Summary.  Background: Soluble thrombomodulin is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. Objectives: We conducted a multicenter, double‐blind, randomized, parallel‐group trial to compare the efficacy and safety of recombinant human soluble thrombomodulin (ART‐123) to those of low‐dose heparin for the treatment of disseminated intravascular coagulation (DIC) associated with hematologic malignancy or infection. Methods: DIC patients (n = 234) were assigned to receive ART‐123 (0.06 mg kg−1 for 30 min, once daily) or heparin sodium (8 U kg−1  h−1 for 24 h) for 6 days, using a double‐dummy method. The primary efficacy endpoint was DIC resolution rate. The secondary endpoints included clinical course of bleeding symptoms and mortality rate at 28 days. Results: DIC was resolved in 66.1% of the ART‐123 group, as compared with 49.9% of the heparin group [difference 16.2%; 95% confidence interval (CI) 3.3–29.1]. Patients in the ART‐123 group also showed more marked improvement in clinical course of bleeding symptoms (P = 0.0271). The incidence of bleeding‐related adverse events up to 7 days after the start of infusion was lower in the ART‐123 group than in the heparin group (43.1% vs. 56.5%, P = 0.0487). Conclusions: When compared with heparin therapy, ART‐123 therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients.

A B S T R A C T The concentration of a2-plasmin inhibitor in blood plasma is higher than that in serum obtained from the blood clotted in the presence ofcalcium ions, but is the same as that in serum obtained in the absence of calcium ions.Radiolabeled a2-plasmin inhibitor was covalently bound to fibrin only when calcium ions were present at the time of clotting of plasma or fibrinogen. Whereas, when batroxobin, a snake venom enzyme that lacks the ability to activate fibrin-stabilizing factor, was used for clotting fibrinogen, the binding was not observed. When fibrin-stabilizing, factor-deficient plasma was clotted, the specific binding of a2-plasmin inhibitor to fibrin did not occur even in the presence of calcium ions and the concentration of a2-plasmin inhibitor in serum was the same as that in plasma.Monodansyl cadaverine, a fluorescent substrate of the fibrin-stabilizing factor, was incorporated into a2-plasmin inhibitor by activated fibrin-stabilizing factor.All these findings indicate that a2-plasmin inhibitor is cross-linked to fibrin by activated fibrin-stabilizing factor when blood is clotted. Analysis of a2-plasmin inhibitor-incorporated fibrin by sodium dodecyl sulfate gel electrophoresis showed that the inhibitor was mainly cross-linked to polymerized a-chains of crosslinked fibrin. Cross-linking of a2-plasmin inhibitor to fibrin renders fibrin clot less susceptible to fibrinolysis by plasmin.

Myocardial ischemia and reperfusion have been shown to impair coronary vasorelaxation to endothelium-dependent vasodilators. To examine the time course of this dysfunction, occlusion of the left anterior descending (LAD) coronary artery (90 minutes) was followed by reperfusion for 0, 2.5, 5, 20, 180, or 270 minutes. Coronary arterial rings from the ischemic LAD and control left circumflex (LCx) arteries were tested for responsiveness to the endothelium-dependent receptormediated vasodilator, acetylcholine (ACh), and the endothelium-dependent nonreceptor-mediated vasodilator, A23187, as well as the endothelium-independent vasodilator, NaNO2. ACh relaxation was not impaired after 90 minutes of ischemia without reperfusion. However, 2.5 minutes of reperfusion resulted in depressed ACh responses (36±10% of control) that was further reduced to 16±6% at 20 minutes, and remained comparably depressed at every time thereafter. A23187 vasodilator responses were also attenuated after reperfusion, although the reduced response occurred later (that is, at 20 minutes). There was no significant decrease in response to NaNO2 in the LAD at any time or to any vasodilator in LCx control rings. Treatment with recombinant human superoxide dismutase (hSOD, 5 mg/kg/hr, that is, 15,545 SOD units/kg/ hr), starting 10 minutes before reperfusion, preserved the vasodilator response to ACh (82+±6%) and A23187, but treatment with the hydroxyl ion scavenger N-(2-mercapto proprionyl)-glycine (MPG) (8 mg/kg/hr) only protected the A23187 response. No damage to the surface of the endothelium was observed by scanning electron microscopy at any time point. Myocardial cell damage increased with time of reperfusion as assessed by increasing plasma CK activities and amounts of necrotic tissue indexed to area at risk. Significant myocardial injury occurred at 3 hours after reperfusion. These findings suggest that endothelial dysfunction resulting in reduced endothelium-derived relaxing factor release occurs before the development of myocardial cell necrosis and may be due to oxygen-derived free radicals produced rapidly on reperfusion. (Circulation 1990;82:1402-1412 M y yocardial ischemia initiated by occlusion or blockade of a major coronary artery leads to a complex series of cellular events that can result in myocardial cell death. Although reperfusion can produce salvage of ischemic tissue, it may also contribute to myocardial cellular injury. Reperfusion can accelerate necrosis in irreversibly injured myocytes because of an increase in cell swelling, From the Department of Physiology (P.S.T., N.A., G.J.,

A B S T R A C T When blood is clotted, a2-plasmin inhibitor (a2PI) is cross-linked to fibrin by activated fibrin-stabilizing factor (activated coagulation Factor XIII, plasma transglutaminase). The amount of crosslinked a2-PI is proportional to the amount of a2PI present at the time of clotting. Plasma from a patient with congenital deficiency of a2PI was supplemented with various amounts of purified a2PI. Clots were prepared from these plasmas and were suspended in plasma containing a normal concentration of a2PI, and spontaneous clot lysis was observed. When the clot was formed in the presence of calcium ions and thereby allowing cross-linking to occur, the rate and extent of fibrinolysis were found to be inversely proportional to the concentrations of a2PI present in the clot at the time of clotting. When the clot was formed in the absence of calcium ions so that no cross-linking occurred, the clot underwent fibrinolysis at similar rates, regardless of the concentrations of a2PI in the clot. When the clot formed in the presence of calcium ions was squeezed and washed to remove unbound proteins before being suspended in plasma, the extent of fibrinolysis was also inversely proportional to the amount of a2PI cross-linked to fibrin. Similar results were obtained when the clot was suspended in buffered saline instead of plasma. These observations suggest that spontaneous fibrinolysis is mainly carried out by plasminogen/plasminogen activator bound to fibrin, and this fibrinolysis caused by fibrin-associated activation of plasminogen was mainly inhibited by a2PI crosslinked to fibrin. To further support this concept, a2PI treated with activated fibrin-stabilizing factor and that had lost most of its cross-linking capacity was used in similar experiments. This modified a2PI had the same inhibitory activity on plasmin as the native inhibitor, but gave significantly less inhibition of fibrinolysis in

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