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Rangarajan S.,Center for Haemostasis and Thrombosis | Kessler C.,Comprehensive Care | Aledort L.,Mount Sinai School of Medicine
Thrombosis Research | Year: 2013

Apart from TTP, ADAMTS13 may be an important player in those conditions where Von Willebrand Factor and the Platelet Glycoprotein GP Ib axis have a part to play in the pathogenesis. This includes stroke, myocardial infarction, sepsis and inflammatory condition. This article reviews the literature in these conditions. © 2013 Elsevier Ltd.

Collins P.W.,University of Wales | Palmer B.P.,UK National Haemophilia Database | Chalmers E.A.,Royal Hospital for Sick Children | Hart D.P.,Haemophilia Center | And 5 more authors.
Blood | Year: 2014

The effect of recombinant factor VIII (rFVIII) brand on inhibitor development was investigated in all 407 severe hemophilia A previously untreated patients born in the United Kingdom (UK) between 1 January 2000 and 31 December 2011. Eighty-eight (22%) had been in the RODIN study. Information was extracted from the National Haemophilia Database. Because exposure days (EDs) were not known for some patients, time from first treatment was used as a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titer, after a median (interquartile range) of 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate NexGen, 45 (35.2%, 95% confidence interval [CI] 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95% CI 18.6% to 31.4%) with Advate (P = .04). The adjusted hazard ratio (HR) (95% CI) for Kogenate Bayer/Helixate NexGen compared with Advate was 2.14 (1.12-4.10) (P = .02) for high titer and 1.75 (1.11-2.76) (P = .02) for all inhibitors. When excluding UK-RODIN patients, the adjusted HR (95% CI) for high-titer inhibitors was 2.00 (0.93-4.34) (P = .08). ReFacto AF was associated with a higher incidence of all, but not high-titer, inhibitors than Advate. These resultswill help informdebate around the relative immunogenicity and use of rFVIII brands. © 2014 by The American Society of Hematology.

Shearer M.J.,Center for Haemostasis and Thrombosis | Newman P.,Cancer Research UK Research Institute
Journal of Lipid Research | Year: 2014

In contrast to other fat-soluble vitamins, dietary vitamin K is rapidly lost to the body resulting in comparatively low tissue stores. Deficiency is kept at bay by the ubiquity of vitamin K in the diet, synthesis by gut microflora in some species, and relatively low vitamin K cofactor requirements for γ-glutamyl carboxylation. However, as shown by fatal neonatal bleeding in mice that lack vitamin K epoxide reductase (VKOR), the low requirements are dependent on the ability of animals to regenerate vitamin K from its epoxide metabolite via the vitamin K cycle. The identification of the genes encoding VKOR and its paralog VKOR-like 1 (VKORL1) has accelerated understanding of the enzymology of this salvage pathway. In parallel, a novel human enzyme that participates in the cellular conversion of phylloquinone to menaquinone (MK)-4 was identified as UbiA prenyltransferase-containing domain 1 (UBIAD1). Recent studies suggest that side-chain cleavage of oral phylloquinone occurs in the intestine, and that menadione is a circulating precursor of tissue MK-4. The mechanisms and functions of vitamin K recycling and MK-4 synthesis have dominated advances made in vitamin K biochemistry over the last five years and, after a brief overview of general metabolism, are the main focuses of this review. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

Holmes M.V.,Guys and St Thomas NHS Foundation Trust | Holmes M.V.,University College London | Hunt B.J.,Kings College London | Shearer M.J.,Center for Haemostasis and Thrombosis | Shearer M.J.,Kings College London
Blood Reviews | Year: 2012

Vitamin K antagonists (VKA) have been the mainstay of oral anticoagulant therapy for over 60. years. In this review we critically assess the evidence for the importance of vitamin K nutrition during VKA therapy; the methodologies for measuring dietary intakes; the vitamin K intake data in patients on VKA and healthy people; and the experimental evidence for the influence of vitamin K intakes and biochemical measures of vitamin K status on VKA response. Several studies show that dietary intakes of phylloquinone (vitamin K1) are associated to the sensitivity and stability of anticoagulation during initiation and maintenance dosing with low habitual intakes associated with greater instability of the INR and risk of sub-therapeutic anticoagulation. Preliminary evidence suggests that the stability of anticoagulation therapy may be improved by daily vitamin K supplementation, but further studies are needed to find out whether this, or other dietary interventions, can improve anticoagulant control in routine clinical practice. © 2011 Elsevier Ltd.

Knapen M.H.J.,Maastricht University | Schurgers L.J.,Maastricht University | Shearer M.J.,Center for Haemostasis and Thrombosis | Newman P.,Cancer Research UK Research Institute | And 2 more authors.
British Journal of Nutrition | Year: 2012

Osteocalcin (OC) is a vitamin K-dependent protein found in bone and in circulation. High serum γ-carboxylated OC reflects a high, and high uncarboxylated OC (ucOC) reflects a low vitamin K status. A revolutionary hypothesis is that ucOC acts as a hormone improving glucose handling and reducing fat mass. The objective was to test the logical extrapolation of the ucOC hormone hypothesis to humans that elevated ucOC is associated with higher body weight, BMI and fat mass. In a cross-sectional analysis, the associations of vitamin K status with circulating adiponectin and body composition were investigated in 244 postmenopausal women (study I). The effects of vitamin K treatment on adiponectin, body weight and BMI were investigated in archived samples from forty-two young men and women who received varying doses of menaquinone-7 during 12 weeks (study II) and from a cohort of 164 postmenopausal women who participated in a 3-year placebo-controlled trial on 45mg menaquinone-4 (MK-4) (study III). No association was found between vitamin K status and circulating adiponectin before or after vitamin K supplementation. A higher carboxylation of OC was significantly correlated with lower body weight, BMI and fat mass of the trunk. Women taking MK-4 maintained their baseline body weight and BMI, whereas women taking placebo showed significant increases in both indices. These findings demonstrate that a high vitamin K status of bone has no effect on circulating adiponectin in healthy people and long-term vitamin K supplementation does not increase weight in healthy postmenopausal women. © 2011 The Authors.

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