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. 1980 Feb;65(2):329–337. doi: 10.1172/JCI109676

Carbenicillin and Penicillin G Inhibit Platelet Function In Vitro by Impairing the Interaction of Agonists with the Platelet Surface

Sanford J Shattil 1,2, Joel S Bennett 1,2, Margaret McDonough 1,2, Judy Turnbull 1,2
PMCID: PMC371371  PMID: 6243309

Abstract

Carbenicillin or penicillin G administered in large doses can cause a bleeding diathesis as a result of platelet dysfunction. These antibiotics also inhibit platelet aggregation in vitro, although several-fold larger concentrations of drug are required to demonstrate this effect. We wondered whether these antibiotics might impair platelet function by interfering with the initial step of platelet activation: the binding of agonists to their specific receptors on the platelet surface.

Platelet aggregation and [14C]serotonin release induced by epinephrine were competitively inhibited by carbenicillin and penicillin G in vitro. At antibiotic concentrations that inhibited platelet function by more than 80%, the affinity of platelet α-adrenergic receptors for the α-adrenergic antagonist, [3H]dihydroergocryptine, and for epinephrine was reduced twofold by carbenicillin and sixfold by penicillin G (P < 0.01). Platelet aggregation and [14C]serotonin release stimulated by ADP were also competitively inhibited by these antibiotics. In addition, carbenicillin reduced the incorporation of an ADP affinity label, 5′-p-fluorosulfonylbenzoyl [3H]adenosine, into its binding protein in platelet membranes. Moreover, both carbenicillin and penicillin G impaired the interaction of von Willebrand factor with platelets as evidenced by their inhibition of the agglutination of formalin-fixed platelets by ristocetin, snake venom, or bovine factor VIII.

These studies demonstrate that carbenicillin and penicillin G inhibit platelet function in vitro by impairing the interaction of several agonists with their specific receptors on the platelet surface membrane. If this were mechanism operative in vivo, it could account for the hemorrhagic as well as the potential antithrombotic effects of these antibiotics.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andrassy K., Ritz E., Hasper B., Scherz M., Walter E., Storch H. Penicillin-induced coagulation disorder. Lancet. 1976 Nov 13;2(7994):1039–1041. doi: 10.1016/s0140-6736(76)90963-6. [DOI] [PubMed] [Google Scholar]
  2. Barber A. J., Jamieson G. A. Isolation and characterization of plasma membranes from human blood platelets. J Biol Chem. 1970 Dec 10;245(23):6357–6365. [PubMed] [Google Scholar]
  3. Bennett J. S., Colman R. F., Colman R. W. Identification of adenine nucleotide binding proteins in human platelet membranes by affinity labeling with 5'-p-flurosulfonylbenzoyl adenosine. J Biol Chem. 1978 Oct 25;253(20):7346–7354. [PubMed] [Google Scholar]
  4. Bergan T. Penicillins. Antibiot Chemother (1971) 1978;25:1–122. doi: 10.1159/000401058. [DOI] [PubMed] [Google Scholar]
  5. Brinkhous K. M., Graham J. E., Cooper H. A., Allain J. P., Wagner R. H. Assay of von Willebrand factor in von Willebrand's disease and hemophilia: use of a macroscopic platelet aggregation test. Thromb Res. 1975 Mar;6(3):267–272. doi: 10.1016/0049-3848(75)90074-2. [DOI] [PubMed] [Google Scholar]
  6. Brown C. H., 3rd, Natelson E. A., Bradshaw W., Williams T. W., Jr, Alfrey C. P., Jr The hemostatic defect produced by carbenicillin. N Engl J Med. 1974 Aug 8;291(6):265–270. doi: 10.1056/NEJM197408082910601. [DOI] [PubMed] [Google Scholar]
  7. Cazenave J. P., Packham M. A., Guccione M. A., Mustard J. F. Effects of penicillin G on platelet aggregation, release, and adherence to collagen. Proc Soc Exp Biol Med. 1973 Jan;142(1):159–166. doi: 10.3181/00379727-142-36980. [DOI] [PubMed] [Google Scholar]
  8. Cazenave J. P., Reimers H. J., Senyi A. F., Hirsh J., Packham M. A., Mustard J. F. Effects of penicillin G and cephalothin on platelet function in vivo. Proc Soc Exp Biol Med. 1976 Sep;152(4):641–644. doi: 10.3181/00379727-152-39458. [DOI] [PubMed] [Google Scholar]
  9. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  10. Detwiler T. C., Charo I. F., Feinman R. D. Evidence that calcium regulates platelet function. Thromb Haemost. 1978 Oct 31;40(2):207–211. [PubMed] [Google Scholar]
  11. Feinstein M. B., Fernandez S. M., Sha'afi R. I. Fluidity of natural membranes and phosphatidylserine and ganglioside dispersions. Effect of local anesthetics, cholesterol and protein. Biochim Biophys Acta. 1975 Dec 16;413(3):354–370. doi: 10.1016/0005-2736(75)90121-2. [DOI] [PubMed] [Google Scholar]
  12. HARDISTY R. M., MACPHERSON J. C. A one-stage factor VIII (antihaemophilic globulin) assay and its use on venous and capillary plasma. Thromb Diath Haemorrh. 1962 May 15;7:215–228. [PubMed] [Google Scholar]
  13. HUMMEL J. P., DREYER W. J. Measurement of protein-binding phenomena by gel filtration. Biochim Biophys Acta. 1962 Oct 8;63:530–532. doi: 10.1016/0006-3002(62)90124-5. [DOI] [PubMed] [Google Scholar]
  14. Haburchak D. R., Head D. R., Everett E. D. Postoperative hemorrhage associated with carbenicillin administration. Report of two cases and review of the literature. Am J Surg. 1977 Nov;134(5):630–634. doi: 10.1016/0002-9610(77)90451-2. [DOI] [PubMed] [Google Scholar]
  15. Howard M. A., Firkin B. G. Ristocetin--a new tool in the investigation of platelet aggregation. Thromb Diath Haemorrh. 1971 Oct 31;26(2):362–369. [PubMed] [Google Scholar]
  16. Insel P. A., Nirenberg P., Turnbull J., Shattil S. J. Relationships between membrane cholesterol, alpha-adrenergic receptors, and platelet function. Biochemistry. 1978 Nov 28;17(24):5269–5274. doi: 10.1021/bi00617a029. [DOI] [PubMed] [Google Scholar]
  17. Jerushalmy Z., Zucker M. B. Some effects of fibrinogen degradation products (FDP) on blood platelets. Thromb Diath Haemorrh. 1966 May 15;15(3):413–419. [PubMed] [Google Scholar]
  18. Johnson G. J., Rao G. H., White J. G. Platelet dysfunction induced by parenteral carbenicillin and ticarcillin. Studies of the dose-response relationship and mechanism of action in dogs. Am J Pathol. 1978 Apr;91(1):85–106. [PMC free article] [PubMed] [Google Scholar]
  19. Kao K. J., Pizzo S. V., McKee P. A. Demonstration and characterization of specific binding sites for factor VIII/von Willebrand factor on human platelets. J Clin Invest. 1979 Apr;63(4):656–664. doi: 10.1172/JCI109348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kaywin P., McDonough M., Insel P. A., Shattil S. J. Platelet function in essential thrombocythemia. Decreased epinephrine responsiveness associated with a deficiency of platelet alpha-adrenergic receptors. N Engl J Med. 1978 Sep 7;299(10):505–509. doi: 10.1056/NEJM197809072991002. [DOI] [PubMed] [Google Scholar]
  21. Kirby E. P., Mills D. C. The interaction of bovine factor VIII with human platelets. J Clin Invest. 1975 Aug;56(2):491–502. doi: 10.1172/JCI108116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lacombe M. J., Varet B., Godeau P., Herreman G., Cenac A. Action de fortes doses de pénicilline G sur les plaquettes. Etude au cours de la maladie d'Osler. Nouv Presse Med. 1974 Jun 1;3(22):1435–1437. [PubMed] [Google Scholar]
  23. Lyman B. T., Johnson G. J., White J. G. Dose-dependent inhibition of experimental arterial thrombosis by carbenicillin and ticarcillin. Am J Pathol. 1978 Aug;92(2):473–490. [PMC free article] [PubMed] [Google Scholar]
  24. Macfarlane D. E., Stibbe J., Kirby E. P., Zucker M. B., Grant R. A., McPherson J. Letter: A method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh. 1975 Sep 30;34(1):306–308. [PubMed] [Google Scholar]
  25. Majerus P. W., Miletich J. P. Relationships between platelets and coagulation factors in hemostasis. Annu Rev Med. 1978;29:41–49. doi: 10.1146/annurev.me.29.020178.000353. [DOI] [PubMed] [Google Scholar]
  26. Marcus A. J. The role of lipids in platelet function: with particular reference to the arachidonic acid pathway. J Lipid Res. 1978 Sep;19(7):793–826. [PubMed] [Google Scholar]
  27. Mills D. C., Roberts G. C. Effects of adrenaline on human blood platelets. J Physiol. 1967 Nov;193(2):443–453. doi: 10.1113/jphysiol.1967.sp008369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Moore A., Ross G. D., Nachman R. L. Interaction of platelet membrane receptors with von Willebrand factor, ristocetin, and the Fc region of immunoglobulin G. J Clin Invest. 1978 Nov;62(5):1053–1060. doi: 10.1172/JCI109210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Newman K. D., Williams L. T., Bishopric N. H., Lefkowitz R. J. Identification of alpha-adrenergic receptors in human platelets by [3H]dihydroergocryptine binding. J Clin Invest. 1978 Feb;61(2):395–402. doi: 10.1172/JCI108950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nurden A. T., Caen J. P. Role of surface glycoproteins in human platelet function. Thromb Haemost. 1976 Feb 29;35(1):139–150. [PubMed] [Google Scholar]
  31. O'BRIEN J. R. SOME EFFECTS OF ADRENALINE AND ANTI-ADRENALINE COMPOUNDS ON PLATELETS IN VITRO AND IN VIVO. Nature. 1963 Nov 23;200:763–764. doi: 10.1038/200763a0. [DOI] [PubMed] [Google Scholar]
  32. Padfield J. M., Kellaway I. W. Rheological studies on mixed phospholipid sols and their interaction with penicillins. I. Continuous shear viscometry. Chem Phys Lipids. 1973 May;10(4):356–368. doi: 10.1016/0009-3084(73)90060-1. [DOI] [PubMed] [Google Scholar]
  33. Read M. S., Shermer R. W., Brinkhous K. M. Venom coagglutinin: an activator of platelet aggregation dependent on von Willebrand factor. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4514–4518. doi: 10.1073/pnas.75.9.4514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shattil S. J., Anaya-Galindo R., Bennett J., Colman R. W., Cooper R. A. Platelet hypersensitivity induced by cholesterol incorporation. J Clin Invest. 1975 Mar;55(3):636–643. doi: 10.1172/JCI107971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shattil S. J., Cooper R. A. Membrane microviscosity and human platelet function. Biochemistry. 1976 Nov 2;15(22):4832–4837. doi: 10.1021/bi00667a012. [DOI] [PubMed] [Google Scholar]
  36. Shattil S. J., Cooper R. A. Role of membrane lipid composition, organization, and fluidity in human platelet function. Prog Hemost Thromb. 1978;4:59–86. [PubMed] [Google Scholar]
  37. Spratt B. G. Properties of the penicillin-binding proteins of Escherichia coli K12,. Eur J Biochem. 1977 Jan;72(2):341–352. doi: 10.1111/j.1432-1033.1977.tb11258.x. [DOI] [PubMed] [Google Scholar]
  38. Tangen O., Berman H. J., Marfey P. Gel filtration. A new technique for separation of blood platelets from plasma. Thromb Diath Haemorrh. 1971 Jun 30;25(2):268–278. [PubMed] [Google Scholar]
  39. Tschopp T. B., Weiss H. J., Baumgartner H. R. Decreased adhesion of platelets to subendothelium in von Willebrand's disease. J Lab Clin Med. 1974 Feb;83(2):296–300. [PubMed] [Google Scholar]
  40. Weiss H. J., Hoyer L. W., Rickles F. R., Varma A., Rogers J. Quantitative assay of a plasma factor deficient in von Willebrand's disease that is necessary for platelet aggregation. Relationship to factor VIII procoagulant activity and antigen content. J Clin Invest. 1973 Nov;52(11):2708–2716. doi: 10.1172/JCI107465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zimmerman T. S., Ratnoff O. D., Powell A. E. Immunologic differentiation of classic hemophilia (factor 8 deficiency) and von Willebrand's dissase, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor. J Clin Invest. 1971 Jan;50(1):244–254. doi: 10.1172/JCI106480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. van Obberghen E., de Meyts P., Roth J. Inhibition of insulin receptor binding by dimethyl sulfoxide. Biochim Biophys Acta. 1979 Feb 1;582(3):486–495. doi: 10.1016/0304-4165(79)90139-9. [DOI] [PubMed] [Google Scholar]

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