No abstract

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

No abstract

The identification of NOX4 as a major source of oxidative stress in stroke and demonstration of dramatic protection after stroke in mice by NOX4 deletion or NOX inhibition, opens up new avenues for treatment.

This study examined the role of Schwann cells and hematogenous macrophages in myelin degradation and Ia antigen expression during Wallerian degeneration of rodent sciatic nerve. To identify and distinguish between macrophages and Schwann cells we used, in addition to electron microscopy, immunocytochemical staining of teased nerve fibres and 1 microns thick cryosections. Before the appearance of adherent macrophages the myelin sheath fragmented into ovoids, small whorls of myelin debris appeared within Schwann cell cytoplasm and the Schwann cell displayed numerous lipid droplets. However, at least in large fibres most myelin degradation and removal was accomplished or assisted by macrophages, identified by their expression of the ED1 marker. These cells began entering the nerve from blood vessels by day 2, migrated to degenerating nerve fibres and adhered to nerve fibres in the regions of the ovoids. There they penetrated the Schwann cell basal lamina to occupy an intratubal position and phagocytose myelin. During Wallerian degeneration a subpopulation of ED1-positive monocytes/macrophages expressed Ia antigen; Schwann cells were Ia-negative. Ia expression by monocytes/macrophages appeared to be a transient event and was not seen in post-phagocytic macrophages, as indicated by the fact that ED1-positive phagocytes with large vacuoles were Ia-negative. Our data show that both Schwann cells and macrophages play important roles in degrading and removing myelin during Wallerian degeneration. The expression of Ia antigen during Wallerian degeneration indicates that Ia expression need not necessarily reflect specific immune events but in some instances can represent a nonspecific response to PNS damage.