Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8 −/− ) did not rescue the embryonic death of TFPI null (Tfpi −/− ) mice. Tfpi +/− did not alter the bleeding phenotype of F8 −/− mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8 −/− mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi +/− ;F8 −/− mice with hematopoietic Tfpi −/− cells compared with Tfpi +/− ;F8 −/− mice with Tfpi +/+ hematopoietic cells. Additionally, following femoral vein injury, Tfpi +/− ;F8 −/− mice with Tfpi −/− hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi +/+ hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.hemostasis | Kunitz | coagulopathy

Objective-Tissue factor (TF)-factor VIIa initiates blood coagulation and is found on microparticles that accumulate within intravascular thrombi. Tissue factor pathway inhibitor (TFPI), a factor Xa (fXa)-dependent inhibitor of TF-factor VIIa, is produced by megakaryocytes and is present in platelets. We sought to determine the role of platelet TFPI in regulation of thrombus growth.

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that prevents intravascular coagulation through inhibition of factor Xa (fXa) and the tissue factor (TF)-factor VIIa complex (TF-fVIIa). Localization of TFPI within caveolae enhances its anticoagulant activity. To further define how caveolae contribute to TFPI anticoagulant activity, CHO cells were co-transfected with TF and membrane associated TFPI targeted to either caveolae (TFPI-GPI) or to bulk plasma membrane (TFPI-TM). Stable clones had equal expression of surface TF and TFPI. TX-114 cellular lysis confirmed localization of TFPI-GPI to detergent insoluble membrane fractions, while TFPI-TM localized to the aqueous phase. TFPI-GPI and TFPI-TM were equally effective direct inhibitors of fXa in amidolytic assays. However, TFPI-GPI was a significantly better inhibitor of TF-FVIIa than TFPI-TM, as measured in both amidolytic and plasma clotting assays. Disrupting caveolae by removing membrane cholesterol from EA.hy926 cells, which make TFPIα, CHO cells transfected with TFPIβ, and HUVECs, did not affect their fXa inhibition but significantly decreased their inhibition of TF-fVIIa. These studies confirm and quantify the enhanced anticoagulant activity of TFPI localized within caveolae, demonstrate that caveolae enhance the inhibitory activity of both TFPI isoforms, and define the effect of caveolae as specifically enhancing the anti-TF activity of TFPI.

Contemporary biblical scholarship is changing at a rapid pace. The variety of methods for interpreting the Bible has increased dramatically in recent years, as is shown, for example, by the growing interest in literary approaches such as narrative criticism, and in approaches focused on areas outside both literary and biblical research, for instance, the articles on biblical themes as interpreted in the cinema. The past twenty-five years have seen a growing interest by biblical scholars in structuralist criticism, reader response criticism, rhetorical criticism, social-scientific criticism, feminist interpretation, ideological criticism, and deconstructive criticism, in addition to major advances in the work being done on the broader contexts within which ancient Israel and early Christianity developed. Long-standing methods of research have undergone substantial reappraisal, as, for instance, in the areas of 'biblical' archaeology and the history of early Israel. The field now reaches well beyond the encompassing historicalcritical consensus that had dominated biblical scholarship throughout most of the twentieth century. This increasing variety and flexibility in method has added richness and depth to our understanding of the Bible and its contextual world. The growing variety of approaches is healthy and energizing, and indicates the vitality of contemporary biblical scholarship. However, this variety also makes it very difficult for scholars, especially those who teach or write across a broad spectrum of biblical studies, to stay informed about the numerous recent developments in the many different areas of biblical scholarship. Add to this the virtual explosion in books, journals, Festschriften, encyclopedias and online sites, and one can immediately see the need for a journal to keep readers apprised of recent developments in this rapidly expanding field of scholarship. Given this increasing diversity of methods and interests in contemporary biblical scholarship, the need for Currents is even clearer today than it was when the first issue was published in 1993. Currents also welcomes proposals for articles relating to all facets of Judaism in the late Second Temple and early Rabbinic periods. This includes, but is not limited to, essays on recent research in Pseudepigrapha, Qumran, Mishnah, Midrash and Talmud, as well as studies on ancient Jewish interpreters such as Josephus and Philo. We are especially interested in articles that address texts

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