosis of thrombophilia is useful to determine the causes of VTE, recognizing that this multifactorial disease can also be influenced by various acquired factors including cancer, surgery, trauma, prolonged immobilization, or reproduction-associated risk factors. Diagnosis of inherited thrombophilia rarely affects the acute or long-term management of VTE. However, the risk of recurrent VTE is increased in anticoagulant-deficient patients and in homozygotes for gain-of-function mutations. Screening for inherited thrombophilia in thrombosis-free individuals is indicated only for relatives of a proband who is anticoagulant-deficient or has a family history of VTE. In families with thrombophilia and VTE, primary antithrombotic prophylaxis during risk situations lowers the rate of incident VTE. In this Review, we discuss the main causes of inherited thrombophilia, the associated clinical manifestations, and the implications for antithrombotic prophylaxis in the affected individuals. © 2014 Macmillan Publishers Limited. All rights reserved.

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