Evidence for an Increased Generation of Prostacyclin in the Microvasculature and an Impairment of the Platelet α-Granule Release in Chronic Renal Failure

Summary

The formation of prostacyclin (PGI₂) and thromboxane A₂ and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F_1α (6-keto-PGF_1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI₂ formation in chronic uraemia. Formation of thromboxane B₂ (TxB₂) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI₂ in the micro vasculature.

Keywords

Bleeding time - Thromboxane - Prostacyclin - Beta-thromboglobulin - Chronic renal failure

• References

• 1 Rabiner SF. Uremic bleeding.. Prog Hemostasis Thromb 1972; 1: 233-250
• 2 Larsson SO. On coagulation and fibrinolysis in renal failure. Scand J Haematol 1971; 15: 1-59
• 3 Stewart JH, Castaldi PA. Uraemic bleeding - a reversible platelet defect corrected by dialysis. Q J Med 1967; 36: 409-423
• 4 Castaldi PA, Rozenberg MC, Stewart JH. The bleeding disorder in uraemia. Lancet 1966; 2: 66-69
• 5 Salzman EW, Neri LL. Adhesiveness of blood platelets in uremia. Thromb Diath Haemorrh 1966; 15: 84-92
• 6 Steiner RW, Coggins C, Carvalho ACA. Bleeding time in uraemia: A useful test to assess clinical bleeding. Am J Hematol 1979; 7: 107
• 7 Remuzzi G, Cavenaghi AE, Mecca G, Donati MB, de GaetanoG. Prostacyclin-like activity and bleeding in renal failure. Lancet 1977; ii: 1195-1197
• 8 Hellem AJ, Odegaard AE, Skalhegg A. Platelet adhesiveness in chronic renal failure. Abstracts of Xth Congress of International Society of Haematology, Stockholm 1966: pi
• 9 Eknoyan GS, Wacksman SJ, Glueck HI, Will JJ. Platelet function in renal failure. N Engl J Med 1969; 280: 677-681
• 10 Castillo R, Lozano T, Escolar G, Revert L, Lopez J, Ordinas A. Defective platelet adhesion on vessel subendothelium in uremic patients. Blood 1986; 68: 337-342
• 11 Remuzzi G, Benigni A, Dodesini P, Schieppati A, Livio M, de GaetanoG, Day JS, Smith WL, Pinea E, Patrignani P, Patrano C. Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclooxygenase defect. J Clin Invest 1983; 71: 762-768
• 12 Di MinnoG, Martinez J, McKean ML, De Lä RosaL, Burke JF, Murphy S. Platelet dysfunction in uremia: Multifaceted defect partially corrected by dialysis.. Am J Med 1985; 79: 552-559
• 13 Rao AK. Uraemic platelets. Lancet 1986; i: 913-914
• 14 Hassanein AA, McNicol GP, Douglas AS. Relationship between platelet function test in normal and uraemic subjects. J Clin Pathol 1970; 23: 402-406
• 15 Remuzzi G, Marchesi D, Livio M, Lavenaghi AE, Mecca G, Donati MB, de GaetanoG. Altered platelet and vascular prostaglandin generation in patients with renal failure and prolonged bleeding times. Thromb Res 1978; 13: 1007-1015
• 16 Smith MC, Dunn M. Impaired thromboxane production in renal failure. Nephron 1981; 29: 133
• 17 Thorngren M, Shafi S, Born GV R. Thromboxane A₂ in skinbleeding-time blood and in clotted venous blood before and after administration of acetylsalicylic acid. Lancet 1983; i: 1075-1078
• 18 Kyrie PA, Westwick J, Scully MF. Fibrinopeptide A generation and beta-thromboglobulin release at the site of plug formation - effect of aspirin. Br J Clin Pharm 1986; 21: 563-564
• 19 Kyrie PA, Westwick J, Scully MF, Kakkar VV, Lewis GP. Investigation of the interaction of blood plätelets with the coagulation system at the site of plug formation in vivo in man - effect of low-dose aspirin. Thromb Haemostas 1987; 57: 62-66
• 20 Kyrie PA, Eichler HG, Jäger U, Lechner K. Inhibition of prostacyclin and thromboxane A₂ generation by low-dose aspirin at the site of plug formation in man in vivo. Circulation 1987; 75: 1025-1029
• 21 Hamberg M, Svensson J, Samuelsson B. A new group of biological active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sei USA 1975; 72: 2994-2998
• 22 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
• 23 Moncada S, Vane JR. Arachidonic acid metabolites and the interactions between platelets and blood-vessel wall. N Engl J Med 1979; 300: 1142
• 24 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
• 25 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
• 26 Hensly CN, Jogie M, Elder MJ. et al Comparison of the quantitative analysis of 6-keto-PGF_ralpha on biological fluids by gas chromatography, mass spectrometry and radioimmunoassay. Biomed Mass Spectrom 1981; 8: 111-117
• 27 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
• 28 Livio M, Gorti E, Marchesi D, Mecca G, Remuzzi G, de GaetanoG. Uraemic bleeding: role of anaemia and beneficial effect of red cell transfusion. Lancet 1982; ii: 1013-1015
• 29 Fernandez F, Goudable C, Sie P, Ton-That H, Durand D, Sue JM, Boneu M. Low haemotocrit and prolonged bleeding time in uraemic patients: effect of red cell transfusions. Br J Haematol 1985; 59: 139-148
• 30 Remuzzi G, Livio M, Cavenaghi AE, Marchesi D, Mecca G, Donati MB, de GaetanoG. Unbalanced prostaglandin synthesis and plasma factors in uraemic bleeding: A hypothesis. Thromb Res 1978; 13: 531
• 31 Evans EP, Branch RA, Bloom AL. A clinical and experimental study of platelet function in chronic renal failure. J Clin Pathol 1972; 25: 745-753
• 32 Castaldi PA, Sydney MB. The bleeding disorder in uraemia. A qualitative platelet defect. Lancet 1966; ii: 66-69