Validation of Nafamostat Mesilate as an Anticoagulant in Extracorporeal Membrane Oxygenation: A Large-Animal Experiment

BACKGROUND: Unfractionated heparin is commonly used for anticoagulation in extracorporeal membrane oxygenation (ECMO). Several studies have shown that nafamostat mesilate (NM) has comparable clinical outcomes to unfractionated heparin. This study compared anticoagulation with NM and heparin in a large-animal model. METHODS: Beagle dogs (n=8; weight, 6.5–9 kg) were placed on venovenous ECMO. Blood samples were taken every hour and the following parameters were compared: hemoglobin level, activated partial thromboplastin time (aPTT), thromboelastography (TEG) data, platelet function, and inflammatory cytokine levels. RESULTS: In both groups, the aPTT was longer than the baseline value. Although the aPTT in the NM group was shorter than in the heparin group, the TEG parameters were similar between the 2 groups. Hemoglobin levels decreased in both groups, but the decrease was less with NM than with heparin (p=0.049). Interleukin (IL)-1β levels significantly decreased in the NM group (p=0.01), but there was no difference in the levels of tumor necrosis factor alpha or IL-10 between the 2 groups. CONCLUSION: NM showed a similar anticoagulant effect to that of unfractionated heparin, with fewer bleeding complications. NM also had anti-inflammatory properties during ECMO. Based on this preclinical study, NM may be a good alternative candidate for anticoagulation in ECMO.

A Surgery Case of Heparin-Induced Thrombocytopenia as a Complication of Ventricular Septal Perforation after Acute Myocardial Infarction / 日本心臓血管外科学会雑誌

<p>A 66-year-old man with an unknown medical history developed chest pain and a diagnosis of acute myocardial infarction (AMI) was given by his physician. Percutaneous coronary intervention was performed in the left anterior descending artery. Echocardiography revealed ventricular septal perforation (VSP) ; therefore, the patient was transferred to our hospital. After admission, his platelet count dropped rapidly during heparin administration, and left ventricular thrombosis and deep vein thrombosis were noted, raising a suspicion of heparin-induced thrombocytopenia (HIT). To establish cardiopulmonary bypass, argatroban alone was insufficient to prolong the Powered by Editorial Manager^® and ProduXion Manager^® from the Aries Systems Corporation activated clotting time (ACT) ; thus, nafamostat mesilate was also used for coronary artery bypass grafting and surgical repair of VSP. It took many hours to normalize the ACT, requiring re-exploration for excessive bleeding. On the 37th postoperative day, the patient was transferred to another hospital. We performed cardiac surgical procedures using argatroban in a patient who developed HIT during the course of VSP following AMI ; however, we had difficulty in controlling the ACT. Since, to the best of our knowledge, there are no previous studies reporting surgical case of VSP complicated by HIT, we present this case with a review of the relevant literature.</p>

Cardiac arrest caused by nafamostat mesilate

A 65-year-old man was transferred from the Department of Vascular Surgery to Nephrology because of cardiac arrest during hemodialysis. He underwent incision and drainage for treatment of a buttock abscess. Nafamostat mesilate was used as an anticoagulant for hemodialysis to address bleeding from the incision and drainage site. Sudden cardiac arrest occurred after 15 minutes of dialysis. The patient was treated in the intensive care unit for 5 days. Continuous veno-venous hemodiafiltration was started without any anticoagulant in the intensive care unit. Conventional hemodialysis was reinitiated, and nafamostat mesilate was used again because of a small amount of continued bleeding. Ten minutes after hemodialysis, the patient complained of anaphylactic signs and symptoms such as dyspnea, hypotension, and facial swelling. Epinephrine, dexamethasone, and pheniramin were injected under the suspicion of anaphylactic shock, and the patient recovered. Total immunoglobulin E titer was high, and skin prick test revealed weak positivity for nafamostat mesilate. We first report a case of anaphylactic shock caused by nafamostat mesilate in Korea.

Nafamostat mesilate promotes endothelium-dependent vasorelaxation via the Akt-eNOS dependent pathway

Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has anticoagulant and anti-inflammatory properties. The intracellular mediator and external anti-inflammatory external signal in the vascular wall have been reported to protect endothelial cells, in part due to nitric oxide (NO) production. This study was designed to examine whether NM exhibit endothelium dependent vascular relaxation through Akt/endothelial nitric oxide synthase (eNOS) activation and generation of NO. NM enhanced Akt/eNOS phosphorylation and NO production in a dose- and time-dependent manner in human umbilical vein endothelial cells (HUVECs) and aorta tissues obtained from rats treated with various concentrations of NM. NM concomitantly decreased arginase activity, which could increase the available arginine substrate for NO production. Moreover, we investigated whether NM increased NO bioavailability and decreased aortic relaxation response to an eNOS inhibitor in the aorta. These results suggest that NM increases NO generation via the Akt/eNOS signaling pathway, leading to endothelium-dependent vascular relaxation. Therefore, the vasorelaxing action of NM may contribute to the regulation of cardiovascular function.

Nafamostat Mesilate Inhibits TNF-alpha-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production

Nafamostat mesilate (NM) is a serine protease inhibitor with anticoagulant and anti-inflammatory effects. NM has been used in Asia for anticoagulation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation. Oxidative stress is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial function. We investigated whether NM could inhibit endothelial dysfunction induced by tumor necrosis factor-alpha (TNF-alpha). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-alpha for 24 h. The effects of NM on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) protein expression, p38 mitogen-activated protein kinase (MAPK) activation, and intracellular superoxide production were then examined. NM (0.01~100 microg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-alpha (3 ng/mL), and it dose dependently prevented the TNF-alpha-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-alpha-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-alpha-induced monocyte adhesion and the expression of endothelial cell adhesion molecules, and that the anti-adhesive effect of NM is mediated through the inhibition of p66shc, ROS production, and p38 MAPK activation.

The Use of Nafamostat Mesilate as an Anticoagulant during Continuous Renal Replacement Therapy for Children with a High Risk of Bleeding

PURPOSE: Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has been investigated as an anticoagulant for adult patients with a high risk of bleeding, who need chronic renal replacement therapy (CRRT). However, little is known about the use of NM as an anticoagulant in pediatric CRRT. The aim of this study was to evaluate the ideal dosage, efficacy, and safety of NM in pediatric CRRT. METHODS: We conducted a retrospective study of 40 pediatric patients who had undergone at least 24 h of venovenous CRRTs between January 2011 and October 2013. We divided the patients according to risk of bleeding. Those at high risk received no anticoagulation (group 1) or NM as an anticoagulant (group 2), while those at low risk received heparin (group 3). RESULTS: Forty patients (25 male and 15 female; mean age, 8.2+/-6.6 years) were enrolled. The mean duration of CRRT was 13.0 days, and the survival rate was 57.5%. The mean hemofilter lifespan was 39.3 h in group 1 and 11.3 h in group 3. In group 2, hemofilter lifespan was extended from 7.5 h to 27.4 h after the use of NM (P=0.001). The mean hemofilter lifespan with NM was greater than with heparin (P=0.018). No patient experienced a major bleeding event during treatment with NM. CONCLUSION: NM may be a good alternative anticoagulant in pediatric patients with a high risk of bleeding requiring CRRT, and is not associated with bleeding complications.

Protease Inhibitor Treatment of Disseminated Intravascular Coagulation Associated with Aortic Dissection / 대한내과학회지

Disseminated intravascular coagulation (DIC) is a rare complication of aortic dissection. We report an unusual case of a 64-year-old woman with DIC associated with chronic aortic dissection who developed catastrophic intracranial hemorrhage. Computed tomography (CT) revealed partially thrombosed false lumen in the chronic dissected aneurysm of the thoracoabdominal aorta, which remained after surgery for acute type A aortic dissection. The laboratory profile showed features of DIC, including thrombocytopenia, hypofibrinogenemia, and increased D-dimer levels. Bleeding diathesis, including ecchymosis and coagulopathy, showed improvement following treatment with protease inhibitors (nafamostat and camostat).

A Case of Re-operation for Paravalvular Leakage after Mitral Valve Replacement Complicated by Heparin-Induced Thrombocytopenia / 日本心臓血管外科学会雑誌

Anticoagulation management in cardiac surgery can be difficult in patients with heparin-induced thrombocytopenia (HIT). We report a patient who underwent reoperation of cardiopulmonary bypass (CPB) using argatroban in combination with nafamostat mesilate. A bolus of 0.25 mg/kg argatroban was administered, followed by continuous infusion of 5-10 μg/kg/min argatroban and 100 mg/h nafamostat mesilate. No complications such as thrombosis were observed during either CPB or the perioperative period. Although we used argatroban and nafamostat mesilate, which has a shorter half-life than argatroban, the anticoagulant effect was prolonged, and the patient had an uneventful postoperative course despite requiring substantial blood transfusion.

Risk Factors for Post-ERCP Pancreatitis in Patients Pretreated with Nafamostat Mesilate / 대한소화기내시경학회지

BACKGOUND/AIMS: Pancreatitis is the most common and important complication of an endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to identify risk factors for post ERCP-pancreatitis in patients pretreated with nafamostat mesilate, a synthetic protease inhibitor. METHODS: A total of 247 patients who underwent an ERCP were evaluated prospectively. Potential risk factors of post-ERCP pancreatitis in patients pretreated with nafamostat mesilate were evaluated. RESULTS: Twenty-four patients (9.7%) and nine patients (3.6%) developed post-ERCP hyperamylasemia and pancreatitis, respectively. As determined by univariate analysis among the potential risk factors, we found a procedure time over 20 minutes, pancreatic duct cannulation over four times, prior post-ERCP pancreatitis and the absence of a common bile duct (CBD) stone as risk factors for post-ERCP hyperamylasemia. We also found a patient age under 60 years, a procedure time over 20 minutes, pancreatic duct cannulation over four times and the absence of a CBD stone as risk factors for post-ERCP pancreatitis (p<0.05). As determined by multivariate analysis, pancreatic cannulation over four times is independently associated with post-ERCP hyperamylasemia (p=0.038; OR, 5.165; 95% CI, 1.093~24.412) and post-ERCP pancreatitis (p=0.002; OR, 33.122; 95% CI, 3.526~311.138). CONCLUSIONS: A repeated pancreatic duct cannulation is the most important risk factor for post-ERCP pancreatitis in patients pretreated with nafamostat mesilate.

A Multi-Center Phase III Clinical Trial to Assess the Influence to Bleeding and Anticoagulant Effect of Nafamostat Mesilate (Futhan) in Hemodialysis Patients with High Bleeding-Risk / 대한신장학회잡지

BACKGROUND: Routine hemodialysis is performed with systemic anticoagulation, usually with heparin, to prevent thrombosis in the extracorporeal blood circuit. However, systemic anticoagulation can produce hemorrhagic complications in patients at high risk of bleeding. To minimize the risk of bleeding, a number of alternative regimens has been proposed, however, each of those methods has its own limitations and complication. METHODS: 58 hemodialysis patients at risk for bleeding due to previous surgery or hemorrhagic complication were treated with Futhan as regional anticoagulant and compared with that of low-dose heparin anticoagulation. There were 29 (50%) postoperative cases and 29 (50%) cases of hemorrhage from various sites. RESULTS: The exacerbation of bleeding by hemodialysis was noted in only 4% in heparin treated group and none in Futhan group. Clotting times at site A (intracorporeal circulation) were not prolonged with Futhan, whereas those of heparin were prolonged slightly, which is not statistically significant. Degrees of residual blood in the dialyzer and blood clottings in the venous drip-chamber were less in Futhan than in heparin group. Adverse reactions related to Futhan therapy were minor and the incidence of adverse reactions was comparable in both groups. CONCLUSION: Futhan is a safe and effective regional anticoagulant for hemodialysis especially for patients with high bleeding risk.

The Effect of Nafamostat Mesilate for the Treatment of Disseminated Intravascular Coagulation after Surgery Using Cardiopulmonary Bypass / 日本心臓血管外科学会雑誌

To investigate the effect of nafamostat mesilate (FUT) for disseminated intravascular coagulation (DIC) after surgery using cardiopulmonary bypass, we studied DIC scores and parameters of coagulation and fibrinolysis in the DIC cases. Although 12 patients developed DIC, the platelet counts improved by administration of FUT apart from one complicated by sepsis. The DIC scores decreased as a result of the increase of platelets and fibrinogen and improvement of FDP. Thrombin-antithrombin III complex, D-dimer and plasmin-α₂ plasmin inhibitor complex showed an even higher value at the endpoint of FUT administration. These results indicate that patients with DIC after cardiopulmonary bypass may have severe fibrinolytic acceleration and that administration of FUT can be useful in those cases.