IntroductionPhiladelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic disorders that includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). 1,2 Recent studies have confirmed the pathogenetic involvement of an acquired, somatic, gain-offunction, activating, point mutation JAK2V617F in MPNs. [3][4][5][6] This represents a guanine to thymidine mutation in exon 14 resulting in a valine to phenylalanine substitution at codon 617 in the JH2 or pseudokinase domain of the JAK2 gene (a member of the Janus kinase [JAK] family of nonreceptor tyrosine kinases, JAK1, JAK2, JAK3, and TYK2). 2,6 Highly sensitive assays for JAK2 have determined that the JAK2V617F mutation is present in 90% of patients with PV and approximately 50% to 60% of patients with ET or PMF. 7 In addition, a subset of patients, most commonly with PV, are homozygous for the JAK2V617F allele, the result of copy-neutral loss of heterozygosity at the JAK2 locus, especially in patients with PV. 2,7,8 Mutations in exon 12 of JAK2 are present in almost all patients with PV who are JAK2V617F negative. 9,10 The JAK proteins function in the cytoplasm to relay signals initiated by membrane-bound cytokine receptors. Engagement of the receptor results in the phosphorylation of the receptor and JAK2, which recruits its substrate proteins such as signal transducers and activators of transcription (STATs). 11,12 STATs, especially STAT3 and STAT5, translocate to the nucleus and transactivate many genes involved in cell proliferation and survival (eg, Bcl-xL, cyclin D1, and PIM1). 8,11,12 The V617F mutation in JAK2 also activates the downstream signaling pathways through the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK). This contributes to diminished apoptosis of the hematopoietic progenitor cells (HPCs). 2,8 Overexpression of JAK2V617F in murine Ba/F3 cells with coexpression of the erythropoietin receptor (EpoR) confers in vitro cytokine-independent growth. 3,13 Recently, it was shown that enforced expression of JAK2V617F in human hematopoietic stem cells and myeloid progenitors directed differentiation toward the erythroid lineage, along with increased expression and phosphorylation of GATA-1 and decreased expression of PU.1. 14-16 JAK2V617F expression in retroviral models and in transgenic mice is sufficient to cause myeloproliferative disorders in the mice that recapitulate many clinicopathologic features observed in human PV, ET, and PMF. [17][18][19][20][21] 22,23 In vivo studies in mouse models have also shown that mutant JAK2V617F represents a novel target for therapeutic intervention with JAK2-selective tyrosine kinase inhibitors in MPNs. 21,24 For example, TG101348 inhibits myeloproliferation and myelofibrosis in a murine model of JAK2V617F-induced polycythemia. 21,22 Early clinical trials of several JAK2-selective kinase inhibitors (eg, XL019, TG101348, and INCB18424) are under way in JAK2-driven MPNs with poor prognosis (eg, PMF). ...

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Neutralizing antibodies (inhibitors) to replacement Factor-VIII impair the effective management of hemophilia-A1. Individuals with hemophilia-A due to major F8 gene disruptions lack antigenically cross-reactive material in their plasma (CRM-negative) and prevalence of inhibitors is >60%. Conversely, subjects with missense mutations are CRM-positive and the prevalence of inhibitors is <10%2. Individuals with the intron-22-inversion (~50% of individuals with severe hemophilia-A) should be in the former group based on the genetic defect. Although these individuals are CRM-negative, only 20% of them develop inhibitors3. Here we demonstrate the presence of comparable levels of F8 mRNA and intracellular Factor-VIII protein in B-lymphoblastoid cells and liver biopsies from healthy controls and subjects with the intron-22-inversion. These results support the hypothesis that most individuals with the intron-22-inversion are tolerized to Factor-VIII and thus do not develop inhibitors. Furthermore we developed a pharmacogenetic algorithm that permits the stratification of inhibitor risk for sub-populations by predicting immunogenicity using, as input, the number of putative T-cell epitopes in the infused FVIII and the competence of MHC-Class-II molecules to present such epitopes. The algorithm exhibited significant accuracy in predicting inhibitors in 25 unrelated individuals with the intron-22-inversion (AUC = 0.890; P = 0.001).

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Background and Purpose-The effectiveness of prothrombin complex concentrate (PCC) products available in the UnitedStates that contain low levels of factor VII (3-factor PCC) has not been tested. The purpose of this study was to review our experience with 3-factor PCC (Profilnine) in the setting of warfarin-associated intracranial hemorrhage (wICH). Methods-In November 2007, we implemented a protocol for reversal of anticoagulation in wICH using Profilnine.Additional treatment with fresh-frozen plasma was at the discretion of the treating physician.