Investigation of the Interaction of Blood Platelets with the Coagulation System at the Site of Plug Formation In Vivo in Man - Effect of Low-Dose Aspirin

Summary

In 7 healthy volunteers, formation of thrombin (represented by fibrinopeptide A (FPA) generation, α-granule release (represented by β-thromboglobulin [βTG] release) and the generation of thromboxane B₂ (TxB₂) were measured in vivo in blood emerging from a template bleeding time incision. At the site of plug formation, considerable platelet activation and thrombin generation were seen within the first minute, as indicated by a 110-fold, 50-fold and 30-fold increase of FPA, TxB₂ and PTG over the corresponding plasma values. After a further increase of the markers in the subsequent 3 minutes, they reached a plateau during the fourth and fifth minute. A low-dose aspirin regimen (0.42 mg.kg^-1.day^-1 for 7 days) caused >90% inhibition of TxB₂formation in both bleeding time blood and clotted blood. At the site of plug formation, a-granule release was substantially reduced within the first three minutes and thrombin generation was similarly inhibited. We conclude that (a) marked platelet activation and considerable thrombin generation occur in the early stages.of haemostasis, (b) α-granule release in vivo is partially dependent upon cyclo-oxygenase-controlled mechanisms and (c) thrombin generation at the site of plug formation is promoted by the activation of platelets.

Keywords

Platelet coagulation interaction - Aspirin - Bleeding time

• References

• 1 Duke WW. The relation of blood platelets to hemorrhagic disease: description of a method for determining the bleeding time and coagulation time and report of three cases of hemorrhagic disease releaved by transfusion. JAMA 1910; 55: 1185-1192
• 2 Harker LA, Slichter SJ. The bleeding time as a screening test for evaluation of platelet function. N Eng J Med 1972; 287: 155-159
• 3 French JE, MacFarlane RG, Sanders AG. The structure of haemostatic plugs and experimental thrombi in small arteries. Br J Exp Pathol 1962; 45: 467-474
• 4 Wester J, Sixma JJ, Geuze JJ, van der Veen J. Morphology of the early haemostasis in human skin wounds. Influence of acetyl salicylic acid. Lab Invest 1978; 39: 298-311
• 5 Wester J, Sixma JJ, Geuze JJ, Heijnen H. Morphology of the haemostatic plug in human skin wounds. Lab Invest 1979; 41: 182-193
• 6 Thorngreen M, Shafi S, Born G VR. Thromboxane A2 in skinbleeding-time blood and in clotted venous blood before and after administration of acetylsalicylic acid. Lancet 1983; I 1075-1078
• 7 Nossel HL, Yudelman I, Canfield RE, Butler Jr VP, Spanodis K, Wilner GD, Qureshi GD. Measurement of fibrinopeptide A in human blood. J Clin Invest 1974; 54: 43-53
• 8 Hamberg M, Svensson J, Samuelsson B. A new group of biological active compounds derived from prostaglandin endoperoxides. Pro Natl Acad Sci USA 1975; 72: 2994-2998
• 9 Ingerman-Wojenski C, Silver M, Smith JB, Macarak E. Bovine endothelial cells in culture produce thromboxane as well as prostacyclin. J Clin Invest 1981; 67: 1292-1296
• 10 Ludlam CA, Moore S, Bolton AE, Pepper DE, Cash JD. The release of a human platelet specific protein measured by a radioimmunoassay. Thromb Res 1975; 6: 543-553
• 11 Kaplan KL, Nossel HL, Drillings M, Lesznik G. Radioimmunoassay of platelet factor 4 and β-thromboglobulin: development and application to studies of platelet release in relation to fibrinopeptide A generation. Br J Haemostas 1978; 39: 129-146
• 12 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-1372
• 13 Mielke CH, Kaneshiro MM, Mahler IA, Weiner JM, Rapaport SI. The standardized Ivy bleeding time and its prolongation by aspirin. Blood 1969; 34: 204-215
• 14 Wilcoxon F. Individual comparison by ranking methods. Biometric Bulletin 1945; 1: 80-83
• 15 Mann HB, Whitney DR. On a test of whether one of two random variables is stochastically larger than the other. Ann Math Statist 1947; 18: 50-60
• 16 Kaplan KL, Drillings M, Lesznik G. Fibrinopeptide A cleavage and platelet release in whole blood in vitro . J Clin Invest 1981; 67: 1561-1568
• 17 Prowse CV, Vigano S, Borsey DQ, Dawes J. The release of β-thromboglobulin from platelets during clotting of whole blood. Thromb Res 1980; 17: 433-442
• 18 Shuman MA, Levine SP. Thrombin generation and secretion of platelet factor 4 during blood clotting. J Clin Invest 1978; 61: 1102-1106
• 19 Richardson PD. Effect of blood flow velocity on growth rate of platelet thrombi. Nature (London) 1973; 245: 103-104
• 20 Arfors KE, Bergquist D. Platelet aggregability and vessel contraction in microvascular haemostasis. Microvasc Res 1975; 9: 22-28
• 21 Begent N, Born G VR. Growth rate in vivo of platelet thrombi, produced by iontophoresis of ADP, as a function of mean blood flow velocity. Nature 1970; 227: 926-930
• 22 Beaumont JL, Caen J, Bernard J. Influence de l’acide acetylsalicylique dans Jes maladies haemorrhagiques. Sangre 1956; 27: 243-248
• 23 Krishnamurthi S, Westwick J, Kakkar VV. Regulation of human platelet activation - Analysis of cyclo-oxygenase and cyclic AMP-dependent pathways. Biochem Pharmacol 1984; 33 (19) 3025-3035
• 24 Detwiler TC, Huang E. Inter-relationship of platelet aggregation, secretion and prostaglandin synthesis. In: The regulation of Coagulation. Mann KG, Taylor FB. (Ed). Elsevier/North-Holland; Amsterdam: 377-389