Daunorubicin and Platelet Function

Summary

The influence of Daunorubicin on some platelet functions in vitro was investigated, using different concentrations of the drug (0.01-0.02-0.04 μg/ml). Daunorubicin was shown to inhibit Collagen and Thrombin induced platelet aggregation and the intensity of inhibition depended on both drug concentration and the time of preincubation.

Daunorubicin was also shown to inhibit the release reaction, the platelet prostaglandin pathway and the availability platelet factor 3; the drug at concentrations for clinical use does not damage the platelet membrane, as is the case with the freezing and thawing test, in platelet uptake of ¹⁴C-serotonin and as confirmed by the electron microscope. When very high doses (0.16 mg) of Daunorubicin are used, lysis of the platelets can be observed and this is confirmed under the electron microscope by the presence of empty platelets with fractures at the level of the cytoplasmic membrane.

Finally, Daunorubicin causes irreversible inhibition of reptilase clot-retraction, even if this is less severe than with Vincristine. Working with gel-filtered platelets, it would appear that the inhibition exercised by the drug on platelet reactions is not caused through modifications in Ca⁺⁺ metabolism.

The authors suggest that Daunorubicin, at the dosages used clinically, induces in vitro thrombocytopathy without damaging the cellular membrane as confirmed by the electron microscope.

This impairment of platelet functions could play a part in hemorrhagic diathesis observed during Daunorubicin therapy.

Keywords

Inhibitors - Thrombocytopathy - Electron microscope morphology - Ca^{+ +} metabolism - Release reaction

• References

• 1 Boiron M, Jacquillat C, Weil M, Tanzer J, Levy D, Sultan C, Bernard J. Daunorubicin in the treatment of acute myelocitic leukaemia. Lancet 1969; 1: 330-333
• 2 Macrez CI, Marneffe-Lebrequier H, Ripault J, Clauvel J-P, Jacquillat CI, Weil M. Accidents cardiaques observés au cours des traitements par la rubidomycine. Path Biol 1967; 15: 949-953
• 3 Bick RL, Murano G, Fekete L, Wilson WL. Daunomycin and fibrinolysis. Thromb Res 1976; 9: 201-203
• 4 Tangen O, Berman HJ, Marfey P. Gel filtration. A new technique for separation of blood platelets from plasma. Thromb Diath Haemorrh 1971; 25: 268-278
• 5 Born GV R. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-928
• 6 Spaet TH, Cintron J. Studies on platelet factor-3 availability. Brit J Haematol 1965; 11: 269-275
• 7 Hardisty RM, Hutton RA. Platelet aggregation and the availability of platelet factor 3. Brit J Haematol 1966; 12: 764-776
• 8 Jerushalmy Z, Zucker MB. Some effects of F.D.P. on blood platelets. Thromb Diath Haemorrh 1965; 15: 413-419
• 9 Zucker MB, Peterson J. Effect of acetylsalicylic acid, other nonsteroi#dal anti-inflammatory agents, and dypiridamole on human blood platelets. J Lab Clin Med 1970; 76: 66-75
• 10 De Gaetano G, Donati MB, Vermylen J. A simple method to study the “stabilising” effect of chemicals and drugs on the platelet membrane. Thromb Res 1972; 1: 631-636
• 11 Smith JB, Ingerman CM, Silver MJ. Malondialdehyde formation as an indicator of prostaglandin production by human platelets. J Lab Clin Med 1976; 88: 167-172
• 12 De Gaetano G, Bottecchia D, Vermylen J. Retraction of Reptilase-Clots in the presence of agents inducing or inhibiting the platelet adhesion-aggregation reaction. Thromb Res 1973; 2: 71-84
• 13 Klener P, Kubisz P, Suranova J. Influence of cytotoxic drugs on platelet functions and coagulation in vitro. Thromb Haemostas 1977; 37: 53-61
• 14 Picotti GB, Galatulas I. Effetto della daunomicina e dell'adriamicina sulla captazione e sulla liberazione di serotonina da parte di piastrine isolate di cavia. Arch Ital Pat Clin Turn 1973; 16: 101-106
• 15 Anghileri L. Calcium transport inhibition by the antitumor agents adriamycin and daunomycin. Arzneim Forsch 1977; 27: 61-77
• 16 Bossa R, Cegani M, Dubini F, Galatulas I, Tofanetti O. Interferences between daunomycin and calcium. Prog Chemother 1974; 3: 984-992
• 17 Bossa R, Galatulas I, Tofanetti O. Effetto di una serie di farmaci sul transporto di calcio favorito da un estratto mitocondriale di cellule tumorali. Arch Ital Pat Clin Turn 1973; 16: 63-66
• 18 Feinman RD, Detwiler TC. Platelet secretion induced by divalent cation ionophores. Nature 1974; 249: 172-173
• 19 Massini P, Luscher EF. Some effects of ionophores for divalent cations of blood platelets. Comparison with the effect of thrombin. Biochem Biophys Acta 1974; 372: 109-121
• 20 Chao FC, Tullis JL. The in vitro effects of mithramydn on the aggregation and the calcium uptake of human platelets. Thromb Diath haemorrh 1973; 29: 712-721
• 21 White JG. Effects of colchidne and Vinca alkaloids on human platelets. I. Influence on platelet microtubules and contractile function. Am J Path 1968; 53: 281-291