Protamine-Induced Thrombocytopenia and Leukopenia

Summary

Protamine has been reported to cause thrombocytopenia and granulocytopenia. In this article, we report studies examining the relative contribution of protamine and heparin in the pathogenesis of this phenomenon, the dose-effect relationship, and the possible mechanism of cell loss. Protamine alone infused into experimental animals causes mild, transient granulocytopenia and thrombocytopenia. The sequential administration of heparin and protamine results in a more severe cytopenia lasting 30 to over 60 min. Organ scanning with ¹¹¹In-labeled platelets shows a striking though transient accumulation of radioactivity in the lungs following heparin-protamine infusion. Platelet survival, however, is not shortened. Incubation of ¹²⁵I-labeled protamine with blood cells in the presence of heparin results in tight binding of the drug to platelets and granulocytes. These observations suggest that protamine and heparin form a complex that binds to blood cells. The sequestration of coated cells in the lungs results in transient granulocytopenia and thrombocytopenia.

Key words

Protamine - Thrombocytopenia - Leukopenia

• References

• 1 Perkins HA, Harkins G, Gerbode F, Rolfs MR, Acra DJ. Comparison of effects of protamine and polybrene, with special emphasis on the factor VIII (antihemophilic globulin) deficiency induced. J Clin Invest 1961; 40: 1421-1430
• 2 Eika C, Godal HC. Thrombocytopenia in rabbits induced by heparin, protamine and polybrene. Scand J Haematol 1971; 8: 481-486
• 3 Heyns Adu P, Lötter MG, Badenhorst PN, Kotze H, Killian FC, Herbst C, van Reenen OR, Minnaar PC. Kinetics and in vivo redistibution of¹¹¹indiumlabelled human platelets after intravenous protamine sulphate. Thromb Haemostas 1980; 44: 65-68
• 4 Woods JE, Kirklin JW, Owen Jr CA, Thompson Jr JH, Taswell HF. Effect of bypass surgery on coagulation-sensitive clotting factors. Mayo Clin Proc 1967; 42: 724-735
• 5 Harker LA, Malpass TW, Branson HE, Hessel II EA, Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective granule release. Blood 1980; 56: 824-834
• 6 Riba AL, Thakur ML, Gottschalk A, Zaret BL. Imaging experimental infective endocarditis with luindium-labeled blood cellular components. Circulation 1978; 59: 336-343
• 7 Al-Mondhiry H, Pierce WS, Richenbacher W. Platelet survival and function in animals with prosthetic mitral valve. Thromb Haemostas. 1984 in press
• 8 Born GV R, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-195
• 9 Levy-Toledano S, Maclouf J, Bryon P, Savariav E, Hardisty RM, Caen JP. Human platelet activation in the absence of aggregation: a calcium dependent phenomenon independent of thromboxane formation. Blood 1982; 59: 1078-1085
• 10 Marchalonis JJ. An enzymatic method for the trace iodination of immunoglobulins and other proteins. Biochem J 1969; 113: 299-305
• 11 Redl H, Hammerschmidt DE, Schlag G. Augmentation by platelets of granulocyte aggregation in response to chemotoxins: studies utilizing an improved cell preparation technique. Blood 1983; 61: 125-131
• 12 Fotino M, Merson EJ, Allen FH. Micromethod for rapid separation of lymphocytes from peripheral blood. Ann Clin Lab Sci 1971; 1: 131-133
• 13 Al-Mondhiry H, McGarvey V, Leitzel K. Interaction of human tumor cells with human platelets and the coagulation system. Thromb Haemostas 1983; 50: 726-730
• 14 Radegran K, Bergentz SE, Lewis DH, Liungqvist U, Olsson P. Pulmonary effects of induced platelet aggregation. Intravascular obstruction or vasoconstriction Scand J Clin Lab Invest 1971; 28: 423-427
• 15 Hammerschmidt DE, Stroncek DF, Bowers TK, Lammi-Keefe CJ, Kurth DM, Ozalins A, Nicoloff DM, Lillehei RC, Craddock PR, Jacob HS. Complement activation and neutropenia occurring during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1981; 81: 370-377
• 16 Eika C. On the mechanism of platelet aggregation induced by heparin, protamine and polybrene. Scand J Haematol 1972; 9: 248-257
• 17 Ellison N, Edmunds LH, Colman RW. Platelet aggregation following heparin and protamine administration. Anesthesiology 1978; 48: 65-68
• 18 Jaques LB. A study of the toxicity of the protamine salmine. Br J Pharmacol 1949; 4: 135-144
• 19 Goldman BS, Joison J, Austen WG. Cardiovascular effects of protamine sulfate. Ann Thorac Surg 1969; 7: 459-471
• 20 Bjoraker DG, Ketcham TR. In vivo platelet response to clinical protamine sulfate infusion. Anesthesiology 1982; 57 A 7
• 21 Rent R, Ertel N, Eisenstein R, Gewurz H. Complement activation by interaction of polyanions and polycations. I. Heparin-protamine induced consumption of complement. J Immunol 1975; 114-120
• 22 Godal HC, Gjengedal G. Activation of coagulation by heparinprotamine complexes as demonstrated by thrombotest. Scand J Haematol 1971; 8: 194-199