Download PDF
Thromb Haemost 1998; 79(02): 342-347
DOI: 10.1055/s-0037-1614989
Letters to the Editor
Schattauer GmbH

The Influence of a Serine Protease Inhibitor, Nafamostat Mesilate, on Plasma Coagulation, and Platelet Activation during Experimental Extracorporeal Life Support (ECLS)

Karin Mellgren
1   From the Departments of Paediatrics (Division for Paediatrics)
,
Maria Skogby
2   From the Anaesthesiology (Division for Paediatric Anaesthesiology)
,
Lars Göran Friberg
3   From the Department of Paediatrics (Division for Paediatric Surgery)
,
Lilian Tengborn
4   From the Internal Medicine, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
,
Hans Wadenvik
4   From the Internal Medicine, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
› Author Affiliations
Further Information

Publication History

Received 24 February 1997

Accepted after resubmission 25 September 1997

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

Introduction: During extracorporeal circulation the contact between blood and the artificial surface of the circuit induces several changes in the hemostatic system. The objective of the present study was to assess the effect of a serine protease inhibitor – Nafamostat mesilate (FUT-175) – on coagulation and on platelets during experimental extracorpo-real circulation. Methods: Two identical Extra Corporeal Life Support (ECLS) circuits were primed with fresh, heparinized human blood and circulated for 24 h. FUT-175 was added to one of the paired circuits and the other was used as a control. The following FUT-175 concentrations were employed: (1) 7.1 mg/l/h, (2) 14.2 mg/l/h, (3) 14.2 mg/l/h + 85.5 mg given as an initial bolus, (4) 28.5 mg/l/h + 171 mg given as an initial bolus. Blood samples were collected from the circuits before the start of the perfusion and at 0.5, 1, 3, 12, and 24 h of perfusion, and analysed for platelet count, plasma betathromboglobulin ( -TG), platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa expression, thrombin/ antithrombin III complex (TAT), prothrombin fragment 1+2 (F1+2), fibrinogen, D-dimer, and plasminogen activator inhibitor 1 activity (PAI-1). Results: Significantly higher platelet membrane GPIb expression and lower plasma -thromboglobulin levels were observed in the circuits holding FUT-175, suggesting a lower degree of platelet activation. Also, a reduced activation of the coagulation system was observed in the “FUT-circuits”, as reflected by the levels of F1+2 and TAT, and the PAI-1 activity that was rapidly inactivated. Conclusion: FUT-175 reduces the activation of platelets and plasma coagulation in an in vitro ECLS model.

 

  • References

  • 1 Plötz FB, van Oeveren W, Bartlett RH, Wildevuur CRH. Blood activation during neonatal extra corporeal life support. J Thorac Cardiovasc Surg 1993; 105: 823-32.
    CrossrefPubMedGoogle Scholar
  • 2 Woodman RC, Harker LA. Bleeding complications associated with cardio-pulmonary bypass. Blood 1990; 76: 1680-97.
    PubMedGoogle Scholar
  • 3 Zwichenberger JB, Nguyen TT, Upp JR. et al. Complications of neonatal extracorporeal membrane oxygenation: Collective experience from the Extra corporeal Life Support Organisation. J Thorac Cardiovasc Surg 1994; 107: 838-49.
    PubMedGoogle Scholar
  • 4 Moront MG, Katz NM, Keszler M. et al. Extracorporeal membrane oxygenation for neonatal respiratory failure: a report of 50 cases. J Thorac Cardiovasc Surg 1989; 97: 706-14.
    PubMedGoogle Scholar
  • 5 Harker LA, Malpass TW, Branson HE, Hessel II EA, Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: Acquired transient platelet dysfunction associated with selective alpha-granule release. Blood 1980; 56: 824-33.
    PubMedGoogle Scholar
  • 6 Mellgren K, Friberg LG, Hedner T, Mellgren G, Wadenvik H. Blood platelet activation and membrane glycoprotein changes during extracorporeal life support (ECLS). In vitro studies. Int J Artif Organs 1995; 18: 315-21.
    CrossrefPubMedGoogle Scholar
  • 7 Rinder CS, Gaal D, Student LA, Smith BR. Platelet-leukocyte activation and modulation of adhesion receptors in paediatric patients with congenital heart disease undergoing cardiopulmonary bypass. J Thorac Surg 1994; 107: 280-8.
    PubMedGoogle Scholar
  • 8 Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman RW, Edmunds Jr LH. Aprotinin inhibits the contact, neutrophil, and plate-let activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993; 106: 1-10.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Tanaka K, Kondo C, Takagi I, Sato T, Yada I, Yvasa H, Kusagawa M. Effects of nafamostat mesilate on platelets and coagulofibrinolysis during cardiopulmonary bypass surgery. ASAIO J 1993; 39: M545-9.
    PubMedGoogle Scholar
  • 10 Sundaram S, Gikakis N, Hack E, Niewiarowski S, Edmunds Jr. LH, Rao A, Sun L, Cooper SL, Colman R. Nafamostat Mesilate, a broad spectrum protease inhibitor, modulates platelet, neutrophil and contact activation in simulated extracorporeal circulation. Thromb Haemost 1996; 75: 76-82.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Swolin B, Roberts D, Waldenström J. Quantitative determination of plasma haemoglobin using dicarboxidine. Clin Chim Acta 1982; 121: 389-91.
    CrossrefPubMedGoogle Scholar
  • 12 Clauss A. Rapid physiological coagulation method for the determination of fibrinogen. Acta Haematol 1957; 17: 237-46.
    CrossrefPubMedGoogle Scholar
  • 13 Sawa Y, Shimazaka Y, Kadoba K, Masai T, Fukuda H, Ohata T, Taniguchi K, Matsuda H. Attenuation of cardiopulmonary bypass-derived inflammatory reactions reduces myocardial reperfusion injury in cardiac operations. J Thorac Cardiovasc Surg 1996; 111: 29-35.
    CrossrefPubMedGoogle Scholar
  • 14 Murase M, Usui A, Tomita Y, Maeda M, Koyama T, Abe T. Nafamostat mesilate reduces blood loss during open heart surgery. Circulation 1993; 88: 432-6.
    PubMedGoogle Scholar
  • 15 Akizava T, Koshikawa S, Ota K, Kazama M, Mimura N, Hirasawa Y. Nafamostat Mesilate; A regional anticoagulant for hemodialysis in patients at high risk for bleeding. Nephron 1993; 64: 376.
    CrossrefPubMedGoogle Scholar
  • 16 Okamoto T, Chung YK, Choi H, Terasaki H, Morioka T. Experimental results using nafamostat mesilate as anticoagulant during extracorporeal lung assist for 24 hours in dogs. Artif Organs 1993; 17: 30-5.
    PubMedGoogle Scholar
  • 17 Coller BS, Kalomiris E, Steinberg M, Scudder LE. Evidence that glycocalicin circulates in normal plasma. J Clin Invest 1984; 73: 794-9.
    CrossrefPubMedGoogle Scholar
  • 18 Wachtfogel YT, Bischoff R, Bauer R, Hack CE, Nuijens JH, Kucich U, Niewiarowski S, Edmunds Jr LH, Colman RW. 1-Antitrypsin Pittsburgh (Met358 Arg) inhibits the contact pathway of intrinsic coagulation and alters the release of human neutrophil elastase during simulated extracorpo-real circulation. Thromb Haemost 1994; 72: 843-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 George JN, Pickett EB, Saucerman S, McEver RP, Kunicki TJ, Kieffer N, Newman PJ. Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects and observations in patients during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 1986; 78: 340-8.
    CrossrefPubMedGoogle Scholar
  • 20 Michelson AD, Adelman B, Barnard MR, Carroll E, Handin RI. Platelet storage result in a redistribution of glycoprotein Ib molecules. Evidence for a large pool of glycoprotein Ib. J Clin Invest 1988; 81: 1734-40.
    CrossrefPubMedGoogle Scholar
  • 21 Mellgren K, Friberg LG, Mellgren G, Hedner T, Wennmalm Å, Wadenvik H. Nitric oxide in the oxygenator sweep gas reduces platelet activation during experimental perfusion. Ann Thorac Surg 1996; 61: 1194-8.
    CrossrefPubMedGoogle Scholar
  • 22 Mellgren K. The platelets in extracorporeal circulation. Thesis. Vasastadens bokbinderi. Göteborg: 1997
    Google Scholar
  • 23 van Meijer M. Structure of plasminogen activator inhibitor 1 (PAI-1) and its function in fibrinolysis: an update. Fibrinolysis 1995; 9: 263-76.
    PubMedGoogle Scholar
  • 24 Fink SM, Bockman DE, Howell CG, Falls DG, Kanto Jr WP. Bypass circuit as the source of thromboemboli during extracorporeal membrane oxygenation. J Pediatr 1989; 115: 621-4.
    CrossrefPubMedGoogle Scholar
  • 25 Wachtfogel YT, Harpel PC, Edmunds Jr LH, Colman RW. Formation of C1s-C1-inhibitor, kallikrein-C1-inhibitor, and plasmin-alpha 2-plasmin-inhibitor complexes during cardiopulmonary bypass. Blood 1989; 73: 468-71.
    PubMedGoogle Scholar
  • 26 Wachtfogel YT, Hack CE, Nuijens JH, Kettner CK, Reilly TM, Knabb RM, Bishoff R, Tschesche H, Wenzel H, Kucich U, Edmunds Jr LH, Colman RW. Selective kallikrein inhibitors alter human neutrophil elastase release during extracorporeal circulation. Am J Physiol 1995; 268: H1352-7.
    PubMedGoogle Scholar
  • 27 Colman RW. Activation of plasminogen by human plasma kallikrein. Biochem Biophys Res Commun 1969; 35: 273-9.
    CrossrefPubMedGoogle Scholar