Vitamin K und medikamenteninduzierte Hypoprothrombinämie

H. Bechtold; K. Andrassy

doi:10.1055/s-0038-1659943

Hämostaseologie, Inhaltsverzeichnis

Hamostaseologie 1988; 08(01): 8-17
DOI: 10.1055/s-0038-1659943

Originalarbeiten

Schattauer GmbH

Vitamin K und medikamenteninduzierte Hypoprothrombinämie

H. Bechtold

^*Caritaskrankenhaus, Bad Mergentheim

,

K. Andrassy

^**Medizinische Universitäts-Klinik, Heidelberg

› Institutsangaben

Abstract

Zusammenfassung

Aus den vorliegenden Untersuchungen und aus den Mitteilungen der Literatur läßt sich auf die Bedeutung folgender zwei Faktoren für die Genese der Cephalosporin-induzierten HP schlieβen:

1. Latenter Vitamin-K-Mangelzustand des Organismus durch fehlende oder reduzierte exogene Vitamin-K-Zufuhr (z.B. bei ausschlieβlich parenteraler Ernährung) und möglicherweise durch Unterdrückung der Vitamin-K₂-produzie-renden (Dünn-)Darmflora.

2. Kumarinartige Hemmung des Vit-amin-K₁Stoffwechsels in der Leber durch bestimmte Cephalosporine (z.B. NMTT-Cephalosporine).

Das Zusammenwirken dieser Faktoren führt funktionell zu einem manifesten Vitamin-K-Mangelzustand, erkenntlich an einem Abfall der Vitamin-K-abhängigen Gerinnungsfaktoren. Aufgrund dieses Mechanismus ist es verständlich, daß die Cephalosporin-induzierte HP durch prophylaktische Vitamin-K₁Gaben verhindert (ca. 10 mg Vitamin K₁ pro Woche) bzw. eine manifeste HP korrigiert werden kann.

Der Vollständigkeit halber sei auf die hier nicht näher erläuterten Anta-bus®-ähnlichen Reaktionen nach Alkoholzufuhr hingewiesen, die - in Analogie zu der kumarinartigen Hemmung des Vitamin-K₁Stoffwechsels -ebenfalls die Gruppe der NMTT- und MTD-Cephalosporine betreffen und durch entsprechende Alkoholkarenz vermeidbar sind (60).

Volltext

Referenzen

Literatur
1 Andrassy K, Bechtold H, Ritz E. Hypoprothrom-binemia caused by cephalosporins. J Antimicrob Chemother 1985; 15: 133-6.
2 Ansell J.E, Kumar R, Deykin D. The spectrum of vitamin K deficiency. JAMA 1977; 238: 40-2.
3 Aronoff G.R, Wolen R.L, Obermeyer B.D, Black H.R. Pharmacokinetics and protein binding of cefamandole and its 1-methyl-1-H-tetrazole-5-thiol side chain in subjects with normal and impaired renal function. J Infect Dis 1986; 153: 1069-74.
4 Arvidsson A, Gunnar A, Angelin B, Borga O, Nord C.E. Ceftriaxone: renal and biliary excretion and effect on the colon microflora. J Antimicrob Chemother 1982; 10: 207-15.
5 Balant L, Dayer P, Auckenthaler R. Clinical pharmacokinetics of the third generation cephalosporins. Clin Pharmacokinet 1985; 10: 101-43.
6 Bang N.U, Tessler S.S, Heiderich R.O, Marks C.A, Mattler L.E. Effects of moxalactam on blood coagulation and platelet function. Rev Infect Dis 1982; 4 Suppl 546-54.
7 Bang N.U, Kammer R.B. Hematologic complications associated with β-lactam antibiotics. Rev Infect Dis 1983; 5 (Suppl. 02) 380-93.
8 Barckow D, Schirop T, Schwigon C.D. Blutgerinnungsstörungen bei Intensivpatienten unter Therapie mit Cephalosporinen. Intensivmed 1984; 21: 162-4.
9 Barrow M.V, Quick D.T, Cunningham R.W. Salicylate hypothrombinemia in rheumatoid arthritis with liver disease. Arch Intern Med 1967; 120: 620-4.
10 Bechtold H. Untersuchungen zum Vitamin-K₁ Stoffwechsel beim Menschen - Beziehung zur hypoprothrombinämischen Wirkung von Phen-procoumon, Acetylsalicylsäure und neueren Cephalosporinen. Habilitationsschrift, Universität Mainz 1985.
11 Bechtold H, Andrassy K, Jähnchen E, Koderisch J, Koderisch H, Weilemann L, Sonntag H, Ritz E. Evidence for impaired hepatic vitamin K₁ metabolism in patients treated with N-methyl-thiotetrazole cephalosporins. Thromb Haemost 1984; 51: 358-61.
12 Bechtold H, Andrassy K, Koderisch J, Trenk D, Sonntag H, Jähnchen E. Coumarin-like inhibition of vitamin K metabolism by N-methyl-thiotetrazole cephalosporins - influence of the chemical structure of the side-chain. Haemosta-sis; Recent Advances and New Developments in Haemostaseology, 4th Congress of the Society on Thrombosis and Haemostasis, Düsseldorf 1986; A 157, p 117.
13 Bechtold H, Andrassy K, Koderisch J, Trenk D, Sonntag H. Cumarinartige Hemmung des Vitamin-K₁-Stoffwechsels durch strukturell unterschiedliche Cephalosporine. Fortschr antimikr antineoplast Chemother 1987; 6-4: 609-22.
14 Bechtold H, Lorenz J, Weilemann L.S, Meinertz T, Trenk D, Andrassy K, Jähnchen E. Possible coumarin-like mechanism of action for cephalosporins. Klin Wschr 1984; 62: 885-6.
15 Bechtold H, Trenk D, Jähnchen E, Meinertz T. Plasma vitamin K₁ 2,3-epoxide as diagnostic aid to detect surreptitious ingestion of oral anticoagulant drugs. Lancet 1983; I: 595-7.
16 Bechtold H, Trenk D, Meinertz T, Rowland M, Jähnchen E. Cyclic interconversion of vitamin K₁ and vitamin K₁-2,3-epoxide in man. Br J Clin Pharmacol 1983; 16: 683-9.
17 Bechtold H, Trenk D, Meinertz T, Jähnchen E. Effect of salicylate on the vitamin K₁ metabolism in man. Naunyn-Schmiedebergs Arch Pharmacol 1984; 325 (Suppl): R12, A 48.
18 Bell R.G. Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin epoxide cycle. Fed Proc 1978; 37: 2599-604.
19 Bell R.G, Matschiner J.T. Warfarin and the inhibition of vitamin K activity by an oxide metabolite. Nature 1972; 237: 32-3.
20 Bjornssen T.D, Meffin R.J, Swezey S.E, Blaschke T.F. Effects of Clofibrate and warfarin alone and in combination on the disposition of vitamin K₁ . J Pharmacol Exp Ther 1979; 210: 322-6.
21 Black H.R, Buening M.K, Wolen R.L. Lata-moxef, its side chain, and coagulation. Lancet 1983; II: 1090.
22 Bruch K. Hypoprothrombinaemia and cephalosporins. Lancet 1983; I: 535-6.
23 Caldwell P.T, Ren P, Bell R.G. Warfarin and metabolism of vitamin K₁ . Biochem Pharmacol 1974; 23: 3353-62.
24 Clouse L.H, Comp P.C. The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314: 1298-304.
25 Conly J.M, Ramotar K, Chubb H, Bow E.Y, Louie T.J. Hypoprothrombinemia in febrile, neutropenic patients with cancer: association with antimicrobial suppression of intestinal microflora. J Infect Dis 1984; 150: 202-12.
26 Creedon K.A, McTigue J.J, Engelke J.A, Suttie J.W. Antibiotic induced hypoprothrombinemia: effect of NMTT on vitamin K-dependent reactions. Thromb Haemost 1985; 54: 150 (A 888)
27 Creedon K.A, Suttie J.W. Effect of N-methyl-thiotetrazole on vitamin K in epoxide reductase. Thrombos Res 1986; 44: 147-53.
28 Dam H. The antihaemorrhagic vitamin of the chick. Biochem J 1935; 29: 1273-85.
29 Dam H, Søndegaard E, Olson R.E. Vitamin K. In: Barker B.M, Bender D.A. (eds) Vitamin in Medicine. 4th ed. London: Heinemann; 1982: 92-113.
30 Frick P.G, Riedeler G, Brogli H. Dose response and minimal daily requirement for vitamin K in man. J Appl Physiol 1967; 23: 387-9.
31 Friedman P.A. Vitamin-K-dependent proteins. N Engl J Med 1984; 310: 1458-60.
32 Gallop P.M, Lian J.B, Hauschka P.V. Carboxyla-ted calcium-binding proteins and vitamin K. New Engl J Med 1980; 302: 1460-6.
33 Ganrot P.O, Niléhn J-E. Plasma prothrombin during treatment with dicumarol. II. Demonstration of an abnormal prothrombin fraction. Scand J Clin Lab Invest 1968; 22: 23-8.
34 Graham G.G, Champion G.D, Day R.O.P, Pauli P.D. Patterns of plasma concentrations and urinary excretion of salicylate in rheumatoid arthritis. Clin Pharmacol Ther 1977; 22: 410-20.
35 Ham J. Hypoprothrombinemia in patients undergoing prolonged intensive care. Med J Austr 1971; 2: 716-9.
36 Hauschka P.V. Osteocalcin in developing bone systems. In: Suttie J.W. Vitamin K Metabolism and Vitamin K-Dependent Proteins. Baltimore: University Park Press; 1979: 227-36.
37 Hemker H.C, Veltkamp J.J, Hensen A, Loeliger E.A. Nature of prothrombin biosynthesis: pre-prothrombinaemia in vitamin K deficiency. Nature 1963; 200: 589-90.
38 Hildebrandt E.F, Suttie J.W. The effects of salicylate on enzymes of vitamin K metabolism. J Pharm Pharmacol 1983; 35: 421-6.
39 Hildebrand E, Suttie J.W. Indirect inhibition of vitamin K epoxide reduction by salicylate. J Pharm Pharmacol 1984; 36: 586-91.
40 Hochman R, Ciak J, Rolla A, Thomas S, Kaldany A, D’Elia J.A. Bleeding in patients with infections. Are antibiotics helping or hurting?. Arch Int Med 1982; 142: 1440-2.
41 Howard J.B, Nelsestuen G.L. Isolation and characterization of vitamin K-dependent region of bovine blood clotting factor X. Proc Natl Acad Sci USA 1975; 72: 1281-5.
42 Kager L, Malborg A.S, Nord C.E, Pieper R. The effect of short-term cefoxitin prophylaxis on the colonic microflora in patients undergoing colorectal surgery. Infection 1982; 10: 338-40.
43 Kerremans A.L, Lipsky J.J, van Loon J, Gallego M.O, Weishilboum R.M. Cephalosporin-induced hypoprothrombinemia: possible role for thiol methylation of 1-methyltetrazole-5-thiol and 2-methyl-1,2,4-thiadiazole-5-thiol. J Pharmacol Exp Ther 1985; 235: 382-8.
44 Langenberg J.P. Bioanalysis of ultra-trace levels of K vitamins using electrofluorometric detection in HPLC. The influence of the variable vitamin K availability from normal diets on the stability of the oral anticoagulant therapy. Dissertation, Universität Leiden 1985.
45 Langenberg J.P, Tjaden U.R. Determination of (endogenous) vitamin K₁ in human plasma by reversed-phase high performance liquid chromatography using fluorometric detection after post-column electrochemical reduction. J Chromatogr 1984; 305: 61-72.
46 Larson A.E, Suttie J.W. Vitamin K-dependent carboxylase: evidence for a hydroperoxidase intermediate in the reaction. Proc Natl Acad Sci 1978; 75: 5413-6.
47 Link K.P. The discovery of dicoumarol and its sequels. Circulation 1959; 19: 97-107.
48 Lipsky J.J. N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic associated hypoprothrombinemia. Lancet 1983; II: 192-3.
49 Lipsky J.J. Mechanisms of the inhibition of the y-carboxylation of glutamic acid by N-methylthiote-trazole-containing antibiotics. Proc Natl Acad Sci 1984; 81: 2893-7.
50 Lipsky J.J, Lewis J.C, Novick W. Production of hypoprothrombinemia by moxalactam and 1-me-thyl-5-thiotetrazole in rats. J Antimicrob Chemother 1984; 25: 380-1.
51 Lipsky J.J, Lewis J.C, Novick Jr W.J. Production of hypoprothrombinemia by cefazolin and 2-methyl-1,3,4-thiadiazole-5-thiol in the rat. J Antimicrob Chemother 1986; 18: 131-7.
52 Lowenthal J, MacFarlane J.A. The nature of the antagonism between vitamin K and indirect anticoagulants. J Pharmacol Exp Ther 1963; 143: 273-7.
53 Magnusson S, Sottrup-Jensen L, Petersen T.E, Morris H.R, Dell A. Primary structure of the vitamin K-dependent part of prothrombin. FEBS Lett 1974; 44: 189-93.
54 Mandel H.G, Cohn V.H. Fat soluble vitamins. Vitamin A, K and E. In: Gilman A.G, Goodman L.S, Rail T.W, Murad F. (eds) The Pharmacological Basis of Therapeutics. New York: MacMillan; 1985: 1582-6.
55 Matschiner J.T, Bell R.G, Amelotti J.M, Knauer T.E. Isolation and characterization of a new metabolite of phylloquinone in the rat. Biochim Biophys Acta 1970; 201: 309-15.
56 McCarthy P.T, Shearer M.J, Gau G, Crampton O.E, Barkhan P. Vitamin K content of human liver at different ages. In: Sutor A.H, Künzer W. (eds) Physiologie und Pathophysiologie des Vitamin K. Basel/Grenzach-Wyhlen: Editiones Roche; 1986: 95-104.
57 Menge H. Sind Bakterien im Dünndarm pathogen und behandlungsbedürftig?. Leber Magen Darm 1986; 2: 82-92.
58 Ñatelson E, Brown C, Bradshaw W, Alfrey C, Williams T. Influence of cephalosporin antibiotics on blood coagulation and platelet function. Antimicrob Agents Chemother 1976; 9: 91-3.
59 Nelsestuen G, Zytkovicz T.H, Howard J.B. The mode of action of vitamin K. Identification of γ-carboxyglutamin acid as a component of prothrombin. J Biol Chem 1974; 249: 6347-50.
60 Neu H.C. Adverse effects of new cephalosporins. Ann Int Med 1983; 98: 415-6.
61 Olson R.E. The function and metabolism of vitamin K. Ann Rev Nutr 1984; 4: 281-337.
62 O’Reilly R.A. Vitamin K and the oral anticoagulant drugs. Ann Rev Med 1976; 27: 245-61.
63 O’Reilly R.A. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman A.G, Goodman L.S, Rail T.W, Murad F. (eds) The Pharmacological Basis of Therapeutics. New York: MacMillan; 1985: 1338-59.
64 Owens M.R, Cimino C.D. The interaction of salicylate and vitamin K in synthesis of factor II (prothrombin). Thromb Res 1983; 31: 135-43.
65 Pabinger-Fasching I. Protein C, ein in der Leber gebildeter Gerinnungsinhibitor. Hämostaseologie 1984; 2: 50-3.
66 Park B.K, Leck J.B. On the mechanisms of salicylate-induced hypoprothrombinemia. J Pharm Pharmacol 1981; 33: 25-8.
67 Park B.K, Wilson A.C, Kaatz G, Ohnhaus E.E. Enzyme induction by phenobarbitone and vitamin K, disposition in man. Br J Clin Pharmacol 1984; 18: 94-7.
68 Park B.K, Scott A.K, Wilson A.C, Haynes B.P, Beckenridge A.M. Plasma disposition of vitamin K₁ in relation to anticoagulant poisoning. Br J Clin Pharmacol 1984; 18: 655-62.
69 Pineo G.F, Gallus A.S, Hirsch J. Unexpected vitamin K deficiency in hospitalized patients. Can Med Assoc J 1973; 109: 880-3.
70 Price P.A, Epstein D.J, Lothringer J.W, Nishimoto S.K, Poser J.W, Williamson M.K. Structure and function of the vitamin K-dependent protein of bone. In: Suttie J.W. Vitamin K Metabolism and Vitamin K-Dependent Proteins. Baltimore: University Park Press; 1979: 219-26.
71 Romatar K, Conly J.M, Chubb H, Louie T.J. Production of menaquinones by intestinal anaerobes. J Infect Dis 1984; 150: 213-8.
72 Rothschild B.M. Hematologic perturbations associated with salicylate. Clin Pharmacol Ther 1979; 26: 145-52.
73 Sadowski J.A, Suttie J.W. Mechanism of action of coumarins. Significance of vitamin K epoxide. Biochemistry 1974; 13: 3696-9.
74 Sattler F.R, Weitekamp M.R, Bllard J.O. Potential bleeding with the new beta-lactam antibiotics. Ann Int Med 1986; 105: 924-31.
75 Shah D.V, Suttie J.W. Mechanism of action of vitamin K: evidence for the conversion of a precursor protein to prothrombin in the rat. Proc Natl Acad Sci 1971; 68: 1653-7.
76 Shearer M.J, Allan V.E, Haroon Y, Barkhan P. Nutritional aspects of vitamin K in the human. In: Suttie J.W. Vitamin K Metabolism and Vitamin K-Dependent Proteins. Baltimore: University Park Press; 1979: 317-27.
77 Shearer M.J, BcBurney A, Barkhan P. Studies over the absorption and metabolism of phylloqui-none (Vitamin K₁) in man. Vitam Horm 1974; 32: 513-42.
78 Shearer M.J, Crampton O.E, McCarthy P.T, Mattock M.B. Vitamin K in plasma: measurement and relationship to vitamin K status, age, pregnancy, diet and disease. In: Sutor A.H, Künzer W. (eds) Physiologie und Pathophysiologie des Vitamin K. Basel/Grenzach-Wyhlen: Editiones Roche; 1986: 95-104.
79 Shearer M.J, Rahim S, Barkhan P, Stimmler L. Plasma vitamin K₁ in mothers and their newborn babies. Lancet 1982; II: 460-3.
80 Smith C.R, Lipsky J.J. Hypoprothrombinemia and platelet dysfunction caused by cephalosporin and moxalactam antibiotics. J Antimicrob Chemother 1983; 11: 496-9.
81 Smith G, Sundboom J. The effects of 1-methyl-5-thiotetrazole in a rat liver vitamin K-dependent carboxylase assay. Thromb Res 1984; 33: 633-44.
82 Stenflo J. Structure and function of protein C. Semin Thromb Haemost 1984; 10: 109-21.
83 Sunakawa K, Akita H, Iwata S, Sato Y. The influence of cefotaxime on intestinal flora and bleeding diathesis in infants and neonates, compared with other β-lactams. J Antimicrob Chemother 1984; 14(Suppl B): 317-24.
84 Suttie J.W. The fat-soluble vitamins. In: DeLuca H.F. Handbook of Lipid Research, Vol. 2. New York, London: Plenum Press; 1978: 211-77.
85 Suttie J.W. Mechanism of action of vitamin K: demonstration of a liver precursor of prothrombin. Science 1973; 179: 192-4.
86 Suttie J.W. Mechanism of action of vitamin K: Synthesis of γ-carboxyglutamic acid. CRC Crit Rev Biochem 1980; 8: 191-223.
87 Suttie J.W, Jackson C.M. Prothrombin structure, activation and biosynthesis. Physiol Rev 1977; 57: 1-70.
88 Uchida K, Ishigami T, Komeno T. Effects of latamoxef and methyltetrazolethiol on gamma-glutamylcarboxylase activity. Jpn J Pharmacol 1984; 35: 330-3.
89 Uchida K, Ishigami T, Matsubara T, Narisada M. Effects of N-methyltetrazolethiol (NMTT) and NMTT containing antibiotics on γ-glutamylcarbo-xylation. 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington 1984 (abstr).
90 Uchida K, Komeno T. Relationship between dietary and intestinal vitamin K’s, clotting factor levels, plasma vitamin K and urinary Gla. Proceedings of the 17th Steenbock Symposium “Current Advances in Vitamin K Research”. University of Wisconsin-Madison. June 21-25, Madison (USA) 1987 (in press).
91 Uchida K, Nomura Y, Takase T, Harauchi T, Yoshizaki T, Nakao H. Effects of fasting and vitamin K deficient diets on blood coagulation factors on conventional and germ-free rats. Thromb Res 1985; 39: 741-50.
92 Udall J.A. Human sources and absorption of vitamin K in relation to anticoagulant stability. JAMA 1965; 194: 107-9.
93 Uotila L, Suttie J.W. Recent findings in understanding the biological function of vitamin K. Med Biol 1982; 60: 16-24.
94 Uotila L, Suttie J.W. Inhibition of vitamin K-dependent carboxylase in vitro by cefamandole and its structural analogs. J Infect Dis 1983; 148: 571-8.
95 Wallin R, Martin F. Vitamin K-dependent carbo-xylation and vitamin K metabolism in liver - effects of warfarin. J Clin Invest 1985; 76: 1879-84.
96 Wessler S, Gitel S.N. Warfarin - from bedside to bench. N Engl J Med 1984; 311: 645-52.
97 Whitlon D.S, Sadowski J.A, Suttie J.W. Mechanism of cumariri action : significance of vitamin K epoxide reductase inhibition. Biochem 1978; 17: 1371-7.
98 Willingham A.K, Matschiner J.T. Changes in phylloquinone epoxide activity related to prothrombin synthesis and microsomal clotting activity in the rat. Biochem J 1974; 140: 435-41.
99 Wise R, Dent J. Stability of β-lactam antibiotics containing N-methylthiotetrazole side-chain. Lancet 1983; II: 624-5.
100 Zaugg H. Sind salicylartige Analgetika Vitamin-K-Antagonisten?. Eine Deutung der spontanen subnormalen Quickwerte. Schweiz Med Wschr 1978; 108: 1277-8.
101 Zbinden G, Schärer K, Studer A. Experimentelle Untersuchungen über Erythrozytenschädigung durch Menadionderivate im Vergleich zu Vitamin K₁ . Schweiz Med Wschr 1957; 87: 1238.