Effects of Nafamostat Mesilate on Coagulopathy With Chronic Aortic Dissection

A 65-year-old man with chronic aortic dissection experienced two massive subcutaneous hemorrhages. Laboratory data indicated disseminated intravascular coagulation, whereas a contrast computed tomographic scan revealed a dilatated aortic arch with a partial thrombosis at the false lumen. Because disseminated intravascular coagulation can be caused by chronic aortic dissection, and the aortic arch was 6 cm in diameter, we performed graft replacement from the ascending to the descending aorta in a single stage. Before graft replacement, nafamostat mesilate, a protease inhibitor, was administered and the disseminated intravascular coagulation improved. Nafamostat mesilate may be useful for managing disseminated intravascular coagulation associated with chronic aortic dissection. A 65-year-old man with chronic aortic dissection experienced two massive subcutaneous hemorrhages. Laboratory data indicated disseminated intravascular coagulation, whereas a contrast computed tomographic scan revealed a dilatated aortic arch with a partial thrombosis at the false lumen. Because disseminated intravascular coagulation can be caused by chronic aortic dissection, and the aortic arch was 6 cm in diameter, we performed graft replacement from the ascending to the descending aorta in a single stage. Before graft replacement, nafamostat mesilate, a protease inhibitor, was administered and the disseminated intravascular coagulation improved. Nafamostat mesilate may be useful for managing disseminated intravascular coagulation associated with chronic aortic dissection. Disseminated intravascular coagulation (DIC) is a rare but critical complication of chronic aortic dissection. We administered nafamostat mesilate for DIC associated with chronic aortic dissection, after which we could safely perform the graft replacement.A 65-year-old man was admitted to our hospital due to back pain. A contrast computed tomographic (CT) scan revealed aortic dissection from the ascending aorta extending to the abdominal aorta. However, the false lumen of the ascending aorta was completely thrombosed, and Doppler echocardiography revealed neither pericardial effusion nor aortic regurgitation. Therefore, he received antihypertensive therapy. After 4 months, contrast CT revealed a patent false lumen of the ascending aorta and aortic enlargement of the distal arch. We planned to perform total arch replacement, but he was unable to undergo surgery for financial reasons. One month later, he complained of dyspnea and right chest pain. Contrast CT revealed subcutaneous hemorrhage of the right chest (Fig 1A). Severe anemia, low platelet count, and excessive levels of coagulation and fibrinolytic factors were observed (hemoglobin, 4.7 g/dL; platelets, 115,000/μL; fibrin/fibrinogen degradation product, 113.6 μg/dl; D-dimer, 27.0 μg/dl). Transfusion of red cell concentrate (8 units) and fresh-frozen plasma (4 units) improved his symptoms. However, hemorrhage occurred again 4 months later. He complained of pain in his left thigh, which was markedly swollen with hematoma (Fig 1B). Laboratory data indicated DIC (platelets, 78,000/μL; fibrinogen, 54 mg/dL; fibrin/fibrinogen degradation product, 239.0 μg/dL; D-dimer, 63.8 μg/dL; plasmin-α2-plasmin inhibitor complex, 20.2 μg/mL; thrombin-antithrombin 3 complex > 60.0 ng/mL). Contrast CT revealed a dilatated aortic arch with a partial thrombosis at the false lumen (Fig 1C). We believed that this bleeding tendency was due to DIC associated with chronic aortic dissection. At this stage, the aortic arch was 6 cm in diameter, and it was essential to perform graft replacement of chronic aortic dissection to improve DIC, which was now possible as the patient's financial problems had been resolved. To control the active bleeding of his left thigh, fresh-frozen plasma (8 units) was administered for the first 2 days (days 1 and 2; Fig 2). Simultaneously, continuous venous infusion of nafamostat mesilate was started (200 mg/day). By day 6, nafamostat mesilate improved the platelet count, fibrinogen levels, and D-dimer levels (platelets, 109,000/μL; fibrinogen, 315 mg/dL; D-dimer, 29.1 μg/dL) (Fig 2). However, as hyperkalemia developed, which is one of the most common side effects of nafamostat mesilate, we changed nafamostat mesilate to heparin. Subsequently, the platelet count and fibrinogen concentration did not decrease (Fig 2). He underwent graft replacement from the ascending to the descending aorta, with a single-stage approach through a median sternotomy and anterior thoracotomy in the sixth intercostal space. A normothermic cardiopulmonary bypass was initially used during the distal anastomosis, followed by hypothermic cerebral selective perfusion during the total arch replacement. Although re-thoracotomy was performed to remove a hematoma on postoperative day 5, his subsequent postoperative course was uneventful. The DIC was cured without anticoagulant therapy (platelets, 198,000/μL; fibrinogen, 427 mg/dL) and the elevated D-dimer levels also decreased (D-dimer, 17.1 μg/dL).Fig 2Clinical course. Day 1 represents the day that the second subcutaneous hemorrhage occurred in the left thigh. Changes in platelet counts and coagulo-fibrinolytic measurements are shown. The platelet count and plasma concentration of fibrinogen increase with continuous venous infusion of nafamostat mesilate, and the excess levels of D-dimer improve. These improvements in the laboratory results remain after switching to heparin. After the graft replacement from the ascending to descending aorta, D-dimer levels further improved.View Large Image Figure ViewerDownload (PPT)CommentNafamostat mesilate is frequently used for treatment of DIC in Japan. Nafamostat mesilate is a synthetic protease-inhibiting agent that has potent inhibitory activity with respect to plasmin, thrombin, coagulation factors in the active form (Xlla, Xa), kalikrein, complement factor (C1r, C1s), and trypsin [1Aoyama T. Ino Y. Ozeki M. et al.Pharmacological studies of FUT-175, nafamostat mesilate I. inhibition of protease activity in in vitro and in vivo experiments.Jpn J Pharmacol. 1984; 35: 203-227Crossref PubMed Scopus (232) Google Scholar]. Nafamostat mesilate also inhibits platelet aggregation. An in vitro study showed that agonist-induced surface expression of activated glycoprotein IIb/IIIa was inhibited by nafamostat mesilate. Because this inhibitory effect was parallel with the inhibition of platelet aggregation, the main inhibitory mechanism of nafamostat mesilate against platelet aggregation seems to be the suppression of activated glycoprotein IIb/IIIa expression, which enables it to bind to fibrinogen [2Fuse I. Higuchi W. Toba K. Aizawa Y. Inhibitory mechanism of human platelet aggregation by nafamostat mesilate.Platelets. 1999; 10: 212-218Crossref PubMed Scopus (13) Google Scholar].The balance of coagulation and fibrinolysis activation in DIC varies according to the underlying disease. In DIC with predominant coagulation activation, the plasma thrombin-antithrombin 3 complex levels are greatly increased, whereas the serum plasmin-α2-plasmin inhibitor complex levels are slightly increased. In DIC with predominant fibrinolysis activation, the plasma levels of both thrombin-antithrombin 3 complex and plasmin-α2-plasmin inhibitor complex are greatly increased and bleeding is a major clinical manifestation [3Asakura H. Saito M. Classification and treatment of DIC.Rinsho Ketsueki. 1995; 36: 314-319PubMed Google Scholar]. The DIC associated with chronic aortic dissection is commonly known as a type with predominant fibrinolysis activation and thrombin-antithrombin 3 complex and plasmin-α2-plasmin inhibitor complex levels are usually elevated, as in our case.We believe that repeated local thrombus formation at the dilated false lumen causes DIC associated with chronic aortic dissection, regardless of the extension of the thrombus. Repeated local thrombus formation at the dilated false lumen would result in the consumption of coagulation factors and platelets. Furthermore, locally activated fibrinolysis factors would spread through the systemic circulation, resulting in DIC with predominant fibrinolysis activation.Nafamostat mesilate exerts inhibitory effects on fibrinolysis, because it inhibits Xlla, kallikrein, and plasmin [1Aoyama T. Ino Y. Ozeki M. et al.Pharmacological studies of FUT-175, nafamostat mesilate I. inhibition of protease activity in in vitro and in vivo experiments.Jpn J Pharmacol. 1984; 35: 203-227Crossref PubMed Scopus (232) Google Scholar]. Nafamostat mesilate also has direct inhibitory effects on platelet aggregation in contrast with heparin [2Fuse I. Higuchi W. Toba K. Aizawa Y. Inhibitory mechanism of human platelet aggregation by nafamostat mesilate.Platelets. 1999; 10: 212-218Crossref PubMed Scopus (13) Google Scholar]. Therefore, nafamostat mesilate should be effective in managing DIC associated with chronic aortic dissection, which is a common type of DIC with predominant fibrinolysis activation. Moreover, nafamostat mesilate does not require antithrombin III for its activities because of its competitive inhibition of coagulative enzymes, and the half-life of nafamostat mesilate in human circulating blood is shorter than that of heparin, which reduces the risk of hemorrhagic complications [4Miyahara S. Yasu T. Yamada Y. Kobayashi N. Saito M. Momomura S. Subcutaneous injection of heparin calcium controls chronic disseminated intravascular coagulation associated with inoperable dissecting aortic aneurysm in an outpatient clinic.Intern Med. 2007; 46: 727-732Crossref PubMed Scopus (13) Google Scholar]. Disseminated intravascular coagulation (DIC) is a rare but critical complication of chronic aortic dissection. We administered nafamostat mesilate for DIC associated with chronic aortic dissection, after which we could safely perform the graft replacement. A 65-year-old man was admitted to our hospital due to back pain. A contrast computed tomographic (CT) scan revealed aortic dissection from the ascending aorta extending to the abdominal aorta. However, the false lumen of the ascending aorta was completely thrombosed, and Doppler echocardiography revealed neither pericardial effusion nor aortic regurgitation. Therefore, he received antihypertensive therapy. After 4 months, contrast CT revealed a patent false lumen of the ascending aorta and aortic enlargement of the distal arch. We planned to perform total arch replacement, but he was unable to undergo surgery for financial reasons. One month later, he complained of dyspnea and right chest pain. Contrast CT revealed subcutaneous hemorrhage of the right chest (Fig 1A). Severe anemia, low platelet count, and excessive levels of coagulation and fibrinolytic factors were observed (hemoglobin, 4.7 g/dL; platelets, 115,000/μL; fibrin/fibrinogen degradation product, 113.6 μg/dl; D-dimer, 27.0 μg/dl). Transfusion of red cell concentrate (8 units) and fresh-frozen plasma (4 units) improved his symptoms. However, hemorrhage occurred again 4 months later. He complained of pain in his left thigh, which was markedly swollen with hematoma (Fig 1B). Laboratory data indicated DIC (platelets, 78,000/μL; fibrinogen, 54 mg/dL; fibrin/fibrinogen degradation product, 239.0 μg/dL; D-dimer, 63.8 μg/dL; plasmin-α2-plasmin inhibitor complex, 20.2 μg/mL; thrombin-antithrombin 3 complex > 60.0 ng/mL). Contrast CT revealed a dilatated aortic arch with a partial thrombosis at the false lumen (Fig 1C). We believed that this bleeding tendency was due to DIC associated with chronic aortic dissection. At this stage, the aortic arch was 6 cm in diameter, and it was essential to perform graft replacement of chronic aortic dissection to improve DIC, which was now possible as the patient's financial problems had been resolved. To control the active bleeding of his left thigh, fresh-frozen plasma (8 units) was administered for the first 2 days (days 1 and 2; Fig 2). Simultaneously, continuous venous infusion of nafamostat mesilate was started (200 mg/day). By day 6, nafamostat mesilate improved the platelet count, fibrinogen levels, and D-dimer levels (platelets, 109,000/μL; fibrinogen, 315 mg/dL; D-dimer, 29.1 μg/dL) (Fig 2). However, as hyperkalemia developed, which is one of the most common side effects of nafamostat mesilate, we changed nafamostat mesilate to heparin. Subsequently, the platelet count and fibrinogen concentration did not decrease (Fig 2). He underwent graft replacement from the ascending to the descending aorta, with a single-stage approach through a median sternotomy and anterior thoracotomy in the sixth intercostal space. A normothermic cardiopulmonary bypass was initially used during the distal anastomosis, followed by hypothermic cerebral selective perfusion during the total arch replacement. Although re-thoracotomy was performed to remove a hematoma on postoperative day 5, his subsequent postoperative course was uneventful. The DIC was cured without anticoagulant therapy (platelets, 198,000/μL; fibrinogen, 427 mg/dL) and the elevated D-dimer levels also decreased (D-dimer, 17.1 μg/dL). CommentNafamostat mesilate is frequently used for treatment of DIC in Japan. Nafamostat mesilate is a synthetic protease-inhibiting agent that has potent inhibitory activity with respect to plasmin, thrombin, coagulation factors in the active form (Xlla, Xa), kalikrein, complement factor (C1r, C1s), and trypsin [1Aoyama T. Ino Y. Ozeki M. et al.Pharmacological studies of FUT-175, nafamostat mesilate I. inhibition of protease activity in in vitro and in vivo experiments.Jpn J Pharmacol. 1984; 35: 203-227Crossref PubMed Scopus (232) Google Scholar]. Nafamostat mesilate also inhibits platelet aggregation. An in vitro study showed that agonist-induced surface expression of activated glycoprotein IIb/IIIa was inhibited by nafamostat mesilate. Because this inhibitory effect was parallel with the inhibition of platelet aggregation, the main inhibitory mechanism of nafamostat mesilate against platelet aggregation seems to be the suppression of activated glycoprotein IIb/IIIa expression, which enables it to bind to fibrinogen [2Fuse I. Higuchi W. Toba K. Aizawa Y. Inhibitory mechanism of human platelet aggregation by nafamostat mesilate.Platelets. 1999; 10: 212-218Crossref PubMed Scopus (13) Google Scholar].The balance of coagulation and fibrinolysis activation in DIC varies according to the underlying disease. In DIC with predominant coagulation activation, the plasma thrombin-antithrombin 3 complex levels are greatly increased, whereas the serum plasmin-α2-plasmin inhibitor complex levels are slightly increased. In DIC with predominant fibrinolysis activation, the plasma levels of both thrombin-antithrombin 3 complex and plasmin-α2-plasmin inhibitor complex are greatly increased and bleeding is a major clinical manifestation [3Asakura H. Saito M. Classification and treatment of DIC.Rinsho Ketsueki. 1995; 36: 314-319PubMed Google Scholar]. The DIC associated with chronic aortic dissection is commonly known as a type with predominant fibrinolysis activation and thrombin-antithrombin 3 complex and plasmin-α2-plasmin inhibitor complex levels are usually elevated, as in our case.We believe that repeated local thrombus formation at the dilated false lumen causes DIC associated with chronic aortic dissection, regardless of the extension of the thrombus. Repeated local thrombus formation at the dilated false lumen would result in the consumption of coagulation factors and platelets. Furthermore, locally activated fibrinolysis factors would spread through the systemic circulation, resulting in DIC with predominant fibrinolysis activation.Nafamostat mesilate exerts inhibitory effects on fibrinolysis, because it inhibits Xlla, kallikrein, and plasmin [1Aoyama T. Ino Y. Ozeki M. et al.Pharmacological studies of FUT-175, nafamostat mesilate I. inhibition of protease activity in in vitro and in vivo experiments.Jpn J Pharmacol. 1984; 35: 203-227Crossref PubMed Scopus (232) Google Scholar]. Nafamostat mesilate also has direct inhibitory effects on platelet aggregation in contrast with heparin [2Fuse I. Higuchi W. Toba K. Aizawa Y. Inhibitory mechanism of human platelet aggregation by nafamostat mesilate.Platelets. 1999; 10: 212-218Crossref PubMed Scopus (13) Google Scholar]. Therefore, nafamostat mesilate should be effective in managing DIC associated with chronic aortic dissection, which is a common type of DIC with predominant fibrinolysis activation. Moreover, nafamostat mesilate does not require antithrombin III for its activities because of its competitive inhibition of coagulative enzymes, and the half-life of nafamostat mesilate in human circulating blood is shorter than that of heparin, which reduces the risk of hemorrhagic complications [4Miyahara S. Yasu T. Yamada Y. Kobayashi N. Saito M. Momomura S. Subcutaneous injection of heparin calcium controls chronic disseminated intravascular coagulation associated with inoperable dissecting aortic aneurysm in an outpatient clinic.Intern Med. 2007; 46: 727-732Crossref PubMed Scopus (13) Google Scholar]. Nafamostat mesilate is frequently used for treatment of DIC in Japan. Nafamostat mesilate is a synthetic protease-inhibiting agent that has potent inhibitory activity with respect to plasmin, thrombin, coagulation factors in the active form (Xlla, Xa), kalikrein, complement factor (C1r, C1s), and trypsin [1Aoyama T. Ino Y. Ozeki M. et al.Pharmacological studies of FUT-175, nafamostat mesilate I. inhibition of protease activity in in vitro and in vivo experiments.Jpn J Pharmacol. 1984; 35: 203-227Crossref PubMed Scopus (232) Google Scholar]. Nafamostat mesilate also inhibits platelet aggregation. An in vitro study showed that agonist-induced surface expression of activated glycoprotein IIb/IIIa was inhibited by nafamostat mesilate. Because this inhibitory effect was parallel with the inhibition of platelet aggregation, the main inhibitory mechanism of nafamostat mesilate against platelet aggregation seems to be the suppression of activated glycoprotein IIb/IIIa expression, which enables it to bind to fibrinogen [2Fuse I. Higuchi W. Toba K. Aizawa Y. Inhibitory mechanism of human platelet aggregation by nafamostat mesilate.Platelets. 1999; 10: 212-218Crossref PubMed Scopus (13) Google Scholar]. The balance of coagulation and fibrinolysis activation in DIC varies according to the underlying disease. In DIC with predominant coagulation activation, the plasma thrombin-antithrombin 3 complex levels are greatly increased, whereas the serum plasmin-α2-plasmin inhibitor complex levels are slightly increased. In DIC with predominant fibrinolysis activation, the plasma levels of both thrombin-antithrombin 3 complex and plasmin-α2-plasmin inhibitor complex are greatly increased and bleeding is a major clinical manifestation [3Asakura H. Saito M. Classification and treatment of DIC.Rinsho Ketsueki. 1995; 36: 314-319PubMed Google Scholar]. The DIC associated with chronic aortic dissection is commonly known as a type with predominant fibrinolysis activation and thrombin-antithrombin 3 complex and plasmin-α2-plasmin inhibitor complex levels are usually elevated, as in our case. We believe that repeated local thrombus formation at the dilated false lumen causes DIC associated with chronic aortic dissection, regardless of the extension of the thrombus. Repeated local thrombus formation at the dilated false lumen would result in the consumption of coagulation factors and platelets. Furthermore, locally activated fibrinolysis factors would spread through the systemic circulation, resulting in DIC with predominant fibrinolysis activation. Nafamostat mesilate exerts inhibitory effects on fibrinolysis, because it inhibits Xlla, kallikrein, and plasmin [1Aoyama T. Ino Y. Ozeki M. et al.Pharmacological studies of FUT-175, nafamostat mesilate I. inhibition of protease activity in in vitro and in vivo experiments.Jpn J Pharmacol. 1984; 35: 203-227Crossref PubMed Scopus (232) Google Scholar]. Nafamostat mesilate also has direct inhibitory effects on platelet aggregation in contrast with heparin [2Fuse I. Higuchi W. Toba K. Aizawa Y. Inhibitory mechanism of human platelet aggregation by nafamostat mesilate.Platelets. 1999; 10: 212-218Crossref PubMed Scopus (13) Google Scholar]. Therefore, nafamostat mesilate should be effective in managing DIC associated with chronic aortic dissection, which is a common type of DIC with predominant fibrinolysis activation. Moreover, nafamostat mesilate does not require antithrombin III for its activities because of its competitive inhibition of coagulative enzymes, and the half-life of nafamostat mesilate in human circulating blood is shorter than that of heparin, which reduces the risk of hemorrhagic complications [4Miyahara S. Yasu T. Yamada Y. Kobayashi N. Saito M. Momomura S. Subcutaneous injection of heparin calcium controls chronic disseminated intravascular coagulation associated with inoperable dissecting aortic aneurysm in an outpatient clinic.Intern Med. 2007; 46: 727-732Crossref PubMed Scopus (13) Google Scholar].