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Thromb Haemost 1998; 79(04): 747-751
DOI: 10.1055/s-0037-1615058
Rapid Communication
Schattauer GmbH

Increased Thromboxane Metabolites Excretion in Liver Cirrhosis

Giovanni Davì
1   From the Departments of Medicine, Universities of Chieti, Rome
,
Domenico Ferro
2   From the Departments of Medicine, “La Sapienza”, Rome
,
Stefania Basili
2   From the Departments of Medicine, “La Sapienza”, Rome
,
Luigi Iuliano
2   From the Departments of Medicine, “La Sapienza”, Rome
,
Caterina Camastra
2   From the Departments of Medicine, “La Sapienza”, Rome
,
Carlo Giammarresi
1   From the Departments of Medicine, Universities of Chieti, Rome
,
Stella Santarone
1   From the Departments of Medicine, Universities of Chieti, Rome
,
Bianca Rocca
3   From the Departments of Medicine, Rome Catholic University, Italy
,
Raffaele Landolfi
3   From the Departments of Medicine, Rome Catholic University, Italy
,
Giovanni Ciabattoni
4   From the Departments of Medicine, Institute of Pharmacology, Catholic University of Rome, Italy
,
Corrado Cordova
2   From the Departments of Medicine, “La Sapienza”, Rome
,
Francesco Violi
2   From the Departments of Medicine, “La Sapienza”, Rome
› InstitutsangabenSupported by grants from Consiglio Nazionale delle Ricerche (CNR), Progetto Finalizzato Prevenzione e Controllo dei Fattori di Malattia (SP8: 94.00560. PF41, and 95.00807. PF41)
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Publikationsverlauf

Received 13. März 1997

Accepted after resubmission 24. November 1997

Publikationsdatum:
07. Dezember 2017 (online)

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Summary

An augmented systemic production of thromboxane (TX) A2, as assessed by urinary excretion of the thromboxane metabolites, has been described in severe liver cirrhosis. However, the significance of this finding remains unclear since in liver cirrhosis a number of phenomena i.e. altered hepatic TXA2 metabolism, increased intrasplenic platelet destruction, may affect TXA2 entry into systemic circulation as well as its metabolism. In order to further clarify this, we measured both major enzymatic metabolites of TXB2 in the urine of 44 patients affected by liver cirrhosis, subdivided in three classes on the basis of Child-Pugh criteria. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were assayed with previously validated RIA techniques.

The urinary excretion rate of 11-dehydro-TXB2 was significantly (p = 0.0001) increased in the cirrhotic patients (673.5 pg/mg cr, median) in comparison with the controls (275 pg/mg cr, median) but no significant difference could be demonstrated among the excretion rates of the three patient subgroups. The excretion rate of 2,3 dinor-TXB2 was also significantly (p = 0.0001) increased in the patients (824 pg/mg cr, median) in comparison with controls (175 pg/mg cr, median), with a significant (p <0.05) increase from class A (381 pg/mg cr) to class C (1337 pg/mg cr). The sum of the two enzymatic metabolites was significantly (p = 0.0001) increased in the cirrhotic patients in comparison to controls, with a progressive increase from class A (1003 pg/mg cr, median) to class C (2240 pg/mg cr, median). The urinary excretion of 2,3 dinor-TXB2 was significantly (p = 0.008) related to plasma prothrombin fragment 1+2 (F1+2).

This study provides further evidence of increased thromboxane biosynthesis in liver cirrhosis. Moreover, we demonstrate intraliver shift of thromboxane metabolic disposition, due to progressive liver decompensation, because only the fraction undergoing β-oxidation to 2,3-dinor-TXB2 was progressively increased with the degree of liver failure. We, also, find a significant correlation between urinary excretion of 2,3-dinor-TXB2 and plasma F1+2, suggesting that clotting activation could partly account for in vivo platelet activation.

 

  • References

  • 1 Moore K, Ward PS, Taylor GW, Williams R. Systemic and renal production of thromboxane A2 and prostacyclin in decompensated liver disease and hepatorenal syndrome. Gastroenterology 1991; 100: 1069-77.
    CrossrefPubMedGoogle Scholar
  • 2 Guarner F, Guarner C, Prieto J, Colina I, Quiroga J, Casas J, Freixa R, Rosello J, Gelpi E, Balanzo J. Increased synthesis of systemic prostacyclin in cirrhotic patients. Gastroenterology 1986; 90: 687-94.
    CrossrefPubMedGoogle Scholar
  • 3 Laffi G, Cinotti S, Filimberti E, Ciabattoni G, Caporale R, Marra F, Melani L, Grossi A, Gentilini P. Defective aggregation in cirrhosis is independent of in vivo platelet activation. J Hepatol 1996; 24: 436-43.
    CrossrefPubMedGoogle Scholar
  • 4 FitzGerald GA, Brash AR, Falardeau P, Oates JA. Estimated rate of prostacyclin secretion into the circulation of normal man. J Clin Invest 1981; 68: 1272-6.
    CrossrefPubMedGoogle Scholar
  • 5 FitzGerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 1983; 67: 1174-7.
    CrossrefPubMedGoogle Scholar
  • 6 Violi F, Leo R, Vezza E, Basili S, Cordova C, Balsano F. and the CALC Group. Bleeding time in patients with cirrhosis: relation with degree of liver failure and clotting abnormalities. J Hepatol 1994; 20: 531-6.
    CrossrefPubMedGoogle Scholar
  • 7 Roberts LJ, Sweetman BJ, Oates JA. Metabolism of thromboxane B2 in man: identification of twenty urinary metabolites. J Biol Chem 1981; 256: 8384-93.
    PubMedGoogle Scholar
  • 8 Ciabattoni G, Pugliese F, Davì G, Pierucci A, Simonetti BM, Patrono C. Fractional conversion of thromboxane B2 to urinary 11-dehydro-thromboxane B2 in man. Biochim Biophys Acta 1989; 992: 66-70.
    CrossrefPubMedGoogle Scholar
  • 9 Violi F, Ferro D, Basili S, Saliola S, Quintarelli C, Alessandri C, Cordova C. Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology 1995; 109: 531-39.
    CrossrefPubMedGoogle Scholar
  • 10 Pugh RNH, Murray-Lyon IM, Dawson JL. Transection of oesophagus for bleeding oesophagus varices. Br J Surg 1973; 60: 646-9.
    CrossrefPubMedGoogle Scholar
  • 11 Conn HO. A peak at the Child-Turcotte classification. Hepatology 1981; 1: 673-6.
    CrossrefPubMedGoogle Scholar
  • 12 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-40.
    CrossrefPubMedGoogle Scholar
  • 13 Cordova C, Violi F, Alessandri C, Ferro D, Saliola M, Musca A, Balsano F. Prekallikrein and factor VII as prognostic indexes of liver failure. Am J Clin Pathol 1986; 85: 579-82.
    CrossrefPubMedGoogle Scholar
  • 14 Pelzer H, Schwartz A, Stuber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost 1991; 65: 153-9.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 15 Violi F, Ferro D, Basili S, Quintarelli C, Musca A, Cordova C, Balsano F. and the CALC Group. Hyperfibrinolysis resulting from clotting activation in patients with different degrees of liver cirrhosis. Hepatology 1993; 17: 78-83.
    CrossrefPubMedGoogle Scholar
  • 16 Carr JM. Disseminated intravascular coagulation in cirrhosis. Hepatology 1989; 10: 103-10.
    CrossrefPubMedGoogle Scholar
  • 17 Ciabattoni G, Maclouf J, Catella F, FitzGerald GA, Patrono C. Radio-immunoassay of 11-dehydrotromboxane B2 in human plasma and urine. Biochim Biophis Acta 1987; 918: 293-7.
    PubMedGoogle Scholar
  • 18 Di Minno G, Davì G, Margaglione M, Cirillo F, Grandone E, Ciabattoni G, Catalano I, Strisciuglio P Andria G, Patrono C Mancini M. Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism. J Clin Invest 1993; 92: 1400-6.
    CrossrefPubMedGoogle Scholar
  • 19 Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar BA. Low-dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-27.
    CrossrefPubMedGoogle Scholar
  • 20 Armitage P, Berry G. Statistical methods in medical research. 2nd ed. Oxford: Blackwell Scientific Publications; 1990: 200-15.
    Google Scholar
  • 21 FitzGerald GA, Brash AR, Oates JA, Pedersen AK. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest 1983; 72: 1336-43.
    CrossrefPubMedGoogle Scholar
  • 22 Laffi G, Cominelli F, Ruggiero M, Fedi S, Chiarugi VP, La Villa G, Pinzani M, Gentilini P. Altered platelet function in cirrhosis of the liver: impairment of inositol lipid and arachidonic acid metabolism in response to agonists. Hepatology 1988; 6: 1620-6.
    PubMedGoogle Scholar
  • 23 Laffi G, Marra F, Gresele P, Romagnoli P, Palermo A, Bartolini O, Simoni A, Orlandi L, Selli ML, Nenci GG, Gentilini P. Evidence for a Storage Pool Defect in Platelets from Cirrhotic Patients with Defective Aggregation. Gastroenterology 1992; 103: 641-6.
    CrossrefPubMedGoogle Scholar
  • 24 Violi F, Leo R, Davì G, Praticò D, Iuliano L, Balsano F. Thrombocytopenia and thrombocytopathia in liver cirrhosis. Platelets 1992; 3: 233-9.
    PubMedGoogle Scholar
  • 25 Ferro D, Quintarelli C, Lattuada A, Leo R, Alessandroni M, Mannucci PM, Violi F. High plasma von Willebrand factor as marker of endothelial perturbation in liver cirrhosis: relationship to endotoxemia. Hepatology 1996; 23: 1377-83.
    CrossrefPubMedGoogle Scholar
  • 26 Bauer KA, Rosemberg RD. The pathophysiology of the prothrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50.
    PubMedGoogle Scholar
  • 27 Beer JH, Clerici N, Baillod P, von Felten A, Schlappritzi E, Buchi L. Quantitative and qualitative analysis of platelet GPIb and von Willebrand factor in liver cirrhosis. Thromb Haemost 1995; 73: 601-9.
    Artikel in Thieme ConnectPubMedGoogle Scholar