High Levels of Tissue Factor Pathway Inhibitor in Patients with Nephrotic Proteinuria

Summary

Acquired deficiency of naturally occurring anticoagulant proteins, due to loss in the urine, has been proposed as one of the major thrombogenic alterations in nephrotic proteinuria. The aim of this study was to investigate if proteinuria may induce deficiency of tissue factor pathway inhibitor (TFPI). TFPI, protein C (PC) and antithrombin (AT) were measured in 31 patients with nephrotic proteinuria, compared with 62 age- and sex-matched controls. Plasma levels of TFPI activity, total TFPI antigen and free TFPI antigen were significantly higher in patients with nephrotic proteinuria than in controls, and none of the patients had TFPI deficiency. Intravenous injection of 7500 IU unfractionated heparin induced a significant further increase of TFPI in two patients with high pre-heparin levels. Also plasma levels of PC were significantly higher in patients than in controls. Mean AT antigen levels were not significantly different between patients and controls, and AT activity was only marginally increased with borderline significance. Three out of 31 patients had substantial acquired AT deficiency. In conclusion, proteinuria is not associated with TFPI deficiency, but with a marked increase of this anticoagulant protein. The acquired thrombophilic diathesis of patients with nephrotic proteinuria can therefore not be attributed to TFPI deficiency.

• References

• 1 Llach F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Int 1985; 28: 429-39.
• 2 Rabelink TJ, Zwaginga JJ, Koomans HA, Sixma JJ. Thrombosis and hemostasis in renal disease. Kidney Int 1994; 46: 287-96.
• 3 Kauffman RH, Veltkamp JJ, van Tilburg NH, van Es LA. Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome. Am J Med 1978; 65: 607-13.
• 4 Boneu B, Bouissou F, Abbal M, Sie P, Caranobe C, Barthe P. Comparison of progressive antithrombin activity and the concentration of three thrombin inhibitors in nephrotic syndrome. Thromb Haemost 1981; 46: 623-5.
• 5 Vaziri ND, Paule P, Toohey J, Hung E, Alikhani S, Drawish R, Pahl M. Acquired deficiency and urinary excretion of antithrombin III in nephrotic syndrome. Arch Int Med 1984; 144: 1802-3.
• 6 Vigano-D’Angelo S, D’Angelo A, Kaufman CE, Scholer C, Esmon CT, Comp PC. Protein S deficiency occurs in the nephrotic syndrome. Ann Int Med 1987; 170: 42-7.
• 7 Gouault-Heilmann M, Gadelha-Parente T, Levent M, Intrator L, Rostoker G, Lagrue G. Total and free protein S in nephrotic syndrome. Thromb Res 1988; 49: 37-42.
• 8 Rydzewski A, Mysliwiec M, Soszka J. Concentration of three thrombin inhibitors in the nephrotic syndrome in adults. Nephron 1986; 42: 200-3.
• 9 Toulon P, Gandrille S, Remy P, Chadeuf G, Jouvin MH, Aiach M. Significance of high levels of heparin cofactor II in the plasma and urine of adult patients with nephrotic syndrome. Nephron 1992; 60: 176-80.
• 10 Soff GA, Sica DA, Marlar RA, Evans HJ, Qureshi GD. Protein C levels in nephrotic syndrome: Use of a new enzyme-linked immunosorbent assay for protein C antigen. Am J Hematol 1986; 22: 43-9.
• 11 Cosio FG, Harker C, Batard MA, Brandt JT, Griffin JH. Plasma concentrations of the natural anticoagulants protein C and protein S in patients with proteinuria. J Lab Clin Med 1985; 106: 218-22.
• 12 Pabinger-Fashing I, Lechner K, Niessner H, Schmidt P, Balzar E, Mannhalter CH. High levels of plasma protein C in nephrotic syndrome. Thromb Haemost 1985; 53: 5-7.
• 13 Mannucci PM, Vaisecchi C, Bottasso B, D’Angelo A, Casati S, Ponticelli C. High plasma levels of protein C activity and antigen in the nephrotic syndrome. Thromb Haemost 1986; 55: 31-3.
• 14 Broze GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP. The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood 1988; 71: 335-43.
• 15 Warn-Cramer BJ, Rao LVM, Maki SL, Rapaport SI. Modifications of extrinsic pathway inhibitor (EPI) and factor Xa that affect their ability to interact and to inhibit factor VIIa/tissue factor: Evidence for a two-step model of inhibition. Thromb Haemost 1988; 60: 453-6.
• 16 Lindahl AK, Sandset PM, Abildgaard U. The present status of tissue factor pathway inhibitor. Blood Coag Fibrinol 1992; 3: 439-49.
• 17 Salvesen G, Pizzo SV. Proteinase Inhibitors: α-Macroglobulins, Serpins and Kunins. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Colman RW, Hirsch J, Marder VJ, Salzman EW. eds. Philadelphia, PA: J. B. Lippincott Company: 1994: 241-58.
• 18 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-13.
• 19 Ariëns RAS, Faioni EM, Mannucci PM. Repeated release of the tissue factor pathway inhibitor. Thromb Haemost 1994; 72: 327-8.
• 20 Bombeli T, Mueller M, Haeberli A. Anticoagulant properties of the vascular endothelium. Thromb Haemost 1997; 77: 408-23.
• 21 Sandset PM, Warn-Cramer BJ, Rao LVM, Maki SL, Rapaport SI. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: Evidence supporting a physiological role for EPI as a natural anticoagulant. Proc Nat Acad Sci USA 1991; 88: 708-12.
• 22 Sandset PM, Warn-Cramer BJ, Maki SL, Rapaport SI. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Shwartzman reaction. Blood 1991; 78: 1496-502.
• 23 Ariëns RAS, Alberio G, Moia M, Mannucci PM. Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 1999; 81: 203-7.
• 24 Hubbard AR, Jennings CA. Inhibition of the tissue factor-factor VII complex: involvement of factor Xa and lipoproteins. Thromb Res 1987; 46: 527-37.
• 25 Novotny WF, Girard JP, Miletich JP, Broze GJ. Purification and characterization of the lipoprotein associated coagulation inhibitor from human plasma. J Biol Chem 1989; 264: 18832-7.
• 26 Hansen JB, Huseby NE, Sandset PM, Svensson B, Lyngmo V, Nordøy A. Tissue factor pathway inhibitor and lipoproteins: Evidence for association with and regulation by LDL in human plasma. Arterioscler Thromb 1994; 14: 223-9.
• 27 Sandset PM, Larsen ML, Abildgaard U, Lindahl AK, Ødegaard OR. Chromogenic substrate assay of extrinsic pathway inhibitor (EPI): Levels in the normal population and relation to cholesterol. Blood Coag Fibrinol 1991; 2: 425-33.
• 28 Marsh JB, Drabkin DL. Experimental reconstruction of metabolic pattern of lipid nephrosis: Key role of hepatic protein synthesis in hyperlipidemia. Metabolism 1960; 9: 946-55.
• 29 Alexander JH, Schapel GJ, Edwards KDG. Increased incidence of coronary heart disease associated with combined elevation of serum triglyceride and cholesterol concentrations in the nephrotic syndrome in man. Med J Aust 1974; 2: 119-22.
• 30 Appel GB, Valeri A, Appel AS, Blum C. The hyperlipidemia of the nephrotic syndrome. Am J Med 1989; 87: 45N-50N.
• 31 Deen WM, Meyers BD, Brenner BM. The glomerular barrier to macromolecules, theoretical and experimental considerations. In: Nephrotic Syndrome. Brenner BM, Stein JH. eds. New York: Churchill Livingstone; 1982: 1-29.
• 32 Girot RF, Jaubert F, Leon M, Bellon B, Aiach M, Josso F, Lepelletier O, Beguin S, Monnet JP. Albumin, fibrinogen, prothrombin and antithrombin III variations in blood, urines and liver in rat nephrotic syndrome. Thromb Haemost 1983; 49: 13-7.
• 33 Ibarra-Rubbio ME, Pedraza-Chaverri J, Panduro A. Differential regulation in the expression of hepatic genes in nephrotic and pair-fed rats. Nephron 1993; 65: 119-24.