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Semin Thromb Hemost 2004; 30(5): 579-589
DOI: 10.1055/s-2004-835678
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Platelet Dysfunction in Renal Failure

Paola Boccardo1 , Giuseppe Remuzzi1 , 2 , Miriam Galbusera1
  • 1Mario Negri Institute for Pharmacological Research, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy
  • 2Director, Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy
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Publication History

Publication Date:
21 October 2004 (online)

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Patients with end-stage renal disease suffer from complex hemostatic disorders. Uremic patients show a bleeding diathesis that is mainly due to abnormalities of primary hemostasis; in particular, platelet dysfunction and impaired platelet-vessel wall interaction. However, despite decreased platelet function, these patients have a high prevalence of cardiovascular and thrombotic complications. Platelet dysfunction in uremic patients is partially due to uremic toxins present in circulating blood. Dialysis improves platelet abnormalities and reduces, but does not eliminate, the risk of hemorrhage. Hemodialysis can even contribute to the bleeding through the continuous platelet activation induced by the interaction between blood and artificial surfaces. Thrombocytopenia, glomerular thrombosis, and thrombi in small arteries and glomerular capillaries are common pathological features in many renal diseases. Platelets are also involved directly in the pathogenesis of glomerular diseases through a variety of mechanisms, including release of active molecules, by enhancing immune complex deposition, and by altering glomerular permeability.

KEYWORDS

Platelet - renal diseases - uremia - bleeding - thrombosis

REFERENCES

  • 1 Morgagni G B. Opera Omnia. Ex Typographia Remondiniana. Venezia, Italy; 1764
    Google Scholar
  • 2 Lewis J H, Zucker M B, Ferguson J H. Bleeding tendency in uremia.  Blood. 1956;  11 1073-1076
    PubMedGoogle Scholar
  • 3 Rath C E, Mailliard J A, Schreiner G E. Bleeding tendency in uremia.  N Engl J Med. 1957;  257 808-811
    CrossrefPubMedGoogle Scholar
  • 4 Rosenblatt S G, Drake S, Fadem S, Welch R, Lifschitz M D. Gastrointestinal blood loss in patients with chronic renal failure.  Am J Kidney Dis. 1982;  1 232-236
    PubMedGoogle Scholar
  • 5 Moia M, Mannucci P M, Vizzotto L et al.. Improvement in the haemostatic defect of uraemia after treatment with recombinant human erythropoietin.  Lancet. 1987;  2 1227-1229
    PubMedGoogle Scholar
  • 6 Larsson S O. On coagulation and fibrinolysis in renal failure.  Scand J Haematol. 1971;  15(Suppl) 1-59
    PubMedGoogle Scholar
  • 7 Stewart J H. Platelet numbers and life span in acute and chronic renal failure.  Thromb Diath Haemorrh. 1967;  17 532-542
    PubMedGoogle Scholar
  • 8 Joist J H, Remuzzi G, Mannucci P M. Abnormal bleeding and thrombosis in renal disease. In: Colman RW, Hirsh J, Marder VJ, Salzman EW Hemostasis and Thrombosis: Basic Principles and Clinical Practice Philadelphia; J.B. Lippincott 1994: 921-935
    Google Scholar
  • 9 Panicucci F, Sagripanti A, Pinori E et al.. Comprehensive study of haemostasis in chronic uremia.  Nephron. 1983;  33 5-8
    PubMedGoogle Scholar
  • 10 Willoughby M LN, Crouch S J. An investigation of the haemorrhagic tendency in renal failure.  Br J Haematol. 1961;  7 315
    PubMedGoogle Scholar
  • 11 Castaldi P A, Rozenberg M C, Stewart J H. The bleeding disorder of uremia: a qualitative platelet defect.  Lancet. 1966;  2 66-69
    PubMedGoogle Scholar
  • 12 Hakim R M, Schafer A I. Hemodialysis-associated platelet activation and thrombocytopenia.  Am J Med. 1985;  78 575-580
    CrossrefPubMedGoogle Scholar
  • 13 Knudsen F, Nielsen A H, Kristensen S D. The effect of dialyzer membrane material on intradialytic changes in platelet count, platelet aggregation, circulating platelet aggregates and antithrombin III.  Scand J Urol Nephrol. 1985;  19 227-232
    PubMedGoogle Scholar
  • 14 Matsuo T, Yamada T, Yamanaehi T, Ryo R. Anticoagulant therapy with MD 805 of a hemodialysis patient with heparin-induced thrombocytopenia.  Thromb Res. 1990;  58 663-666
    CrossrefPubMedGoogle Scholar
  • 15 Hall A V, Clark W F, Parbtani A. Heparin-induced thrombocytopenia in renal failure.  Clin Nephrol. 1992;  38 86-89
    PubMedGoogle Scholar
  • 16 Michalak E, Walkowiak B, Paradowski M, Cieriewski C S. The decreased circulating platelet mass and its relation to bleeding time in chronic renal failure.  Thromb Haemost. 1991;  65 11-14
    PubMedGoogle Scholar
  • 17 DiMinno G, Martinez J, McKean M L et al.. Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis.  Am J Med. 1985;  79 552-559
    CrossrefPubMedGoogle Scholar
  • 18 Eknoyan G, Brown III C H. Biochemical abnormalities of platelets in renal failure. Evidence for decreased platelet serotonin, adenosine diphosphate and Mg-dependent adenosine triphosphatase.  Am J Nephrol. 1981;  1 17-23
    CrossrefPubMedGoogle Scholar
  • 19 Vlachoyannis J, Schoeppe W. Adenylate cyclase activity and cAMP content of human platelets in uremia.  Eur J Clin Invest. 1982;  12 379-381
    PubMedGoogle Scholar
  • 20 Gura V, Creter D, Levi J. Elevated thrombocyte calcium content in uremia and its correction by alpha (OH) vitamin D treatment.  Nephron. 1982;  30 237-239
    PubMedGoogle Scholar
  • 21 Ware J A, Clark B A, Smith M, Salzman E W. Abnormalities of cytoplasmic Ca2+ in platelets from patients with uremia.  Blood. 1989;  73 172-176
    CrossrefPubMedGoogle Scholar
  • 22 Remuzzi G, Benigni A, Dodesini P et al.. Parathyroid hormone inhibits human platelet function.  Lancet. 1981;  2 1321-1323
    PubMedGoogle Scholar
  • 23 Benigni A, Livio M, Dodesini P et al.. Inhibition of human platelet aggregation by parathyroid hormone. Is cyclic AMP implicated?.  Am J Nephrol. 1985;  5 243-247
    PubMedGoogle Scholar
  • 24 Viganò G, Gotti E, Comberti E et al.. Hyperparathyroidism does not influence the abnormal primary haemostasis in patients with chronic renal failure.  Nephrol Dial Transplant. 1989;  4 971-974
    PubMedGoogle Scholar
  • 25 Remuzzi G, Benigni A, Dodesini P et al.. Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclo-oxygenase defect.  J Clin Invest. 1983;  71 762-768
    PubMedGoogle Scholar
  • 26 Winter M, Frampton G, Bennett A, Machin S J, Cameron J S. Synthesis of thromboxane B2 in uraemia and the effects of dialysis.  Thromb Res. 1983;  30 265-272
    CrossrefPubMedGoogle Scholar
  • 27 Smith M C, Dunn M J. Impaired platelet thromboxane production in renal failure.  Nephron. 1981;  29 133-137
    PubMedGoogle Scholar
  • 28 Bloom A, Greaves M, Preston F E, Brown C B. Evidence against a platelet cyclooxygenase defect in uremia subjects on chronic haemodialysis.  Br J Haematol. 1986;  62 143-149
    CrossrefPubMedGoogle Scholar
  • 29 Benigni A, Boccardo P, Galbusera M et al.. Reversible activation defect of the platelet glycoprotein IIb-IIIa complex in patients with uremia.  Am J Kidney Dis. 1993;  22 668-676
    CrossrefPubMedGoogle Scholar
  • 30 Mezzano D, Tagle R, Panes O et al.. Hemostatic disorder of uremia: the platelet defect, main determinant of the prolonged bleeding time, is correlated with indices of activation of coagulation and fibrinolysis.  Thromb Haemost. 1996;  76 312-321
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Sloand E M, Sloand J A, Prodouz K et al.. Reduction of platelet glycoprotein Ib in uraemia.  Br J Haematol. 1991;  77 375-381
    CrossrefPubMedGoogle Scholar
  • 32 Gawaz M P, Dobos G, Spath M et al.. Impaired function of platelet membrane glycoprotein IIb-IIIa in end-stage renal disease.  J Am Soc Nephrol. 1994;  5 36-46
    PubMedGoogle Scholar
  • 33 Sreedhara R, Itagaki I, Hakim R M. Uremic patients have decreased shear-induced platelet aggregation mediated by decreased availability of glycoprotein IIb-IIIa receptors.  Am J Kidney Dis. 1996;  27 355-364
    CrossrefPubMedGoogle Scholar
  • 34 Castillo R, Lozano T, Escolar G et al.. Defective platelet adhesion on vessel subendothelium in uremic patients.  Blood. 1986;  68 337-342
    PubMedGoogle Scholar
  • 35 Zwaginga J J, Ijsseldijk M JW, Beeser-Visser N et al.. High von Willebrand factor concentration compensates a relative adhesion defect in uremic blood.  Blood. 1990;  75 1498-1508
    PubMedGoogle Scholar
  • 36 Escolar G, Cases A, Bastida E et al.. Uremic platelets have a functional defect affecting the interaction of von Willebrand factor with glycoprotein IIb-IIIa.  Blood. 1990;  76 1336-1340
    PubMedGoogle Scholar
  • 37 Deykin D. Uremic bleeding.  Kidney Int. 1983;  24 698-705
    PubMedGoogle Scholar
  • 38 Turney J H, Woods H F, Fewell M R, Weston M J. Factor VIII complex in uremia and effects of hemodialysis.  BMJ. 1981;  282 1653-1656
    PubMedGoogle Scholar
  • 39 Livio M, Mannucci P M, Vigano G et al.. Conjugated estrogens for the management of bleeding associated with renal failure.  N Engl J Med. 1986;  315 731-735
    CrossrefPubMedGoogle Scholar
  • 40 Janson P A, Jubelirer S J, Weinstein M J, Deykin D. Treatment of the bleeding tendency in uremia with cryoprecipitate.  N Engl J Med. 1980;  303 1318-1322
    CrossrefPubMedGoogle Scholar
  • 41 Mannucci P M, Remuzzi G, Pusineri F et al.. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia.  N Engl J Med. 1983;  308 8-12
    CrossrefPubMedGoogle Scholar
  • 42 Remuzzi G, Cavenaghi A E, Mecca G, Donati M B, de Gaetano G. Prostacyclin-like activity and bleeding in renal failure.  Lancet. 1977;  2 1195-1197
    PubMedGoogle Scholar
  • 43 Kyrle P A, Stockenhuber F, Brenner B et al.. Evidence for an increased generation of prostacyclin in the microvasculature and an impairment of platelet alpha-granule release in chronic renal failure.  Thromb Haemost. 1988;  60 205-208
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Silberbauer K, Sinzinger H, Winter M. Increased prostacyclin availability of vascular tissue in experimentally induced acute uremia in rats.  Artery. 1978;  4 554-563
    PubMedGoogle Scholar
  • 45 Zoja C, Vigano G, Bergamelli A et al.. Prolonged bleeding time and increased vascular prostacyclin in rats with chronic renal failure: effects of conjugated estrogens.  J Lab Clin Med. 1988;  112 380-386
    PubMedGoogle Scholar
  • 46 Defreyn G, Dauden M V, Machin S J, Vermylen J. A plasma factor in uraemia which stimulates prostacyclin release from cultured endothelial cells.  Thromb Res. 1980;  19 695
    CrossrefPubMedGoogle Scholar
  • 47 Radomski M W, Palmer R M, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation.  Proc Natl Acad Sci USA. 1990;  87 5193-5197
    CrossrefPubMedGoogle Scholar
  • 48 Neri I, Marietta M, Piccinini F, Volpe A, Facchinetti F. The L-arginine-nitric oxide system regulates platelet aggregation in pregnancy.  J Soc Gynecol Investig. 1998;  5 192-196
    PubMedGoogle Scholar
  • 49 Marietta M, Facchinetti F, Neri I et al.. L-arginine infusion decreases platelet aggregation through an intraplatelet nitric oxide release.  Thromb Res. 1997;  88 229-235
    CrossrefPubMedGoogle Scholar
  • 50 Noris M, Benigni A, Boccardo P et al.. Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension.  Kidney Int. 1993;  44 445-450
    CrossrefPubMedGoogle Scholar
  • 51 Noris M, Remuzzi G. Uremic bleeding: closing the circle after 30 years of controversies?.  Blood. 1999;  94 2569-2574
    PubMedGoogle Scholar
  • 52 Matsumoto A, Hirata Y, Kakoki M et al.. Increased excretion of nitric oxide in exhaled air of patients with chronic renal failure.  Clin Sci. 1999;  96 67-74
    PubMedGoogle Scholar
  • 53 Madore F, Prud’homme L, Austin J S et al.. Impact of nitric oxide on blood pressure in hemodialysis patients.  Am J Kidney Dis. 1997;  30 665-671
    PubMedGoogle Scholar
  • 54 Yokokawa K, Kohno M, Yoshikawa J. Nitric oxide mediates the cardiovascular instability of haemodialysis patients.  Curr Opin Nephrol Hypertens. 1996;  5 359-363
    PubMedGoogle Scholar
  • 55 Martensson L, Hegbrandt J, Thysell H. Generation of nitrate during dialysis as a measure of nitric oxide synthesis.  Artif Organs. 1997;  21 163-167
    PubMedGoogle Scholar
  • 56 Thuraisingham R C, Cramp H A, McMahon A C et al.. Increased superoxide and nitric oxide production results in peroxynitrite formation in uremic vasculature.  J Am Soc Nephrol. 1997;  8 340A
    PubMedGoogle Scholar
  • 57 Descamps-Latscha B, Herbelin A, Nguyen A T et al.. Balance between IL-1β, TNF-α, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes.  J Immunol. 1995;  154 882-892
    PubMedGoogle Scholar
  • 58 Pereira B JG, Dinarello C A. Production of cytokines and cytokine inhibitory proteins in patients on dialysis.  Nephrol Dial Transplant. 1994;  9(suppl 2) 60-71
    PubMedGoogle Scholar
  • 59 Rabiner S F, Molinas F. The role of phenol and phenolic acids on the thrombocytopathy and defective platelet aggregation of patients with renal failure.  Am J Med. 1970;  49 346-351
    CrossrefPubMedGoogle Scholar
  • 60 Horowitz H I, Stein I M, Cohen B D, White J G. Further studies on the platelet inhibitory effect of guanidinosuccinic acid and its role in uremic bleeding.  Am J Med. 1970;  49 336-345
    CrossrefPubMedGoogle Scholar
  • 61 Remuzzi G, Livio E, Marchiaro G, Mecca G, de Gaetano G. Bleeding in renal failure: Altered platelet function in chronic uraemia only partially corrected by haemodialysis.  Nephron. 1978;  22 347-353
    PubMedGoogle Scholar
  • 62 Stein I M, Cohen B D, Horowitz H I. Guanidinosuccinic acid: the “X” factor in uremic bleeding?.  Clin Res. 1968;  16 397A
    PubMedGoogle Scholar
  • 63 Horowitz H I. Uremic toxins and platelet function.  Arch Intern Med. 1970;  126 823-826
    CrossrefPubMedGoogle Scholar
  • 64 Remuzzi G, Marchesi D, Livio M et al.. Altered platelet and vascular prostaglandin-generation in patients with renal failure and prolonged bleeding times.  Thromb Res. 1978;  13 1007-1015
    CrossrefPubMedGoogle Scholar
  • 65 Sloand E M, Bern M M, Kaldany A. Effect on platelet function of hypoalbuminemia in peritoneal dialysis.  Thromb Res. 1986;  44 419-425
    CrossrefPubMedGoogle Scholar
  • 66 Turitto V T, Weiss H J. Red blood cells: their dual role in thrombus formation.  Science. 1980;  207 541-543
    CrossrefPubMedGoogle Scholar
  • 67 Gaarder A, Jonsen J, Lland S et al.. Adenosine diphosphate in red cells as a factor in the adhesiveness of human blood platelets.  Nature. 1961;  192 531-532
    PubMedGoogle Scholar
  • 68 Willems C, Stel H V, van Aken W G, Van Novrik J A. Binding and inactivation of prostacyclin (PGI2) by human erythrocytes.  Br J Haematol. 1983;  54 43-52
    PubMedGoogle Scholar
  • 69 Fernandez F, Goudable C, Sie P et al.. Low hematocrit and prolonged bleeding time in uraemic patients: effect of red cell transfusions.  Br J Haematol. 1985;  59 139-148
    PubMedGoogle Scholar
  • 70 Howard A D, Moore Jr J, Welch P G, Gouge S F. Analysis of the quantitative relationship between anemia and chronic renal failure.  Am J Med Sci. 1989;  297 309-313
    CrossrefPubMedGoogle Scholar
  • 71 Viganò G, Benigni A, Mendogni D et al.. Recombinant human erythropoietin to correct uremic bleeding.  Am J Kidney Dis. 1991;  18 44-49
    CrossrefPubMedGoogle Scholar
  • 72 Van Geet C, Hauglustaine D, Verresen L, Vanrusselt M, Vermylen J. Haemostatic effects of recombinant human erythropoietin in chronic haemodialysis patients.  Thromb Haemost. 1989;  61 117-121
    PubMedGoogle Scholar
  • 73 Zwaginga J J, Ijsseldijk M J, de Groot P G et al.. Treatment of uremic anemia with recombinant erythropoietin also reduces the defects in platelet adhesion and aggregation caused by uremic plasma.  Thromb Haemost. 1991;  66 638-647
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Minetti L. Erythropoietin treatment in renal anemia: how high should the target hematocrit be?.  J Nephrol. 1997;  10 117-119
    PubMedGoogle Scholar
  • 75 Besarab A, Bolton W K, Browne J K et al.. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.  N Engl J Med. 1998;  339 584-590
    CrossrefPubMedGoogle Scholar
  • 76 Fass R J, Copelan E A, Brandt J T, Moeschberger M L, Ashton J J. Platelet-mediated bleeding caused by broad-spectrum penicillins.  J Infect Dis. 1987;  155 1242-1248
    CrossrefPubMedGoogle Scholar
  • 77 Shattil S J, Bennett J S, McDonough M, Turnbull J. Carbenicillin and penicillin G inhibit platelet function in vitro by impairing the interaction of agonists with the platelets surface.  J Clin Invest. 1980;  65 329-337
    CrossrefPubMedGoogle Scholar
  • 78 Andrassy K, Ritz E. Uremia as a cause of bleeding.  Am J Nephrol. 1985;  5 313-319
    PubMedGoogle Scholar
  • 79 Bang N, Tessler S, Heidenreich R, Marks C. Effects of moxolactan on blood coagulation and platelet function.  Rev Infect Dis. 1982;  4 S546-S554
    PubMedGoogle Scholar
  • 80 Bechtold H, Andrassy K, Jahnchen E et al.. Evidence for impaired hepatic vitamin K metabolism in patients treated with N-methyl-thiotetrazole cephalosporin.  Thromb Haemost. 1984;  51 358-361
    PubMedGoogle Scholar
  • 81 Harter H R, Burch J W, Majerus P W et al.. Prevention of thrombosis in patients on hemodialysis by low dose of aspirin.  N Engl J Med. 1979;  301 577-579
    PubMedGoogle Scholar
  • 82 Lindsay R M, Ferguson D, Prentice C R, Burton J A, McNicol G P. Reduction of thrombus formation on dialyser membranes by aspirin and RA233.  Lancet. 1972;  2 1287-1290
    PubMedGoogle Scholar
  • 83 Livio M, Benigni A, Viganò G, Mecca G, Remuzzi G. Moderate doses of aspirin and risk of bleeding in renal failure.  Lancet. 1986;  1 414-416
    PubMedGoogle Scholar
  • 84 Gaspari F, Viganò G, Orisio S et al.. Aspirin prolongs bleeding time in uremia by a mechanism distinct from platelet cyclooxygenase inhibition.  J Clin Invest. 1987;  79 1788-1797
    PubMedGoogle Scholar
  • 85 Zuckerman G R, Cornette G L, Clouse R E, Harter H R. Upper gastrointestinal bleeding in patients with chronic renal failure.  Ann Intern Med. 1985;  102 588-592
    CrossrefPubMedGoogle Scholar
  • 86 Simon S L, Mills J A. Non-steroidal anti-inflammatory drugs.  N Engl J Med. 1980;  302 1237-1343
    PubMedGoogle Scholar
  • 87 Harker L A, Fuster V. Pharmacology of platelet inhibitors.  J Am Coll Cardiol. 1986;  8 21B-32B
    PubMedGoogle Scholar
  • 88 Hammel F S, Johnson G C, Collins G M. A critical appraisal of the changing approaches to vascular access for chronic dialysis.  Proc Eur Dial Transplant Assoc. 1982;  19 325-330
    PubMedGoogle Scholar
  • 89 Kaegi A, Pineo G F, Shimizu A, Trivedi H, Hirsh J, Gent M. Arteriovenous shunt thrombosis. Prevention by sulfinpyrazone.  N Engl J Med. 1974;  290 304-306
    PubMedGoogle Scholar
  • 90 Fiskerstrand C E, Thompson I W, Burnet M E, Williams P, Anderton J L. Double-blind randomized trial of the effect of ticlopidine in arteriovenous fistulas for hemodialysis.  Artif Organs. 1985;  9 61-63
    PubMedGoogle Scholar
  • 91 Avram M M. Cholesterol and lipids in renal disease.  Am J Med. 1989;  87 1N-2N
    PubMedGoogle Scholar
  • 92 Cameron J S. Coagulation and thromboembolic complications in the nephrotic syndrome.  Adv Nephrol Necker Hosp. 1984;  13 75-114
    PubMedGoogle Scholar
  • 93 Llach F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome.  Kidney Int. 1985;  28 429-439
    CrossrefPubMedGoogle Scholar
  • 94 Barnett H L. Minimal change nephrotic syndrome in children: deaths during the first 5-15 years’ observation. Report of the International Study of Kidney Disease in Children.  Pediatrics. 1984;  73 497-501
    PubMedGoogle Scholar
  • 95 Mehls O, Andrassy K, Koderisch J, Herzog U, Ritz E. Hemostasis and thromboembolism in children with nephrotic syndrome: Differences from adults.  J Pediatr. 1987;  110 862-867
    PubMedGoogle Scholar
  • 96 Kendall A G, Lohmann R C, Dossetor J B. Nephrotic syndrome. A hypercoagulable state.  Arch Intern Med. 1971;  127 1021-1027
    CrossrefPubMedGoogle Scholar
  • 97 Schieppati A, Dodesini P, Benigni A et al.. The metabolism of arachidonic acid by platelets in nephrotic syndrome.  Kidney Int. 1984;  25 671-676
    PubMedGoogle Scholar
  • 98 Robert A, Olmer M, Sampol J, Gugliotta J E, Casanova P. Clinical correlation between hypercoagulability and thromboembolic phenomena.  Kidney Int. 1987;  31 830-835
    CrossrefPubMedGoogle Scholar
  • 99 Andrassy K, Ritz E, Bommer J. Hypercoagulability in the nephrotic syndrome.  Klin Wochenschr. 1980;  58 1029-1036
    CrossrefPubMedGoogle Scholar
  • 100 Walter E, Deppermann D, Andrassy K, Koderisch J. Platelet hyperaggregability as a consequence of the nephrotic syndrome.  Thromb Res. 1981;  23 473-479
    CrossrefPubMedGoogle Scholar
  • 101 Cameron J S. Platelets in glomerular disease.  Annu Rev Med. 1984;  35 175-180
    CrossrefPubMedGoogle Scholar
  • 102 Zoja C, Livio M, Benigni A, Remuzzi G. Eicosanoids and platelet activating factor as mediators of injury in renal disease. In: Remuzzi G, Rossi EC Haemostasis and the Kidney. London; Butterworths 1989: 92-104
    Google Scholar
  • 103 Carruthers J A, Ralfs I, Gimlette T M, Finn R. Platelet survival in acute proliferative glomerulonephritis.  Clin Sci Mol Med. 1974;  47 507-513
    PubMedGoogle Scholar
  • 104 Clark W F, Lewis M L, Cameron J S, Parsons V. Intrarenal platelet consumption in the diffuse proliferative nephritis of systemic lupus erythematosus.  Clin Sci Mol Med. 1975;  49 247-252
    PubMedGoogle Scholar
  • 105 George C RP, Slichter S J, Quadracci L J, Striker G E, Harker L A. A kinetic evaluation of hemostasis in renal disease.  N Engl J Med. 1974;  291 1111-1115
    PubMedGoogle Scholar
  • 106 Parbtani A, Clark W F, Cameron J S. Pathogenic significance of platelet activation in lupus nephritis.  Transplant Proc. 1986;  18 657-658
    PubMedGoogle Scholar
  • 107 Kant K S, Pollak V E, Weiss M A et al.. Glomerular thrombosis in systemic lupus erythematosus: prevalence and significance.  Medicine (Baltimore). 1981;  60 71-86
    PubMedGoogle Scholar
  • 108 Heptinstall R H. Hemolytic uremic syndrome, thrombotic, thrombocytopenic purpura, and systemic sclerosis (systemic scleroderma). In: Heptinstall RH Pathology of the Kidney. Boston; Little, Brown 1992: 1163-1233
    Google Scholar
  • 109 Amenta P S, Katz S M. Platelets in renal scleroderma.  Arch Pathol Lab Med. 1983;  107 439-440
    PubMedGoogle Scholar
  • 110 Porter K A. Renal transplantation. In: Heptinstall RH Pathology of the Kidney. Boston; Little, Brown 1992: 1799-1933
    Google Scholar
  • 111 Heptinstall R H. Hypertension I: Essential hypertension. In: Heptinstall RH Pathology of the Kidney. Boston; Little, Brown 1992: 951-1028
    Google Scholar
  • 112 Duffy J L, Cinque T, Grishman E, Churg J. Intraglomerular fibrin, platelet aggregation, and subendothelial deposits in lipoid nephrosis.  J Clin Invest. 1970;  49 251-258
    PubMedGoogle Scholar
  • 113 Nakajima M, Hewitson T D, Mathews D C, Kincaid-Smith P. Platelet-derived growth factor mesangial deposits in mesangial IgA glomerulonephritis.  Nephrol Dial Transplant. 1991;  6 11-16
    PubMedGoogle Scholar
  • 114 Duffus P, Parbtani A, Frampton G, Cameron J S. Intraglomerular localization of platelet related antigens, platelet factor 4 and β-thromboglobulin in glomerulonephritis.  Clin Nephrol. 1982;  17 288-297
    PubMedGoogle Scholar
  • 115 Camussi G. Potential role of platelet-activating factor in renal pathophysiology.  Kidney Int. 1986;  29 469-477
    PubMedGoogle Scholar
  • 116 Lianos E A, Zanglis A. Glomerular platelet-activating factor levels and origin in experimental glomerulonephritis.  Kidney Int. 1990;  37 736-740
    PubMedGoogle Scholar
  • 117 Bertani T, Livio M, Macconi D et al.. Platelet activating factor (PAF) as a mediator of injury in nephrotoxic nephritis.  Kidney Int. 1987;  31 1248-1256
    PubMedGoogle Scholar
  • 118 Yoo J, Schlondorff D, Neugarten J. Protective effects of specific platelet-activating factor receptor antagonists in experimental glomerulonephritis.  J Pharmacol Exp Ther. 1991;  256 841-844
    PubMedGoogle Scholar
  • 119 Camussi G, Tetta C, Deregitus C et al.. Platelet-activating factor (PAF) in experimentally-induced rabbit acute serum sickness: role of basophil-derived PAF in immune complex deposition.  J Immunol. 1982;  128 86-94
    PubMedGoogle Scholar
  • 120 Stahl R AK, Thaiss F, Oberle G et al.. The platelet activating factor receptor antagonist WEB 2170 improves glomerular hemodynamics and morphology in a proliferative model of mesangial cell injury.  J Am Soc Nephrol. 1991;  2 37-44
    PubMedGoogle Scholar
  • 121 Morigi M, Macconi D, Riccardi E et al.. Platelet-activating factor receptor blocking reduces proteinuria and improves survival in lupus autoimmune mice.  J Pharmacol Exp Ther. 1991;  258 601-606
    PubMedGoogle Scholar
  • 122 Macconi D, Noris M, Benfenati E et al.. Increased urinary excretion of platelet activating factor in mice with lupus nephritis.  Life Sci. 1991;  48 1429-1437
    CrossrefPubMedGoogle Scholar
  • 123 Barnes J L, Levine S P, Venkatachalam M A. Binding of platelet factor four (PF 4) to glomerular polyanion.  Kidney Int. 1984;  25 759-765
    PubMedGoogle Scholar
  • 124 Tetta C, Coda R, Camussi G. Human platelet cationic proteins bind to rat glomeruli, induce loss of anionic charges and increase glomerular permeability.  Agents Actions. 1985;  16 24-26
    PubMedGoogle Scholar
  • 125 Camussi G, Tetta C, Segoloni G, Coda R, Vercellone A. Localization of neutrophil cationic proteins and loss of anionic charges in glomeruli of patients with systemic lupus erythematosus glomerulonephritis.  Clin Immunol Immunopathol. 1982;  24 299-314
    CrossrefPubMedGoogle Scholar
  • 126 Barnes J L. Platelets in renal disease. In: Tetta C Immunopharmacology of the Renal System. Handbook of Immunopharmacology London; Academic Press 1993: 88-118
    Google Scholar
  • 127 Abboud H E. Growth factors in glomerulonephritis.  Kidney Int. 1993;  43 252-267
    PubMedGoogle Scholar
  • 128 Shultz P J, DiCorleto P E, Silver B J, Abboud H E. Mesangial cells express PDGF mRNAs and proliferate in response to PDGF.  Am J Physiol. 1988;  255 F674-F684
    PubMedGoogle Scholar
  • 129 Silver B J, Jaffer F E, Abboud H E. Platelet-derived growth factor synthesis in mesangial cells: induction by multiple peptide mitogens.  Proc Natl Acad Sci USA. 1989;  86 1056-1060
    PubMedGoogle Scholar
  • 130 Barnes J L, Hevey K A. Glomerular mesangial cell migration. Response to platelet secretory products.  Am J Pathol. 1991;  138 859-866
    PubMedGoogle Scholar
  • 131 Taraboletti G, Morigi M, Figliuzzi M et al.. Thrombospondin induces glomerular mesangial cell adhesion and migration.  Lab Invest. 1992;  67 566-571
    PubMedGoogle Scholar
  • 132 Johnson R J, Raines E W, Floege J et al.. Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor.  J Exp Med. 1992;  175 1413-1416
    CrossrefPubMedGoogle Scholar
  • 133 Gesualdo L, Pinzani M, Floriano J J et al.. Platelet-derived growth factor expression in mesangial proliferative glomerulonephritis.  Lab Invest. 1991;  65 160-167
    PubMedGoogle Scholar
  • 134 Gesualdo L, Di Paolo S, Milani S et al.. Expression of platelet-derived growth factor receptors in normal and diseased human kidney. An immunohistochemistry and in situ-hybridization study.  J Clin Invest. 1994;  94 50-58
    PubMedGoogle Scholar
  • 135 Rubin K, Tingstrom A, Hasson G K et al.. Induction of B-type receptors for platelet-derived growth factor in vascular inflammation: possible implications for development of vascular proliferative lesions.  Lancet. 1988;  1 1353-1356
    PubMedGoogle Scholar
  • 136 Fellström B, Klareskog L, Heldin C H et al.. Platelet-derived growth factor receptors in the kidney. Upregulated expressions in inflammation.  Kidney Int. 1989;  36 1099-1102
    PubMedGoogle Scholar
  • 137 Border W A, Ruoslahti E. Transforming growth factor-β in disease: the dark side of tissue repair.  J Clin Invest. 1992;  90 1-7
    CrossrefPubMedGoogle Scholar
  • 138 Roberts A B, Sporn M B. The transforming growth factors-β. In: Sporn MB, Roberts AB Handbook of Experimental Pharmacology, Peptide Growth Factors and Their Receptors. Berlin; Springer 1990: 419
    Google Scholar
  • 139 Border W A, Noble N A. Transforming growth factor β in tissue fibrosis.  N Engl J Med. 1994;  331 1286-1292
    CrossrefPubMedGoogle Scholar
  • 140 Okuda S, Languino L R, Ruoslahti E, Border W A. Elevated expression of transforming growth factor-β and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix.  J Clin Invest. 1990;  86 453-462
    PubMedGoogle Scholar
  • 141 Kincaid-Smith P. The treatment of chronic mesangiocapillary (membranoproliferative) glomerulonephritis with impaired renal function.  Med J Aust. 1972;  2 587-592
    PubMedGoogle Scholar
  • 142 Cattran D, Charron R, Cardella C. Controlled trial in mesangio-capillary glomerulonephritis (MCGN). In: Zurukzoglu W, Papadimitriou M, Sion M Eighth International Congress of Nephrology: Advances in Basic and Clinical Nephrology Basel; Karger 1981: 287 (abst)
    Google Scholar
  • 143 Donadio Jr J V, Anderson C F, Mitchell III J C et al.. Membranoproliferative glomerulonephritis. A prospective clinical trial of platelet-inhibitor therapy.  N Engl J Med. 1984;  310 1421-1426
    CrossrefPubMedGoogle Scholar
  • 144 McTavish D, Faulds D, Gao K L. Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders.  Drugs. 1990;  40 238-259
    PubMedGoogle Scholar
  • 145 Hardisty R M, Powling M J, Nokes T JC. The action of ticlopidine on human platelets. Studies on aggregation, secretion, calcium mobilization and membrane glycoproteins.  Thromb Haemost. 1990;  64 150-155
    PubMedGoogle Scholar
  • 146 Grekas D, Alivanis P, Kalekou H, Syrganis C, Tourkantonis A. Are antiplatelet agents of value in the treatment of chronic glomerular disease?.  Nephrol Dial Transplant. 1987;  2 377-379
    PubMedGoogle Scholar
  • 147 Bennett C L, Kiss J E, Weinberg P D et al.. Thrombotic thrombocytopenic purpura after stenting and ticlopidine.  Lancet. 1998;  352 1036-1037
    CrossrefPubMedGoogle Scholar
  • 148 Bennett C L, Weinberg P D, Rozenberg-Ben-Dror K et al.. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases.  Ann Intern Med. 1998;  128 541-544
    CrossrefPubMedGoogle Scholar
  • 149 Moncada S, Higgs E A. Arachidonate metabolism in blood cells and the vessel wall.  Clin Haematol. 1986;  15 273-292
    PubMedGoogle Scholar
  • 150 Leaf A, Weber P C. Cardiovascular effects of ω-3 fatty acids.  N Engl J Med. 1988;  318 549-557
    PubMedGoogle Scholar
  • 151 Hamazaki T, Tateno S, Shishido H. Eicosapentaenoic and IgA nephropathy.  Lancet. 1984;  1 1017-1018
    PubMedGoogle Scholar
  • 152 Bennett W M, Walker R G, Kincaid-Smith P. Treatment of IgA nephropathy with eicosapentaenoic acid (EPA): a 2-year prospective trial.  Clin Nephrol. 1989;  31 128-131
    PubMedGoogle Scholar
  • 153 Cheng I K, Chan P C, Chan M K. The effects of fish oil dietary supplement on the progression of mesangial IgA glomerulonephritis.  Nephrol Dial Transplant. 1990;  5 241-246
    PubMedGoogle Scholar
  • 154 Pettersson E E, Rekola S, Berglund L et al.. Treatment of IgA nephropathy with omega-3-polyunsaturated fatty acids: a prospective, double-blind, randomized study.  Clin Nephrol. 1994;  41 183-190
    PubMedGoogle Scholar
  • 155 Donadio J V, Bergstralh E J, Offord K P, Spencer D C, Holley K E. A controlled trial of fish oil in IgA nephropathy. Mayo nephrology collaborative group.  N Engl J Med. 1994;  331 1194-1199
    CrossrefPubMedGoogle Scholar
  • 156 Dillon J J. Fish oil therapy for IgA nephropathy: efficacy and interstudy variability.  J Am Soc Nephrol. 1997;  8 1739-1744
    PubMedGoogle Scholar

Giuseppe RemuzziM.D. F.R.C.P. 

Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11

24125 Bergamo, Italy

Email: manuelap@marionegri.it

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