Yukio Suga

Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation

Abstract: We investigated whether depressed plasma antithrombin and protein C activity, considered as a specific finding of disseminated intravascular coagulation (DIC), is due to consumption coagulopathy in septic patients with DIC. An analysis of hemostatic parameters was performed in 139 septic patients (68 with DIC and 71 without DIC). Plasma activity of antithrombin and protein C tended to be significantly decreased in septic patients with DIC but not in those without DIC (p < 0.001). However, when the septic patients were classified into three groups according to the albumin (or choline esterase) level, no significant differences in antithrombin activity or protein C activity were observed between the patients with and without DIC in any of the subgroups. Notably, neither the plasma activity of antithrombin nor protein C was decreased even in septic patients with DIC who had normal plasma levels of albumin (or choline esterase). No significant correlation was observed between plasma levels of thrombin–antithrombin complex (TAT) and antithrombin activity, or between plasma levels of TAT and protein C activity either in septic patients with DIC or without DIC. It is reasonable to conclude that the markedly reduced plasma activity of antithrombin and protein C is not due to consumption coagulopathy in septic patients with DIC.

Mycophenolate Mofetil Is Effective and Well Tolerated in the Treatment of Refractory Acute and Chronic Graft-versus-Host Disease

We enrolled 11 patients with refractory graft-versus-host disease (GVHD) in a prospective trial evaluating the efficacy of mycophenolate mofetil (MMF). Four (67%) of the 6 patients with acute GVHD and all 5 patients with chronic GVHD responded to MMF. Ten (91%) of the 11 patients were able to decrease steroid use (median decrease, 86%; range, 25%-100%). After a median follow-up of 18 months (range, 1-65 months), 7 patients (64%) remained alive. The adverse events were infectious complications (36%), diarrhea (27%), and neutropenia (18%); the only patient discontinuing MMF did so because of grade 4 neutropenia. This preliminary study suggests that MMF is a well-tolerated agent and has a beneficial effect in the treatment of refractory acute and chronic GVHD.

Pathophysiology of disseminated intravascular coagulation (DIC) progresses at a different rate in tissue factor-induced and lipopolysaccharide-induced DIC models in rats

&NA; Tissue factor (TF) and lipopolysaccharide (LPS) are frequently used to induce disseminated intravascular coagulation (DIC) in experimental animal models. Although the pathophysiology of DIC may differ depending on which agent is used for induction, previous studies on models of DIC have not distinguished which DIC‐inducing agent was used. In the present paper, we evaluate the characteristics of TF‐induced and LPS‐induced DIC using two types of DIC models, with special reference to selected hemostatic parameters and pathological findings within the kidney. Male Wistar rats were administered TF (3.75 U/kg; sustained infusion for 4 h) or LPS (30 mg/kg; sustained infusion for 4 h) via the tail vein, and blood sampling was performed at 0, 1, 3, 4, 5, 7, 9, 11, and 28 h. Judging from changes in the levels of thrombin‐antithrombin complex, fibrinogen levels, and platelet counts, it is reasonable to conclude that the severity of both types of experimental DIC is similar with regard to hemostatic activation and consumption coagulopathy. A marked elevation in the level of D‐dimer was noted without any organ dysfunction or much fibrin deposition in the kidney upon administration of TF. However, a markedly prolonged period of elevation in plasminogen activator inibitor activity, a prolonged depression in antithrombin III activity, severe organ failure, and a markedly prolonged period of fibrin deposition in the kidney was observed following LPS administration. A modest number of the rats from the TF‐induced DIC model died during the experimental period, whereas a large number of rats died during LPS‐induced DIC, especially after 9 h. Since the time course of the pathophysiology differed remarkably among the TF‐induced and LPSinduced DIC models in rats, we recommend that TFinduced and LPS‐induced DIC be approached as distinct models in order to determine the implications of their experimental and clinical use. Blood Coagul Fibrinolysis 14:221‐228

Marked difference in pathophysiology between tissue factor- and lipopolysaccharide-induced disseminated intravascular coagulation models in rats

Objective Tissue factor and lipopolysaccharide frequently have been used to induce disseminated intravascular coagulation in experimental animal models. Although the pathophysiology of disseminated intravascular coagulation may differ according to the agents used to induce it, these previous models have not distinguished between the use of different disseminated intravascular coagulation-inducing agents. In this study, we attempted to evaluate the characteristic features of these agents in two types of disseminated intravascular coagulation models, with special reference to selected hemostatic parameters and pathologic findings in the kidney. Design Prospective, comparative, experimental study. Setting Laboratory at a university hospital. Subjects Twenty-seven male Wistar rats, age 6–7 wks, weighing 160–170 g. Interventions Three groups of animals were studied: a control group (n = 8) receiving physiologic saline, a tissue factor-treated group (n = 11) receiving tissue factor 3.75 units/kg, and a lipopolysaccharide-treated group (n = 8) receiving lipopolysaccharide 30 mg/kg; each group sustained infusion for 4 hrs via the tail vein. Measurements and Main Results The degree of hemostatic activation in both types of experimental disseminated intravascular coagulation was identical, based on the results of thrombin-antithrombin III complex levels. Markedly elevated D-dimer concentrations were observed without organ dysfunction or fibrin deposition in the kidney on administration of tissue factor, whereas markedly elevated plasminogen activator inhibitor activity, decreased antithrombin III activity, severe organ failure, and marked fibrin deposition in the kidney were observed for lipopolysaccharide administration. Conclusion Because pathophysiology differed remarkably between the tissue factor- and lipopolysaccharide-induced disseminated intravascular coagulation models in rats, we recommend that they be assessed carefully as distinct entities to determine implications of their experimental and clinical use.

Elevated levels of free tissue factor pathway inhibitor antigen in cases of disseminated intravascular coagulation caused by various underlying diseases.

Tissue factor pathway inhibitor (TFPI) is primarily synthesized by vascular endothelial cells and is foundin vivoin association with endothelial cells, lipoproteins, or in free form. Free TFPI is the most potent and important type, because it is released from endothelial cells following an injection of heparin, or as a result of pathological stimuli. In order to study the role of TFPI in disease, the concentration of free form TFPI was measured in the plasma of 114 patients suffering from disseminated intravascular coagulation (DIC), as the result of several underlying diseases. Plasma antigen levels of free TFPI were significantly higher even in those patients not exhibiting DIC than in normal healthy subjects. These levels were even higher among patients exhibiting DIC, especially those with acute promyelocytic leukemia or cancer, receiving continuous heparin drip infusions. A significant correlation was observed between the plasma antigen levels of free form TFPI and those of fibrin/fibrinogen degradation products, and free form TFPI and plasmin inhibitor complex (r= 0.428,P< 0.0001 andr= 0.329,P< 0.0001, respectively) among 114 DIC patients. There were no significant differences between the plasma levels of free TFPI in DIC patients with or without multiple organ failure. It has been suggested that the plasma levels of free TFPI are closely related to the levels of fibrinolysis occurring in DIC patients, although further study is required to clarify the degree to which TFPI is expressed by endothelial cells during DIC.

All-trans retinoic acid is partially effective against lipopolysaccharide-induced but not against tissue-factor-induced disseminated intravascular coagulation in rat models.

All-trans retinoic acid (ATRA) has been introduced to the management of acute promyelocytic leukemia (APL) as a differentiation treatment. This drug not only causes complete remission, but also improves disseminated intravascular coagulation (DIC) without adding anticoagulants in APL. We have attempted to determine whether ATRA is effective against DIC in rat models induced by tissue factor (TF) or lipopolysaccharide (LPS), because the anticoagulant effect of ATRA has been considered to induce thrombomodulin upregulation and TF downregulation on endothelial cells as well as on APL cells. In male Wistar rats, DIC was induced by a 4-h infusion of thromboplastin (3.75 U/kg) or lipopolysaccharide (30 mg/kg). The rats were given ATRA orally each day at a dose of 100 mg/kg per day for 1 week before the injection of TF or LPS in ATRA treatment groups, or given low molecular weight heparin (LMWH) 10 min before the injection of TF or LPS (200 U/kg, bolus intravenously) in LMWH treatment groups. No significant changes in hemostatic parameters or markers of organ dysfunction were caused by the ATRA administration, while DIC was significantly improved by LMWH in the TF-induced model. DIC was significantly improved by both ATRA and LMWH in the LPS-induced model. These findings suggested that ATRA was useful for treating DIC only in the LPS-induced model, and that drug efficacy should be carefully assessed because the agents used to induce DIC considerably influenced the outcome.

Beneficial effect of JTV-803, a new synthetic inhibitor of activated factor X, against both lipopolysaccharide-induced and tissue factor-induced disseminated intravascular coagulation in rat models.

We examined whether JTV-803, a specific activated factor X inhibitor independent of antithrombin III (ATIII), is effective against disseminated intravascular coagulation (DIC) in rat models induced by tissue factor (TF) or lipopolysaccharides (LPS). In male Wistar rats, DIC was induced by a 4 h infusion of thromboplastin (3.75 U/kg) or LPS (50 mg/kg). The rats were given JTV-803 (0.3 or 3 mg/kg, bolus intravenously) (JTV-803 groups) or low molecular weight heparin (LMWH groups) (200 U/kg, bolus intravenously) prior to an injection of TF or LPS. The results showed that JTV-803 was dose-dependently effective against DIC in both TF-induced and LPS-induced rat models. This anti-DIC effect of JTV-803 at higher doses was almost equivalent to that of LMWH in both types of DIC. Plasma ATIII activity was more prominent in the group treated with JTV-803 than in that treated with LMWH. None of rats died in the TF-induced DIC model with or without drug administration. On the contrary, seven of 22 rats died (mortality rate, 31.8%) in the LPS-induced DIC model without drug administration. Although the mortality rate of rats induced with LPS and treated with LMWH was quite high (6/16, 37.5%), none of the LPS-induced rats treated with JTV-803 died. These findings suggested that JTV-803 can treat both TF-induced and LPS-induced DIC models, and that this drug has greater potential in preserving ATIII and in improving the prognosis of DIC.

Depressed plasma activity of plasminogen or α2 plasmin inhibitor is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation

We have attempted to determine whether depressed plasma plasminogen and α2 plasmin inhibitor (or α2 antiplasmin) activity is, as a result of consumption coagulopathy, a specific finding of disseminated intravascular coagulation (DIC) in septic patients. The hemostatic parameters of 139 septic patients (68 with DIC and 71 without DIC) were analyzed. Among the group as a whole, plasma activities of plasminogen and α2 plasmin inhibitor were significantly depressed in septic patients with DIC relative to those without DIC (P < 0.01 and P < 0.05, respectively). Notably, a significant correlation was observed between plasma levels of albumin and plasminogen activity, as well as between plasma levels of albumin and α2 plasmin inhibitor activity both in septic patients with DIC and those without DIC. However, no significant correlation was observed between plasma levels of plasmin–α2 plasmin inhibitor complex (PIC) and plasminogen activity, nor between PIC and α2 plasmin inhibitor activity either in septic patients with DIC or those without DIC. We concluded that depressed activity of plasminogen or α2 plasmin inhibitor is not as a result of consumption coagulopathy, but rather a result of low synthetic function of the liver in septic patients with DIC.

Investigation for Risk Factor and Preventive Effect of NSAIDs, Opioid on Gemcitabine-induced Vascular Pain

ゲムシタビン塩酸塩(GEM)は,膵臓がん, 胆道がん,肺がん,乳がんなどの治療に用いられ, 良好な治療成績が報告されている .GEM によ る有害事象としては,血小板減少等の重篤な骨髄 抑制が挙げられるが,その毒性は一般的に軽度な ものと考えられている.しかし,GEM に特徴的 な有害事象として,経静脈投与時の血管痛がある. これは,生命を脅かす重篤な有害事象ではないが, GEM 投与中の患者の苦痛が大きい場合もあり, 治療を継続する際の大きな問題となることがあ る. GEM による血管痛の発現頻度は,約 30%との 報告がみられるが ,報告によりその発現頻度 には違いがみられる.また,GEM による血管痛 の予防方法としては,ホットパックを用いて血管 を温める方法や GEM の溶解液を生理食塩液から 5 %ブドウ糖液への変更が行われている .し かし,ホットパックや 5 %ブドウ糖液を使用して も強い血管痛が生じることもあり,血管痛の予防 対策は十分とは言い難い.このため,GEM によ