Philip M. Blatt

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 × 1012 vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of ∼8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression*.

Urgent reversal of warfarin with prothrombin complex concentrate

Summary.  Background: When life‐threatening bleeding occurs in patients on warfarin, timely reversal becomes imperative. In the USA, warfarin effect is commonly reversed with fresh frozen plasma (FFP). The use of FFP is complicated by delays in correction, volume overload and often, inadequate correction. Objective: Evaluate the feasibility and efficacy of a protocol for rapid administration of prothrombin complex concentrate (PCC) in the setting of the urgent need for reversal of warfarin. Methods/patients: We instituted a policy for rapid delivery and administration of PCC. Appropriate patients received 25–50 U kg−1 of PCC. The prothrombin time (PT)/International Normalized Ratios (INR) was recorded before and immediately after dosing, and 24 h postdosing. Patients requiring surgical interventions were cleared for the operating room (OR) immediately. Fifty‐eight patients were treated, with a median age of 75.5 years (range 26–92). Results: The median INR on presentation was 3.8 (1.4–52.8). Immediately following PCC administration the median INR was 1.3 (0.9–5.7), only two patients with INRs exceeding 2.0. The benefit was maintained at 24 h with a median INR of 1.5 (1.1–3.4). Four patients experienced thrombotic events during their hospitalization, (two deep vein thrombosis, two non‐q‐wave myocardial infarction) although none was attributed to PPC therapy. Conclusions: PCC administration is an effective treatment modality for the correction of warfarin anticoagulation in the urgent setting. Advantages over FFP include more timely correction, absence of volume overload and potentially more complete correction. Broader use of PCC in this setting appears to be appropriate.

Thrombogenic Materials in Prothrombin Complex Concentrates

Abstract Prothrombin complex concentrates are now available for use for treatment of bleeding complications associated with deficiencies of factors II, VII, IX, or X. The purpose of this report is ...

Intravascular coagulation with use of human prothrombin complex concentrates.

Prothrombin complex concentrates are used in the treatment of the congenital bleeding disorders associated with Factors II, VII, IX, and X deficiencies. They have also been extensively used to treat acquired coagulation abnormalities secondary to vitamin K deficiency, warfarin ingestion, and various types of liver disease. The reported complications of prothrombin complex concentrates administration include hepatitis, anaphylaxis, and thrombosis. This paper documents the development of disseminated intravascular coagulation in association with the administration of prothrombin complex concentrates to patients with liver disease.

Liver biopsy in hemophilia A.

Hepatitis is a significant complication of the treatment of hemophilia A with factor VIII concentrates. Chronic liver disease in these patients is infrequently documented in the literature. The results of percutaneous liver biopsy, under the coverage of glycine-precipitated factor VIII, in six patients with hemophilia A who had the persistence of abnormal liver-function tests for at least 6 months, are described. Three patients had chronic active hepatitis, and three had chronic persistent hepatitis. No complications were encountered as a result of the biopsy procedure. These results suggest that percutaneous liver biopsy should be considered in patients with hemophilia A with continuously abnormal liver-function tests to establish a histologic diagnosis and to guide further therapy.

Erratum: Successful transduction of liver in hemophilia by AAV- factor IX and limitations imposed by the host immune response (Nature Medicine (2006) 12 (342-347))

Nat. Med. 12, 342–347; 2006; published online 12 February 2006; corrected after print 19 April 2006 In the version of this article originally published, Pradip Rustagi was inadvertently omitted from the author list; John Rasko should be listed as John E. J. Rasko; the affiliations of John E. J. Rasko and Katherine A.