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- Halldén, Christer, et al.
(författare)
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Origin of Swedish hemophilia B mutations
- 2013
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 11:11, s. 2001-2008
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Tidskriftsartikel (refereegranskat)abstract
- Background More than 1100 mutations that cause hemophilia B (HB) have been identified. At the same time, specific F9 mutations are present at high frequencies in certain populations, which raise questions about the origin of HB mutations. ObjectivesTo describe the mutation spectrum of all HB families in Sweden and investigate if mutations appearing in several families are due to independent recurrent mutations (RMs) or to a common mutation event (i.e. are identical by descent (IBD)). Patients/MethodsThe registered Swedish HB population consists of patients from 86 families. Mutations were identified by resequencing and identical haplotypes were defined using 74 markers and a control population of 285 individuals. The ages of IBD mutations were estimated using ESTIAGE. ResultsOut of 77 presumably unrelated patients with substitution mutations, 47 patients (61%) had mutations in common with other patients. Haplotyping of the 47 patients showed that 24 patients had IBD mutations (51%) with estimated ages of between two and 23 generations. A majority of these patients had mild disease. Eight of the 15 mutations observed in more than one family were C>T transitions in CpG sites and all eight were RMs. ConclusionsThe association of IBD mutations with a mild phenotype is similar to what has been previously observed in hemophilia A. Noteworthy features of the mutations that are common to more than one family are the equal proportions of patients with RM and IBD mutations and the correlation between the occurrence of RMs and C>T transitions at CpG sites.
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- Kask, Lena, et al.
(författare)
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Proteomic analysis of tissue factor activation
- 2013
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Ingår i: Journal of Thrombosis and Haemostasis. - 1538-7933 .- 1538-7836. ; 11:S2, s. 379-380
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Ljung, Rolf, et al.
(författare)
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40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics, and preliminary efficacy in hemophilia patients with inhibitors.
- 2013
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 11:7, s. 1260-1268
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A 40K glycoPEGylated, recombinant Factor VIIa (rFVIIa) bypassing agent (N7-GP) with a prolonged half-life (15 h) compared to rFVIIa was developed as a potential candidate for bleed preventive regimens in patients with hemophilia and inhibitors. OBJECTIVES: To evaluate the safety, pharmacokinetics, and preliminary efficacy of multiple doses of N7-GP in congenital hemophilia A and B patients with high-titer inhibitors. PATIENTS/METHODS: In this global, prospective, randomized, double-blinded, phase 2 trial, 25, 100, or 200 μg kg(-1) N7-GP was administered intravenously once every second day during a 3-month bleed preventive regimen and compared with a preceding 3-month observation period with on-demand treatment of bleeds with rFVIIa. The primary endpoint was adverse events; secondary endpoints were evaluation of immunogenicity, pharmacokinetics, and efficacy. RESULTS AND CONCLUSIONS: Overall, 23 patients were randomized and dosed (n = 8/7/8 for 25/100/200 μg kg(-1) ). N7-GP was well tolerated, with a low frequency of adverse events. No serious adverse events, immunogenic or thromboembolic events related to N7-GP were reported. The pharmacokinetic properties of N7-GP were similar to those reported in phase 1. The annualized bleeding rate (ABR) decreased in the treatment period vs. the observation period at all N7-GP dose levels. However, a dose-response relationship in the reduction could not be established in the N7-GP dose range evaluated. The ABR was also reduced at two dose levels during the last part of the observation period, and increased notably in the follow-up period irrespective of previous N7-GP dose. The trial was registered at ClinicalTrials.gov (Registration Number: NCT00951405). This article is protected by copyright. All rights reserved.
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- Rahman, Milladur, et al.
(författare)
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Platelet shedding of CD40L is regulated by matrix metalloproteinase-9 in abdominal sepsis.
- 2013
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 11:7, s. 1385-1398
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: Platelet-derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase-9 might cleave surface expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis. Methods: Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild-type and MMP-9-deficient mice. Edema formation, CXC chemokine, myeloperoxidase levels, neutrophils in the lung as well as plasma levels of CD40L and MMP-9 were quantified. Results: CLP increased plasma levels of MMP-9 but not MMP-2. The CLP-induced decrease of platelet surface CD40L and increase of soluble CD40L levels were significantly attenuated in MMP-9 gene-deficient mice. Moreover, pulmonary MPO activity and neutrophil infiltration in the alveolar space as well as edema formation and lung injury were markedly decreased in septic animals lacking MMP-9. In vitro studies revealed that inhibition of MMP-9 decreased platelet shedding of CD40L. Moreover, recombinant MMP-9 was capable of cleaving surface expressed CD40L on activated platelets. In human studies, plasma levels of MMP-9 were significantly increased in patients with septic shock compared to healthy controls although MMP-9 levels did not correlate with organ injury score. Conclusions: Our novel data propose a role of MMP-9 in regulating platelet-dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD40L shedding from platelets. We conclude that targeting MMP-9 may be a useful strategy to limit acute lung injury in abdominal sepsis. This article is protected by copyright. All rights reserved.
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