Summary:
The present work examines how human coagulation is influenced by gentamicin
(gentamicin×H2SO4), an often used aminoglycoside antibiotic in clinical practice. As a
potent broad-spectrum antibiotic, gentamicin is frequently used in life-threatening,
septic conditions, in which physiologic human coagulation is already affected in terms
of an increased tendency to a pathologic disseminated intravascular coagulation. The
influence of gentamicin on the generation of thrombin, the most important enzyme of
human coagulation, was analysed. 50 μl samples of N=139 unfrozen individual normal
platelet poor citrated plasmas and of N=11 unfrozen normal citrated plasma pools
were supplemented with the clinically relevant concentration of 0 to 19.6 mg/l of
gentamicin on microtiter plates. Instantly afterwards, the RECA (recalcified coagulation
activity assay) was performed. The important approximate 200% stimulatory
concentrations (approx. SC200) of gentamicin on thrombin generation were
determined in the clinically relevant ascending part of the coagulation reaction time
vs. thrombin generation curve. 5 normal plasmas supplemented with gentamicin as
well as with 0 IU/ml or 0.5 IU/ml of the low molecular weight heparin enoxaparinnatrium
were also analysed. 130 of 139 (94%) of the individual normal plasmas
triggered thrombin generation with an approx. SC200 of 2.0 ± 2.5 mg/l (MV ± 1SD).
Of the N=139 individual normal plasmas that were supplemented with up to 20 mg/l of
gentamicin, 6 of 139 (4%) were resistant towards gentamicin-triggered thrombin
generation. 3 of 139 (2 %) plasmas did not have an approx. 200% stimulatory
concentration, but had an approx. 50% inhibitory concentration of 1-2.5 mg/l of
gentamicin.
Gentamicin×H2SO4 triggers intrinsic coagulation and thus thrombin generation with
great inter-individual differences. A hemostatic monitoring and testing of the
individual sensibility to gentamicin is reasonable, especially in a critical pro-coagulant
situation like sepsis.
Bibliographie / References
- Müller-Berghaus G (1999) Hämostaseologie : molekulare und zelluläre Mechanismen, Pathophysiologie und Klinik ; mit 127 Tab., Springer, Berlin:269-284
- Pötzsch B, Gawaz MP (2010) Hämostaseologie [Grundlagen, Diagnostik, Therapie]; mit 163 Tabellen, Springer, Berlin, 2. Auflage:123-127
- Robinson S, Zincuk A, Larsen UL, Ekstrøm C, Nybo M, Rasmussen B, Toft P (2013) A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial. Crit Care 17:1-8
- Wolberg AS, Campbell RA (2008) Thrombin generation, fibrin clot formation and hemostasis. Transfus Apher Sci 38:15-23
- Semeraro N, Ammollo CT, Semeraro F, Colucci M (2012) Sepsis, thrombosis and organ dysfunction. Thromb Res 129:290-295
- Mosesson MW (2007) Update on antithrombin I (fibrin). Thromb Haemost 98:105-108
- Stief, TW (2009) Coagulation activation by lipopolysaccharides. Clin Appl Thromb Hemost 15:209-219
- Newby B, Prevost D, Lotocka-Reysner H (2009) Assessment of gentamicin 7 mg/kg once daily for pediatric patients with febrile neutropenia: a pilot project. J Oncol Pharm Pract 15:211-216
- Nakstad B, Haugen T, Skjønsberg OH, Lyberg T (1998) Expression of leukocyte integrins and tissue factor in mononuclear phagocytes. Eur Respir J 12:601-606
- Stief, TW (2008) Innovative Tests of Plasmatic Hemostasis. LabMedicine, 39:225-227
- Selimoglu E (2007) Aminoglycoside-induced ototoxicity. Curr Pharm Des 13:119-126
- Smid M, Dielis AW, Spronk HM, Rumley A, van Oerle R, Woodward M, Ten Cate H, Lowe G (2013) Thrombin generation in the glasgow myocardial infarction study. PLoS One 8:1-6
- Vogler EA, Siedlecki CA (2009) Contact activation of blood-plasma coagulation. Biomaterials 30:1857-1869
- Pacifici GM (2009) Clinical pharmacokinetics of aminoglycosides in the neonate: a review. Eur J Clin Pharmacol 65:419-427
- Aktories K, Forth W, Allgaier C (2009) Allgemeine und spezielle Pharmakologie und Toxikologie für Studenten der Medizin, Veterinärmedizin, Pharmazie, Chemie und Biologie sowie für Ärzte, Tierärzte und Apotheker ; mit 305 Tabellen. Elsevier, Urban & Fischer, München, 10. Auflage:818-823
- Sha SH, Qiu JH, Schacht J (2006) Aspirin to prevent gentamicin-induced hearing loss. N Engl J Med 354:1856-1857
- Altieri DC, Agbanyo FR, Plescia J, Ginsberg MH, Edgington TS, Plow EF (1990) A unique recognition site mediates the interaction of fibrinogen with the leukocyte integrin Mac-1 (CD11b/CD18). J Biol Chem 265:12119-12122
- Rand MD, Lock JB, van't Veer C, Gaffney DP, Mann KG (1996) Blood clotting in minimally altered whole blood. Blood 88:3432-3445
- Stypulkowska K, Blazewicz A, Fijalek Z, Sarna K (2010) Determination of Gentamicin Sulphate Composition and Related Substances in Pharmaceutical Preparations by LC with Charged Aerosol Detection. Chromatographia 72:1225-1229
- Akbayram S, Dogan M, Akgun C, Peker E, Parlak M, Oner AF (2011) Disseminated intravascular coagulation in a case of brucellosis. Clin Appl Thromb Hemost, United States, 17:E10-12
- Aly EE, Sivasubramaniam SK, Bhatti TH, Sanaka R (2009) Endotoxin-like reaction following once-daily gentamicin. Acta Anaesthesiol Scand 53:830-832
- Stief TW (2009) Enhancement of Thrombin Generation by Normal Thrombocytes. Hemostasis Laboratory 2:65-72
- Simon D, Rao N, Xu H, Wei Y, Majdic O, Ronne E, Kobzik L, Chapman H (1996) Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells., Blood 88:3185-3194
- Nagai J, Takano M (2004) Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity. Drug Metab Pharmacokinet 19:159-170
- Stief, TW (2008) The laboratory diagnosis of the pre-phase of pathologic disseminated intravascular coagulation. Hemostasis Laboratory, 1:3-19
- Siller-Matula JM, Schwameis M, Blann A, Mannhalter C, Jilma B (2011) Thrombin as a multi-functional enzyme. Focus on in vitro and in vivo effects. Thromb Haemost 106:1020-1033
- Stief, TW, Klingmüller, V, Müller-Stüler, EM (2011) Thrombin generation by diagnostic ultrasound. Hemostasis Laboratory, 4:335-363
- Naldini A, Aarden L, Pucci A, Bernini C, Carraro F (2003) Inhibition of interleukin-12 expression by alpha-thrombin in human peripheral blood mononuclear cells: a potential mechanism for modulating Th1/Th2 responses. Br J Pharmacol 140:980-986
- Sakurai S, Shiojima I, Tanigawa T, Nakahara K (1997) Aminoglycosides prevent and dissociate the aggregation of platelets in patients with EDTA-dependent pseudothrombocytopenia. Br J Haematol 99:817-823
- Wada H, Hatada T, Okamoto K, Uchiyama T, Kawasugi K, Mayumi T, Gando S, Kushimoto S, Seki Y, Madoiwa S, Okamura T, Toh CH, subcommittee JSoTHD (2010) Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC. Am J Hematol 85:691-694
- Van Montfoort ML, Meijers JC (2013) Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway? Thromb Haemost 110:223-232
- Simon DI, Ezratty AM, Francis SA, Rennke H, Loscalzo J (1993) Fibrin(ogen) is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway. Blood 82:2414-2422
- Perez RL, Roman J (1995) Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation. J Immunol 154:1879-1887
- Undas A, Brummel-Ziedins KE, Mann KG (2007) Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 109:2285-2292
- Soifer SJ, Peters KG, O'Keefe J, Coughlin SR (1994) Disparate temporal expression of the prothrombin and thrombin receptor genes during mouse development. Am J Pathol 144:60-69
- Rourke T (2007) Aminoglycoside ototoxicity: How practical is this genetic screening test? BMJ 335:952
- Renné T, Pozgajová M, Grüner S, Schuh K, Pauer HU, Burfeind P, Gailani D, Nieswandt B (2005) Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 202:271-281
- Roth SM, Williams SM, Jiang L, Menon KS, Jeka JJ (2008) Susceptibility genes for gentamicin-induced vestibular dysfunction. J Vestib Res 18:59-68
- Ward K, Theiler RN (2008) Once-daily dosing of gentamicin in obstetrics and gynecology. Clin Obstet Gynecol 51:498-506
- Wright SD, Weitz JI, Huang AJ, Levin SM, Silverstein SC, Loike JD (1988) Complement receptor type three (CD11b/CD18) of human polymorphonuclear leukocytes recognizes fibrinogen. Proc Natl Acad Sci U S A 85:7734-7738
- Pierfranceschi MG, Imberti D, Orlando S, Vallisa D, Michieletti E (2011) Effectiveness of recombinant activated factor VII in haemorragic cancer-related disseminated intravascular coagulation: a case report. Blood Transfus 9:336-338
- Revenko AS, Gao D, Crosby JR, Bhattacharjee G, Zhao C, May C, Gailani D, Monia BP, MacLeod AR (2011) Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood 118:5302-5311
- Spronk HM, van der Voort D, Ten Cate H (2004) Blood coagulation and the risk of atherothrombosis: a complex relationship. Thromb J 2:1-10
- Puetz J (2010) Optimal use of recombinant factor VIIa in the control of bleeding episodes in hemophilic patients. Drug Des Devel Ther 4:127-137
- Santos LH, Araujo AN, Reis B, Montenegro MC (2010) Development of a multicommutated flow system with chemiluminometric detection for quantification of gentamicin in pharmaceuticals. J Autom Methods Manag Chem 2010:1-7