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The safety and efficacy of peripheral venous administration of a self-complementary adeno-associated viral vector encoding the human FIX gene (scAAV-LP1-hFIXco) was evaluated in nonhuman primates for gene therapy of hemophilia B. Peripheral vein infusion of 1 ؋ 10 12 vg/kg scAAV-LP1-hFIXco pseudotyped with serotype 8 capsid, in 3 macaques, resulted in stable therapeutic expression (more than 9 months) of human FIX (hFIX) at levels (1.1 ؎ 0.5 g/mL, or 22% of normal) that were comparable to those achieved after direct delivery of the same vector dose into the portal circulation (1.3 ؎ 0.3 g/mL, or 26% of normal). Importantly, the pattern of vector biodistribution after systemic and portal vein administration of scAAV-LP1-hFIXco was almost identical. Additionally, comparable levels of gene transfer were achieved in macaques with preexisting immunity to AAV8 following peripheral vein administration of 1 ؋ 10 12 vg/kg AAV5-pseudotyped scAAV-LP1-hFIXco. This confirms that alternative serotypes can circumvent preexisting naturally acquired immunity to AAV. Thus, peripheral venous administration of AAV5 and AAV8 vectors is safe and as effective at transducing the liver in nonhuman primates as direct vector administration into the portal circulation. These results should make vector administration to patients, especially those with a severe bleeding diathesis, significantly easier and safer. (Blood.

The guideline group was selected to include UK-based medical, scientific and laboratory representatives. Publications known to the writing group were supplemented with additional papers identified by searching MEDLINE/Pubmed using the keywords direct thrombin inhibitors (DTI), direct Xa inhibitors, apixaban, argatroban, bivalirudin, dabigatran, fondaparinux, rivaroxaban, in combination with measurement, monitoring, coagulation assays, haemostasis assays and laboratory tests.The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). The BCSH GRADE system was not applied to this guideline as it is inappropriate for laboratory studies. The guideline was then reviewed by a sounding board of c. 50 UK haematologists, the BCSH and British Society for Haematology (BSH) Committee and comments were incorporated where appropriate.The objective of this guideline is to provide healthcare professionals with clear guidance on the clinically important issues regarding the laboratory assessment of currently used non-coumarin anticoagulants and their impact on laboratory tests of haemostasis.A short summary of the effects of rivaroxaban and dabigatran on routine coagulation screens and assessment of anticoagulation intensity on behalf of the BCSH and international recommendations related to measurement of oral direct inhibitors (Baglin et al, 2013) have recently been published.The sections on heparin and low molecular weight heparin (LMWH) represent an update of the previously issued guidance (Baglin et al, 2006).