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Objective : Effective endogenous fibrinolysis requires rapid release of endothelial tissue plasminogen activator (t-PA). Using the nitric oxide synthase inhibitor, l- N G-monomethylarginine (l-NMMA), we examined the contribution of endogenous nitric oxide to substance P-induced t-PA release in vivo in man. Methods : Blood flow and plasma fibrinolytic and haemostatic factors were measured in both forearms of 8 healthy male volunteers who received unilateral brachial artery infusions of substance P (2–8 pmol/min) and l-NMMA (1–4 μg/min). Results : Substance P caused dose-dependent increases in blood flow ( P

Skin necrosis is a rare but serious side-effect of treatment with warfarin. At particular risk are those with various thrombophilic abnormalities, especially when warfarinisation is undertaken rapidly with large loading doses of warfarin. With the increasing number of patients anticoagulated as out-patients for thromboprophylaxis, we are concerned that the incidence of skin necrosis may increase. If skin necrosis does occur, prompt remedial action may be of benefit in preventing permanent tissue damage. Keywords: warfarin; skin necrosis; protein C; antiphospholipid antibody; adverse drug reaction

Objective— Using a clinical model of deep arterial injury, we assessed the ability of exogenous and endogenous tissue plasminogen activator (t-PA) to limit acute in situ thrombus formation. Approach and Results— Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized cross-over studies of 20 healthy volunteers during extracorporeal administration of recombinant t-PA (0, 40, 200, and 1000 ng/mL) or during endogenous t-PA release stimulated by intra-arterial bradykinin infusion in the presence or absence of oral enalapril. Recombinant t-PA caused a dose-dependent reduction in thrombus area under low and high shear conditions ( P P P P P =0.03) and a trend toward a reduction in the high shear chamber (13±7%; P =0.07). Conclusions— Using a well-characterized clinical model of coronary arterial injury, we demonstrate that endogenous t-PA released from the vascular endothelium enhances fibrinolysis and limits in situ thrombus propagation. These data support a crucial role for the endogenous fibrinolytic system in vivo and suggest that continued exploration and manipulation of its therapeutic potential are warranted.