Download PDF
Thromb Haemost 1976; 36(01): 115-126
DOI: 10.1055/s-0038-1648015
Original Article
Schattauer GmbH

Bleeding in Uremic Patients after Carbenicillin[*]

K Andrassy   **
1   Medizinische Universitätsklinik (Ludolf-Krehl-Klinik), D 6900 Heidelberg (Germany)
,
E Weischedel
1   Medizinische Universitätsklinik (Ludolf-Krehl-Klinik), D 6900 Heidelberg (Germany)
,
E Ritz
1   Medizinische Universitätsklinik (Ludolf-Krehl-Klinik), D 6900 Heidelberg (Germany)
,
T Andrassy
1   Medizinische Universitätsklinik (Ludolf-Krehl-Klinik), D 6900 Heidelberg (Germany)
› Author Affiliations
Further Information

Publication History

Received 06 November 1975

Accepted 28 April 1976

Publication Date:
03 July 2018 (online)

Also available at
    Permissions and Reprints

Summary

Hemorrhagic diathesis was observed in patients with renal insufficiency after carbenicillin at serum levels > 300 μg/ml. Normal coagulation factors (F. I, II, V, VII, VIII, X), normal PTT, normal platelet counts, negative ethanol gelation test (fibrin monomers) were found as well as a prolongation of thromboplastin time (Quick), thrombin time, reptilase time and thrombin coagulase time. Platelet function was disturbed. In addition, the plasmatic system was involved: inhibition of fibrinogen-fibrin conversion (Belitser assay) and enhanced antithrombin III activity; in vivo the latter was ascribed to a heparin-like activity. In vitro, abnormal fibrinogen-fibrin conversion and a modified electrophoretic mobility of antithrombin III was seen: however an enhanced antithrombin III activity in vitro was not found with carbenicillin and various penicillin derivatives.

This study demonstrates that carbenicillin, in addition to its known effect on platelet function, also disturbs the plasmatic coagulation system. This additional effect of carbenicillin is clinically important since protamin chloride effectively blocks bleeding without interfering with antibacterial activity.

Both penicillin and penicillin derivatives have been shown to interfere with hemostasis and to cause clinically manifest hemorrhagic diathesis (Fleming and Fish 1947, Lurie et al. 1970a, b, McClure et al. 1970, Yudis et al. 1972, Demos 1971, Waisbren et al. 1971). Carbenicillin interferes with ADP-, collagen- or thrombin-induced platelet aggregation and with the release reaction both in vivo (McClure et al. 1970, Cazenave et al. 1973) and in vitro (McClure et al. 1970, Cazenave et al. 1973). In addition Lurie and colleagues (1970b) concluded that an inhibition of the conversion of fibrinogen to fibrin is involved although no experimental details were given. Later Brown and colleagues (1974) concluded that carbenicillin at usual dose levels “only affects the platelet component of hemostasis and has little effect on fibrin formation or other phases of coagulation in patients with normal renal function”.

* The results were presented in part at the National Conference on Thrombosis and Hemostasis in Dallas, 1974, and at the VI. Congress Int. Society of Nephrology, Florence (Italy), 1975.


** Reprint requests to Prof. K. Andrassy, Ludolf-Krehl-Klinik, Bergheimer Straße 58, 6900 Heidelberg, Germany.


 

  • References

  • 1 Appel W. 1970. In: Bergmeyer H. U. (ed.). Methoden der enzymatischen Analyse. Verlag Chemie; Weinheim/Bergstraße: 906.
    Search in Google Scholar
  • 2 Astrup T, Mullertz S. 1952; The fibrin plate method for estimating fibrinolytic activity. Arch. Biochem 40: 346.
    CrossrefPubMedSearch in Google Scholar
  • 3 Bachman F, Duckert R, Geiger M, Baer P, Koller F. 1957; Differentiation of the factor VII complex. Studies on the Stuart-Prower-factor. Thrombosis et Diathesis Haemorrhagica 1: 169.
    PubMedSearch in Google Scholar
  • 4 Bauers A. W, Kirby W, Sherries J. C. et al. 1966; Antibiotic susceptibility testing by standardized single disc method. American Journal of Clinical Pathology 45: 493.
    CrossrefPubMedSearch in Google Scholar
  • 5 Belitser V, Varetskaja T, Malueva V. 1968; Fibrinogen-Fibrin interaction. Biochemica et Biophysica Acta 154: 367.
    CrossrefPubMedSearch in Google Scholar
  • 6 Biggs R, MacFarlane R. 1962. Human blood coagulation and its disorders. Blackwell Scientific Publications; Oxford.:
    Search in Google Scholar
  • 7 Brown C, Natelson E, Bradshaw M, Williams T, Alfrey C. 1974; The hemostatic defect produced by carbenicillin. New England Journal of Medicine 291: 265.
    CrossrefPubMedSearch in Google Scholar
  • 8 Cazenave J, Packham M, Guccione M, Mustard J. 1973; Effects of penicillin G on platelet aggregation, release and adherence to collagen. Proceedings of the Society for Experimental Biology and Medicine 142: 159.
    PubMedSearch in Google Scholar
  • 9 Clark A, Freeman T. 1968; Quantitative Immunoelectrophoresis of human serum proteins. Clin. Science 35: 403.
    PubMedSearch in Google Scholar
  • 10 Clauss A. 1957; Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta haematologica 17: 237.
    CrossrefPubMedSearch in Google Scholar
  • 11 Demos Ch. 1971; Carbenicillin and bleeding. Journal of the American Medical Association 218: 739.
    PubMedSearch in Google Scholar
  • 12 Dettli L, Spring P, Ryter S. 1971. Multiple dose kinetics and drug dosage in patients with kidney disease. In: Proc. Sympos. Biol. Pharm. Asp. Pharmacokin. Therap.. Musgaard; Copenhagen: 211.
    Search in Google Scholar
  • 13 Eastwood J, Curtis J. 1968 Carbenicillin administration in patients with severe renal failure. British Medical Journal. 486.
    PubMedSearch in Google Scholar
  • 14 Egli H. 1968; Laboratoriumsdiagnostik der Hämophilen. Dtsch. Med. J 19: 495.
    PubMedSearch in Google Scholar
  • 15 Feissly R, Lüdin H. 1949; Microscopie par contrastes de phase. Applicationes à l’hématologie 4: 481.
    PubMedSearch in Google Scholar
  • 16 Fleming A, Fish E. W. 1947; Influence of penicillin on the coagulation of blood. British Medical Journal 242.
    PubMedSearch in Google Scholar
  • 17 Funk C, Gmür J, Herold R, Straub W. 1971; Reptilase R–a new reagent in blood coagulation. British Journal of Haematology 21: 43.
    CrossrefPubMedSearch in Google Scholar
  • 18 Genton E. 1974; Guide lines for heparin therapy. Annals of Internal Medicine 80: 77.
    CrossrefPubMedSearch in Google Scholar
  • 19 Godal H, Abildgaard U. 1966; Gelation of soluble fibrin in plasma by ethanol. Scandinavian Journal of Haematology 3: 342.
    PubMedSearch in Google Scholar
  • 20 Graeff H, von Hugo R, Kuhn W, Scholz H, Ernst A, Gastroph R. 1973; Fibrinogen derivatives with a higher molecular weight than that of the parent molecule in cord vein plasma of newborns. Klin. Wschr 51: 695.
    CrossrefPubMedSearch in Google Scholar
  • 21 Grannis G. 1970; Plasma fibrinogen: determination, normal values, physiopathological shift and fluctuations. Clinical Chemistry 16: 486.
    PubMedSearch in Google Scholar
  • 22 Harker L, Schlichter S. 1972; The bleeding time as a screening test for evaluation of platelet function. New England Journal of Medicine 287: 155.
    CrossrefPubMedSearch in Google Scholar
  • 23 Hawiger J, Niewiarowsky S, Gurewich V, Thomas D. 1970; Measurement of fibrinogen and fibrin degradation products in serum by staphylococcal clumping test. Journal of Laboratory and Clinical Medicine 75: 93.
    PubMedSearch in Google Scholar
  • 24 Heimburger N. 1967; In: On the proteinase inhibition of human plasma with special reference to antithrombin. First International Symposium on tissue factors on the hemostasis of the coagulation and fibrinolysis system. 353.
    PubMedSearch in Google Scholar
  • 25 Höffler D, Koeppe P, Hoppe H. 1969; Carbenicillindosierung bei normaler und eingeschränkter Nierenfunktion. Arzneimittelforschung 19: 1233.
    PubMedSearch in Google Scholar
  • 26 Ivy A, Nelson D, Bucher G. 1941; The standardization of certain factors in the cutanous venostasis bleeding time technique. Journal of Laboratory and Clinical Medicine 26: 1812.
    PubMedSearch in Google Scholar
  • 27 Junge O. 1972; Dünnschichtchromatographische Auftrennung der Antibiotika Carbenicillin, Polymyxin und Capreomycin. International Journal of Clinical Pharmacology 6 (01) 67.
    PubMedSearch in Google Scholar
  • 28 Koller F, Loeliger A, Duckert F. 1951; Experiments on a new clotting factor (F. VII). Acta haematologica 6: 1.
    CrossrefPubMedSearch in Google Scholar
  • 29 Langdell R, Wagner R, Brinkhous K, Hill C. 1953; Effect of antihemophilic factor on one stage clotting tests. A presumptive test for hemophilia and a simple one stage antihemophilic assay. Journal of Laboratory and Clinical Medicine 41: 637.
    PubMedSearch in Google Scholar
  • 30 Lurie A, Oglivie O, Townsend R, Gold C, Meyers A, Goldberg B. 1970a Carbenicillin induced coagulopathy. Lancet I 1114.
    PubMed
  • 31 Lurie A, Gold C, Meyers A, Goldberg B. 1970b Carbenicillin in renal failure. Lancet II 423.
    PubMed
  • 32 McClure P, Casserly J, Monsier Ch, Crozier D. 1970; Carbenicillin induced bleeding disorder. Lancet II 1307.
    PubMedSearch in Google Scholar
  • 33 Milstone H. 1941; Factor in normal human blood which participates in streptococcal fibrinolysis. J. Immunol 42: 109.
    PubMedSearch in Google Scholar
  • 34 Monkhouse F, France E, Seegers W. 1955; Studies on the antithrombin and heparin cofactor activity of a fraction adsorbed from plasma by aluminium hydroxyde. Circulation Research III 397.
    PubMedSearch in Google Scholar
  • 35 Owren P. 1959; Thrombotest, a new method for controlling anticoagulant therapy. Lancet II 754.
    PubMedSearch in Google Scholar
  • 36 Owren P. 1969; The interrelationship between normotest and thrombotest. Pharmakotherapy 25: 1.
    PubMedSearch in Google Scholar
  • 37 Quick A. 1936; On coagulation defect in peptone shock; consideration of antithrombins. American Journal of Physiology 116: 535.
    PubMedSearch in Google Scholar
  • 38 Quick A. 1937; The coagulation defect in sweet clover disease and in the hemorrhagic chick disease of dietary origin. American Journal of Physiology 118: 260.
    PubMedSearch in Google Scholar
  • 39 Quick J. A. 1938; The normal antithrombin of the blood and its relation to heparin. American Journal of Physiology 123: 712.
    PubMedSearch in Google Scholar
  • 40 Schneider W, Kübler W, Gross R. 1968; Induction of blood platelet aggregation by cationic polypeptides. Thrombosis et Diathesis Haemorrhagica 19: 307.
    PubMedSearch in Google Scholar
  • 41 Smith H. 1970. Chemistry of macromolecular residues in penicillins. In: Advances in penicillin allergy and immunology. Symposium Proceedings Rotterdam, Beecham Research Lab.; 51.
    Search in Google Scholar
  • 42 Soulier J, Prou-Wartelle O, Halle L. 1967; Study of thrombin coagulase. Thrombosis et Diathesis Haemorrhagica 17: 321.
    PubMedSearch in Google Scholar
  • 43 Waisbren B, Evani S, Ziebert A. 1971; Carbenicillin and bleeding. Journal of the American Medical Association 217: 1243.
    PubMedSearch in Google Scholar
  • 44 Yudis M, Mahood W, Maxwell R. 1972; Bleeding problems with carbenicillin. Lancet I 599.
    PubMedSearch in Google Scholar