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Thromb Haemost 1990; 64(01): 161-164
DOI: 10.1055/s-0038-1647274
Original Article
Schattauer GmbH Stuttgart

In Vitro Thromboxane Synthesis of Depleted Blood Platelets Following Renal Transplantation[*]

Rüdiger E Scharf
The Department of Medicine, Division of Hematology, Oncology and Clinical Immunology, Heinrich Heine University of Dilsseldorf, FRG
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Publication History

Received 29 September 1989

Accepted after revision 28 March 1990

Publication Date:
04 September 2018 (online)

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Summary

Renal transplant rejection is associated with platelet activation in vivo which may lead to partially α- and γ-granule-depleted platelets that continue to circulate. These “exhausted” platelets are hemostatically defective. Tb quantitate the extent of platelet granule depletion following kidney transplantation, we determined intraplatelet levels of β-thromboglobulin (βTG), platelet factor 4 (PF4), and serotonin (5-hydroxytryptamine, 5-HT) ex vivo in Tiiton X-1O0-treated platelet lysates. To explore biochemical alterations of partially depleted platelets, we studied platelet thromboxane A2 (TXA2) synthesis in citrated plateletrich plasma (PRP) upon stimulation with thrombin or collagen in 45 recipients of renal allografts and 10 healthy volunteers. The patients were divided into subjects with acute and chronic allograft rejection (N = 15), those with compensated renal failure after kidney transplantation but without evidence of allograft rejection (N = 15), and those with functioning renal transplant (N = 15). The mean intraplatelet content of βTG (38.6 ± 4.2 μE/109 platelets), PF4 (11.8 ± 1.8 μg/109 platelets), and 5-HT (274 ± 31 μg/109 platelets) in patients with acute or chronic renal allograft rejection was significantly lower than in other recipients off < idney transplants or healthy volunteers (βTG: 59.9±4.7 μgl 109 platelets; PF4: 20.4±2.3 ¼g/n platelets; s-rrr: 46lraB ngl 10e platelets; p < 0.ffi5 in all casls). Platelet TxB2 formation upon stimulation with thrombin (10 U/ml) or collagen (6.25 ¼g/ml) for 5 min was significantly reduced in patients with acute or chronic renal allograft rejection (2.25±0.29 and 0.641 0.08 nmoUl0e platelets for thrombin- and collagen-stimulated platelets, respectively) compared to that of healthy volunteers (4.72± 0.60 and 1.35 ± 0.12 nmol/109 platelets, respectively; p <0.05 in all cases). In contrast, platelet TXB2 formation of patients with functioning kidney transplant or those with compensated renal failure but without evidence of transplant rejection did not differ significantly from that of normals. These results confirm that platelets with reduced levels of α- and β-granular constituents are detectable in the circulation following kidney transplantation when acute or chronic renal allograft rejections occur. These platelets are incapable of forming normal amounts of thromboxane upon stimulation with thrombin and collagen in vitro. This dysfunction of thromboxane synthesis, due to alterations in the platelet arachidonate pathway, may reflect the previous activation of platelets in vivo associated with acute or chronic renal allograft rejection.

This work was supported by a grant (Scha 358/1-2) from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG


 

  • References

  • 1 Capitanio A, Mannucci PM, Ponticelli C, Pareti FI. Detection of circulating released platelets after renal transplantation. Transplantation 1982; 33: 298-301
    CrossrefPubMedGoogle Scholar
  • 2 Scharf RE, Reimers HJ, Grzibiela W, Risler T, Schnurr E, Grabensee B, Schneider W. Renal transplant rejection - is it associated with increased platelet activity in vivo?. Haemostasis 1982; 12: 194 (Abstr)
    PubMedGoogle Scholar
  • 3 Scharf RE, Grzibiela W, Hartmann B, Schnurr E, Grabensee B, Schneider W. Plattchenspezifische Proteine und Thrombinaktivitat bei AbstoBungsreaktionen nach Nierentransplantation. Verh Dtsch Ges Inn Med 1983; 976-979
    PubMedGoogle Scholar
  • 4 Scharf RE. Thrombozyten und Mikrozirkulationsstorungen. Klini-sche und experimentelle Untersuchungen zum Sekretionsverhalten und Arachidonsaurestoffwechsel der Blutplattchen FK Schattauer Verlag; Stuttgart: 1986: 172-191
    Google Scholar
  • 5 O’Brien JR. “Exhausted” platelets continue to circulate. Lancet 1978; 02: 1316-1317
    PubMedGoogle Scholar
  • 6 Scharf RE. Acquired platelet storage pool deficiency: Clinical and experimental considerations (Alexander Schmidt Memorial Lecture). In: Wenzel E, Hellstem P, Morgenstern E, Kohler M, van Blohn G. (eds) Rational Diagnosis and Treatment of Haemorrhagic Diathesis and Thromboembolic Disorders. FK Schattauer Verlag; Stuttgart: 1986: 1.27-1.44
  • 7 Harker LA, Malpass TW, Branson HE, Hessel IIE A, Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: Acquired transient platelet dysfunction associated with selective a-granule release. Blood 1980; 56: 824-834
    PubMedGoogle Scholar
  • 8 Pareti FI, Capitanio A, Mannucci L, Ponticelli C, Mannucci PM. Acquired dysfunction due to circulation of “exhausted” platelet. Am J Med 1980; 69: 235-240
    CrossrefPubMedGoogle Scholar
  • 9 Scharf RE, Wehmeier A, Schneider W. Reduced platelet thromboxane formation in acute thrombotic thrombocytopenic purpura: Evidence for an abnormal platelet population with a transient cyclo-oxygenase defect. Thromb Haemostas 1987; 58: 483 (Abstr)
    PubMedGoogle Scholar
  • 10 Weiss HJ. Congenital disorders of platelet function. Semin Hematol 1980; 17: 228-241
    PubMedGoogle Scholar
  • 11 Thiel G, Mihatsch M, Landmann J, Hermle M, Brunner FP, Harder F. Is cyclosporine A-induced nephrotoxicity in recipients of renal allografts progressive?. Transplant Proc 1985; 17 (01) 169-178
    PubMedGoogle Scholar
  • 12 Strom TB, Tilney NL. Renal tansplantation: Clinical aspects. In: Brenner B, Rector FC. (eds). The Kidney; 3rd. ed Saunders, Philadelphia, PA: 1986: 1941
  • 13 Fung JJ, Demetris AJ, Porter KA, Iwatsuki S, Gordon RD, Esquivel CO, Jaffe R, Tzakis A, Shaw BW, Starzl TE. Use of OKT 3 with ciclosporin and steroids for reversal of acute kidney and liver allograft rejection. Nephron 1987; 46 (Suppl. 01) 19-33
    CrossrefPubMedGoogle Scholar
  • 14 Boerner U, Szasz G, Bablok W, Busch EW. Referenzwerte fur Kreatinin im Serum, ermittelt mit einer spezifischen enzymatischen Methode. J Clin Chem Clin Biochem 1979; 17: 679-682
    PubMedGoogle Scholar
  • 15 Scharf RE, Tsamaloukas A, Schneider W. Inhibition of platelet a-granule release in vitro by forskolin. Thromb Res 1984; 33: 661-664
    CrossrefPubMedGoogle Scholar
  • 16 Drummond AH, Gordon JL. Rapid sensitive microassay for platelet 5-HT. Thromb Diathes Haemorrh 1974; 31: 366-367
    PubMedGoogle Scholar
  • 17 Smith JB. The prostanoids in hemostasis and thrombosis. Am J Pathol 1980; 99: 773-804
    PubMedGoogle Scholar
  • 18 Beurling-Harbury C, Galvan CA. Acquired decrease in platelet secretory ADP associated with increased postoperative bleeding in post-cardiopulmonary patients with severe valvular heart disease. Blood 1978; 52: 13-23
    PubMedGoogle Scholar
  • 19 Malpass TW, Harker LA. Acquired disorders of platelet function. Semin Hematol 1980; 17: 242-258
    PubMedGoogle Scholar
  • 20 Pumphrey CW, Dawes J. Platelet a-granule depletion: Findings in patients with prosthetic heart valves and following cardiopulmonary bypass surgery. Thromb Res 1983; 30: 257-264
    CrossrefPubMedGoogle Scholar
  • 21 Weiss HJ, Rosove MH, Lages BA, Kaplan KL. Acquired storage pool deficiency with increased platelet-associated IgG. Report of five cases. Am J Med 1980; 69: 711-717
    PubMedGoogle Scholar
  • 22 Zahavi J, Marder VJ. Acquired “storage pool disease” of platelets associated with circulating antiplatelet antibodies. Am J Med 1974; 56: 883-890
    CrossrefPubMedGoogle Scholar
  • 23 Fong JS C, Kaplan BS. Impairment of platelet aggregation in hemolytic uremic syndrome: Evidence for platelet “exhaustion”. Blood 1982; 60: 564-570
    PubMedGoogle Scholar
  • 24 Pareti FI, Capitanio A, Mannucci PM. Acquired storage pool disease in platelets during disseminated intravascular coagulation. Blood 1976; 48: 511-515
    PubMedGoogle Scholar
  • 25 Scharf RE, Schneider W. Klinische, biochemische und zytomor-phometrische Aspekte zur Thrombozytopenie und Thrombozytopathie bei Leberzirrhose. Hamostaseologie 1984; 4: 43-49
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Weiss HJ, Witte LD, Kaplan KL, Lages BA, Chernoff A, Nossel HL, Goodman DW S, Baumgartner HR. Heterogeneity in storage pool deficiency: studies on granule-bound substances in 18 patients including variant deficient a-granules, platelet factor 4, p-thrombo-globulin, and platelet-derived growth factor. Blood 1979; 54: 1296-1319
    PubMedGoogle Scholar
  • 27 DeChavanne M, Lagarde M, Bryon PA. Thrombopathie avec deficit en cyclooxygenase. Nouv Rev Fr Hematol 1976; 16: 421-426
    PubMedGoogle Scholar
  • 28 Patrono C, Cibattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar B. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-327
    CrossrefPubMedGoogle Scholar
  • 29 McGowan EB, Detwiler TC. Characterization of the thrombin-induced desensitization of platelet activation by thrombin. Thromb Res 1983; 31: 297-304
    CrossrefPubMedGoogle Scholar
  • 30 Reimers HJ, Scharf RE, Baker RK. Thrombin pretreatment of human platelets impairs thromboxane A2 synthesis from endogenous precursors in the presence of normal cyclooxygenase activity. Blood 1984; 63: 858-865
    PubMedGoogle Scholar
  • 31 Reimers HJ, Baker RK, Joist JH. Impaired thromboxane synthesis in preactivated human blood platelets: Agonist-specific, irreversible desensitization to thrombin. Thromb Res 1987; 48: 535-548
    CrossrefPubMedGoogle Scholar
  • 32 Stockschlader M, Scharf RE. Failure of preactivated human blood platelets to restore defective thromboxane synthesis despite prolonged incubation in plasma. Thromb Haemostas 1989; 62: 1016-1022
    PubMedGoogle Scholar
  • 33 Schror K, Latta G, Darius H, Klaus W, Ziegler R. Inhibition of platelet aggregation and thromboxane formation by the calcium antagonist nisoldipine after single oral administration of 10 mg. Klin Wschr 1985; 63: 16-19
    CrossrefPubMedGoogle Scholar
  • 34 Flower R. Steroidal antiinflammatory drugs as inhibitors of phos-pholipase A2. In: Galli C, Galli G, Porcelatti G. (eds). Prostaglandins and Phospholipases. Advances in Prostaglandin and Thromboxane Research, vol. 3. Raven Press; New York: 1978: 105-112
  • 35 Jorgensen KA, Stoffersen E. Hydrocortisone inhibits platelet prostaglandin and endothelial prostacyclin production. Pharmacol Res Commun 1981; 13: 579-587
    CrossrefPubMedGoogle Scholar
  • 36 Vanrenterghem Y, Roels L, Lerut T, Gruwez J, Gresele P, Deckmyn H, Colucci M, Arnout J, Vermylen J. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients. Lancet 1985; 01: 999-1002
    PubMedGoogle Scholar
  • 37 Remuzzi G, Benigni A, Dodesini P, Schieppati A, Livio M, de Gaetano G, Day JS, Smith WL, Pinca E, Patrignani P, Patrono C. Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclooxygenase defect. J Clin Invest 1983; 71: 762-768
    CrossrefPubMedGoogle Scholar