Extending recombinant factor IX Fc fusion protein dosing interval to 14 or more days in patients with hemophilia B.

Background: In the phase 3 B-LONG study (NCT01027364), prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) every 7 to >14 days was associated with low annualized bleed rates (ABRs) in males aged ≥12 years with severe hemophilia B. The long-term safety and efficacy of rFIXFc prophylaxis was confirmed in the B-YOND study (NCT01425723), an extension of the B-LONG clinical trial. Objective: The aim of this post-hoc analysis was to evaluate the efficacy of a ≥14-day rFIXFc dosing interval in patients treated prophylactically during B-LONG or B-YOND. Methods: The analysis included 22 patients aged ≥12 years who received prophylactic rFIXFc with a ≥14-day dosing interval at any time during B-LONG or B-YOND up until the second interim analysis of B-YOND (September 2015). Results: The median (interquartile range [IQR]) rFIXFc exposure on the ≥14-day dosing interval was 3.4 (1.8-4) years. Patients treated with a ≥14-day dosing interval were well controlled with a median (IQR) overall ABR of 1.6 (0.6-2.7) and a median (IQR) spontaneous ABR of 0.7 (0.3-1.1) in 18 evaluable patients. A rFIXFc dosing interval of ≥14 days was well tolerated, with no new safety concerns identified. Conclusion: Most patients on rFIXFc prophylaxis, with a dosing interval of ≥14 days, remained well controlled; ABRs were consistent with those reported in the overall study population. A ≥14-day dosing interval can be utilized in some well controlled individuals and reduces the burden imposed by frequent prophylactic injections while maintaining adequate bleed suppression

von Willebrand disease: proposing definitions for future research

Thrombosis and Hemostasi

High-Throughput Proteomics Detection of Novel Splice Isoforms in Human Platelets

Alternative splicing (AS) is an intrinsic regulatory mechanism of all metazoans. Recent findings suggest that 100% of multiexonic human genes give rise to splice isoforms. AS can be specific to tissue type, environment or developmentally regulated. Splice variants have also been implicated in various diseases including cancer. Detection of these variants will enhance our understanding of the complexity of the human genome and provide disease-specific and prognostic biomarkers. We adopted a proteomics approach to identify exon skip events - the most common form of AS. We constructed a database harboring the peptide sequences derived from all hypothetical exon skip junctions in the human genome. Searching tandem mass spectrometry (MS/MS) data against the database allows the detection of exon skip events, directly at the protein level. Here we describe the application of this approach to human platelets, including the mRNA-based verification of novel splice isoforms of ITGA2, NPEPPS and FH. This methodology is applicable to all new or existing MS/MS datasets

Surgery in patients with hemophilia: Is thromboprophylaxis mandatory?

Patients with hemophilia are considered low risk for thromboembolic complications. However, in the presence of risk factors for thrombosis, such as surgical procedures, and intensive replacement therapy this complication has been reported. Major orthopedic surgeries are often required in patients with hemophilia, due to the presence of hemophiliac arthropathy. In individuals that do not have hemophilia, orthopedic surgeries are particularly well recognized as high risk for venous thromboembolism, and the use of thromboprophylaxis for this condition is recommended. However, for hemophilia patients the use of venous thrombosis prophylaxis during major surgeries, including orthopedic procedures remains controversial. For the majority of the patients the use of gradated compression stockings and early mobilization can be sufficient to prevent venous thromboembolism. The use of anticoagulant prophylaxis should be considered just for patients with relevant additional risk factor for thrombosis. However, for hemophilia patients with inhibitor, pharmacologic thromboprophylaxis is not recommended. For patients with von Willebrand disease receiving factor concentrates replacement therapy undergoing surgical procedures, the FVIII plasma levels should be monitored and thromboprophylaxis should be considered if any other thrombosis risk factor is present. It is important for the future to establish risk assessment tools that can help to determine the most effective and safe practice to prevent venous thrombosis in patients with hemophilia and other bleeding disorderswho undergo surgical procedures. (C) 2012 Elsevier Ltd. All rights reserved.1301S23S26BayerCSL Behrin

Use of recombinant factor VIIa in the management of severe bleeding episodes in patients with Bernard-Soulier syndrome

Bernard - Soulier syndrome (BSS) is a rare congenital platelet disorder characterized by defective platelet adhesion and manifested by spontaneous and often profuse bleeding. Recombinant factor VIIa ( rFVIIa) is a haemostatic agent licensed for the treatment of bleeding episodes in patients with haemophilia and inhibitors, which may represent a low-risk alternative to existing therapies in the management of patients with BSS. Here, we describe the use of rFVIIa for the treatment of three severe bleeding episodes in two patients with BSS. Data were extracted by automated searching of the international, Internet-based registry http://www. haemostasis. com. Patient 1, a 24-year-old woman, was admitted with severe epistaxis and hypotension. The diagnosis of BSS was confirmed by macrothrombocytopenia, absence of ristocetin-induced platelet agglutination ( RIPA) and absence of glycoprotein ( GP) Ib alpha and IX on the platelet surface. Epsilon aminocaproic acid (EACA; two 50-mg/kg doses), packed red blood cells (PRBCs, 2 U) and platelets (30 U) failed to control the bleeding and, after 13 h, three bolus doses of rFVIIa (90 mu g/kg body weight) and a third dose of EACA were administered; bleeding stopped after the third dose of rFV IIa. Patient 2, a 15-year-old girl, initially presented with severe menorrhagia. A lack of RIPA and severe deficiency of GPIb alpha on the platelet surface confirmed the diagnosis of BSS. EACA and fresh-frozen plasma did not control the haemorrhage, but two bolus doses of rFVIIa ( 98 mu g/kg body weight) resulted in a marked decrease in bleeding. On second admission, patient 2 had severe epistaxis and mild menorrhagia. Two rFVIIa doses ( 98 and 122.5 mu g/kg body weight) were given, and the bleeding stopped. No adverse events were reported in these cases. These three admissions highlight the potential of rFVIIa for the treatment of severe bleeds in patients with BSS.841281682

Meeting the challenges of haemophilia care and patient support in China and Brazil

. Projects are underway in many developing countries to try to improve the provision of treatment and access to care for people with haemophilia (PWH), as long-term prophylactic treatment, which improves quality of life for PWH, is still restricted to developed countries. In most developing countries, therapy is limited to on-demand treatment or even no replacement treatment at all. Combined with limited healthcare resources, this lack of treatment can lead to a vicious circle of lack of care, disability, unemployment and lack of access to health insurance for haemophilia patients. In China, the establishment of the Haemophilia Treatment Centre Collaborative Network of China (HTCCNC), in conjunction with the World Federation of Hemophilia, has improved haemophilia care and the identification of PWH. In Brazil, on-demand treatment has improved the health of PWH but does not prevent musculoskeletal (MSK) complications, the major cause of deterioration in quality of life for PWH. The Novo Nordisk Haemophilia Foundation BR2 project was therefore designed to improve quality of life of PWH through improvements in their physical, mental and social wellbeing. This paper will briefly review these projects and describe the current status of haemophilia care in these countries. While there is still a long way to go before optimal care becomes a reality for all PWH in developing countries, significant progress has been made, and knowledge of the impact and outcomes of these projects can inform best practice worldwide.185SI3338Novo Nordisk Haemophilia FoundationNovo Nordisk Health Care AG, Switzerlan

Simultaneous bleeding and thrombosis in superwarfarin poisoning

Superwarfarin poisoning causes a severe acquired coagulation disorder that, despite its frequency, severity and specific therapeutic implications, stilt goes largely unrecognized by physicians. Hematologists are often called to evaluate these patients, but unawareness of the specificities of the problem often precludes adequate diagnosis and treatment. Superwarfarin poisoning differs from coumarin overdose in that the former is resistant to reversal with standard doses of vitamin K, and that anticoagulant effects can last for weeks after drug discontinuation. Here we report a case of superwarfarin poisoning with a previously unreported clinical presentation, in which diffuse bleeding and venous thrombosis were simultaneousty present at diagnosis. The diagnostic implications and the therapeutic dilemmas raised by this new presentation are discussed.123463763

Possible association between cytomegalovirus infection and gastrointestinal bleeding in hemophiliac patients

Cytomegalovirus (CMV) infection is of major concern in immunocompromised and immunosuppressed patients. Prior to the introduction of HIV-1 antibody screening and efficient virucidal processes to inactivate viruses, individuals with a factor VIII or factor IX deficiency had a high risk of contracting HIV-1 infection through the infusion of contaminated blood products, In addition, blood products were also frequently associated with alterations in immune function. This study investigated the frequency of active CMV infection and its clinical relevance in Brazilian hemophiliacs, One hundred hemophiliacs were screened for the presence of CMV-DNA in their blood using nested PCR, Twenty-five out of 100 patients (25%) were positive for CMV-DNA and 24 of these 100 patients (24%) were HIV-1 positive; 6 of these 24 (25%) were positive for CMV-DNA. A similar frequency was observed among HIV-l-negative patients, In 60 hemophiliacs, the clinical relevance of the CMV infection was assessed. Twenty-one patients were positive for CMV-DNA. Of these, 10 had gastrointestinal bleeding compared to only 9 of 39 patients who were CMV-DNA negative (p = 0.05; chi(2) test). These data indicate a high prevalence of active CMV infection in Brazilian hemophiliac patients, irrespective of whether the patients were or were not infected by HIV-1, There was a possible association between the presence of CMV and the occurrence of gastrointestinal bleeding. Copyright (C) 2000 S. Karger AG, Basel.1032737

Efficacy and safety of dapsone as a second-line treatment in non-splenectomized adults with immune thrombocytopenic purpura

In adults with immune thrombocytopenic purpura (ITP), steroids are usually proposed as first-line therapy, but long-term complete responses are obtained in no more than 20% of patients. For the remaining patients, splenectomy is considered the treatment of choice, with reported cure rates from 60-70%. However, the inherent risks of surgery and sepsis after splenectomy without a guarantee of success justify the search for strategies aimed to avoid splenectomy. Here we retrospectively evaluated the results of dapsone treatment in ITP patients that failed first-line therapy with steroids. These patients received dapsone 100 mg/day for a minimum of 30 days before splenectomy was considered. Efficacy was defined as a sustained rise in platelet counts (50 109/l) clearly attributed to dapsone treatment. Among 52 steroid-dependent or refractory patients, dapsone resulted in sustained increases in platelet counts in 44.2% of patients, after a median follow-up of 21.10 months after treatment initiation. The long-term efficacy of dapsone in this setting is further corroborated by the observation that none of the responding patients required splenectomy in the follow-up, compared to 69.0% of the non-responding patients. Dapsone-related adverse events were mild and promptly reversed by treatment withdrawal. The results of our retrospective analysis suggest that dapsone is a safe and effective second-line agent for steroid-dependent or refractory ITP patients. Because of its well-known safety profile and low cost compared to other potential second-line treatments for ITP, a trial course of dapsone should be viewed as an attractive option before splenectomy in steroid-dependent of refractory adult ITP patients.19748949