Exchange transfusion therapy and its effects on real-time microcirculation in pediatric sickle cell anemia patients: an intravital microscopy study.

Periodic blood exchange transfusion is a treatment modality commonly used to manage pediatric sickle cell anemia at the University of California Davis Medical Center. The goal of exchange transfusion therapy is to ameliorate vasoocclusion and improve tissue perfusion by removing sickled red blood cells and introducing normal red blood cells. Using computer-assisted intravital microscopy, pretransfusion and posttransfusion microvascular characteristics were analyzed. In this study, the bulbar conjunctiva exhibited a "blanched" avascular appearance in all 6 pediatric sickle cell anemia patients before transfusion, indicative of tissue hypoperfusion and ischemia. Immediately after transfusion, substantial improvement in vascularization and tissue perfusion resulted, reflected by the enhanced appearance of capillaries and arterioles. In addition, a decrease in red cell velocity was observed. These observations provide evidence that exchange transfusion therapy is beneficial in ameliorating vasoocclusion and improving tissue perfusion. However, with the paradoxical posttransfusion decrease in red cell velocity presumably due to induced hyperviscosity from the large transfusion volume, blood flow is still impaired. This decreased velocity may thwart efforts to improve oxygen delivery through transfusion and may, to some extent, promote vasoocclusion instead. This paradoxical result warrants further investigation on the effects of transfusion volume and viscosity in the exchange transfusion process.

Evaluation of recombinant factor VIII Fc (Eloctate) activity by thromboelastometry in a multicenter phase 3 clinical trial and correlation with bleeding phenotype.

: The aim of this study was to compare the hemostatic efficacy of recombinant factor VIII Fc (rFVIIIFc) (Eloctate) and Advate by ex-vivo rotation thromboelastometry (ROTEM) of whole blood and to explore potential ROTEM parameters that may be more predictive of a patient's bleeding tendency than plasma FVIII activity. Thirteen clinical sites were selected to perform ROTEM on freshly collected blood samples from 44 patients in the phase 3 study for rFVIIIFc, including 16 patients undergoing sequential pharmacokinetic assessment of Advate and rFVIIIFc. Equivalent hemostatic activity was observed for rFVIIIFc and Advate in postinfusion samples, followed by improvements for rFVIIIFc in clotting time, clot formation time and alpha angle (α) for a longer duration than Advate, consistent with the pharmacokinetic improvements reported previously for rFVIIIFc. Our study did not demonstrate a statistical correlation between a patient's ROTEM activity at baseline or at trough and the occurrence of spontaneous bleeds while on prophylactic therapy. However, an association was observed between postinfusion clotting time and the occurrence of one or more spontaneous bleeds vs. no bleeds over a follow-up period of 1 year (P = 0.003). How well a patient's whole blood clotting deficiency is corrected after a dose of FVIII may be an indicator of subsequent bleeding tendency in patients with otherwise equivalent FVIII peak and trough levels. The technical challenges of standardizing the ROTEM, largely overcome in the current study, may however preclude the use of this method for widespread assessment of global hemostasis unless additional assay controls or normalization procedures prove to be effective.

Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B.

Hemophilia B is an X-linked genetic disease caused by mutation of the gene for coagulation protein factor IX (FIX), with an incidence of approximately once every 30,000 male births in all populations and ethnic groups. When severe, the disease leads to spontaneous life threatening bleeding episodes. When untreated, most patients die from bleeding complications before 25 years of age. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing FIX. Most patients administer the infusions at home every few days, and must limit their physical activities to avoid abnormal bleeding when the FIX activity levels are below normal. After completing the pivotal Phase III clinical trial, a new therapeutic FIX preparation that has been engineered for an extended half-life in circulation, received regulatory approval in March 2014 in Canada and the US. This new FIX represents a major therapeutic advance for patients with hemophilia B. The half-life is prolonged due to fusion of the native FIX molecule with the normal constant region of immunoglobulin G. This fusion molecule then follows the normal immunoglobulin recirculation pathways through endothelial cells, resulting in prolonged times in circulation. In the clinical trials, over 150 patients successfully used eftrenonacog alfa regularly for more than 1 year to prevent spontaneous bleeding, to successfully treat any bleeding episodes, and to provide effective coagulation for major surgery. All infusions were well tolerated and effective, with no inhibitors detected and no safety concerns. This promising therapy should allow patients to use fewer infusions to maintain appropriate FIX activity levels in all clinical settings.

Alprolix (recombinant Factor IX Fc fusion protein): extended half-life product for the prophylaxis and treatment of hemophilia B.

Hemophilia B is a genetic disease caused by mutation of the gene for coagulation protein Factor IX. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing Factor IX. Alprolix™ (recombinant Factor IX Fc fusion protein), is a therapeutic Factor IX preparation that has been engineered for a prolonged half-life in circulation, has completed pivotal clinical trials and has been approved recently in the USA, Canada, Australia and Japan for use in the clinic for patients with hemophilia B. This promising therapy should allow patients to use fewer infusions to maintain appropriate Factor IX activity levels in all clinical settings, and its use may be indicated in both on demand and prophylactic treatments.