T hromboembolism in atrial fibrillation is a major cause of stroke.1 Oral anticoagulation (OAC) with the vitamin K antagonist warfarin or one of the new direct oral anticoagulants (nOAC) is highly effective for stroke prevention in atrial fibrillation. [2][3][4][5] The most severe complication of long-term anticoagulation is intracranial hemorrhage. Indeed, intracerebral hemorrhage (ICH) during therapy with vitamin K antagonist is responsible for 88% of all hemorrhage-associated deaths caused by anticoagulation. 6 Moreover, vitamin K antagonistassociated ICH expands more frequently and over a longer time period than spontaneous ICH. [7][8][9] To prevent hematoma expansion-a major therapeutic goal in ICH therapyreplacement of coagulation factors is recommended. 10 Although nOAC appear to carry a substantially lower risk of ICH compared with warfarin, [3][4][5] ICH during nOAC therapy remains a life-threatening complication. Currently, no specific antidote is available, and the effect of administering hemostatic coagulation factors is dubious. 11,12 Recently, an experimental murine model of ICH during OAC has been established in which ICH is induced by injection of collagenase into the striatum during anticoagulation. 13,14 This model shows early hematoma expansion exceeding that of nonanticoagulated mice, during anticoagulation with either warfarin or a high dose of the direct thrombin inhibitor dabigatran. [13][14][15] Excess hematoma expansion in this model could be prevented most effectively by infusing prothrombin complex concentrate (PCC), whereas the effect of recombinant human factor factor VIIa (FVIIa) and fresh frozen plasma (FFP) was less consistent. 15,16 Rivaroxaban is another nOAC that directly inhibits the central coagulation factor Xa. Its widespread clinical use beyond stroke prevention in atrial fibrillation is expected because it has been proven effective and safe for additional indications, including acute coronary syndrome and venous thromboembolism. 17,18 So far, no specific antidote for rivaroxaban is available, and the efficacy of hemostatic factors in the setting of ICH is unknown. 11,12 The purpose of the present study was to establish a murine model of ICH associated with rivaroxaban, and to evaluate the effect of different hemostatic agents on excess hematoma Background and Purpose-Rivaroxaban has recently been approved for stroke prevention in atrial fibrillation. However, lack of an effective antidote represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with rivaroxaban, and to examine the effectiveness of different hemostatic factors in preventing excess hematoma expansion. Methods-In C57BL/6 mice receiving 10 or 30 mg/kg rivaroxaban by gastric gavage, plasma concentration, prothrombin time, and coagulation factor activities were measured repeatedly. Thirty minutes after inducing ICH by intrastriatal collagenase-injection, mice received an intravenous injection of either saline, pro...

Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c ؉ peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals.