α₂-Antiplasmin, Plasminogen Activator Inhibitor (PAI) and Dilute Blood Clot Lysis Time in Selected Disease States

Summary

This paper is an attempt to assess the relevance of the inhibitors of fibrinolysis for clot lysis in selected disease states and to discuss the mechanisms leading to acquired abnormal levels of such inhibitors. When compared to 20 control subjects the 30 hypertriglyceridemic patients (14 with type IIb and 16 with type IV) displayed significantly (p <0.001) increased plasma plasminogen activator inhibitor (PAI) activity (221 ± 88% and 290 ± 104% respectively; mean ± SD), moderately (p <0.01) increased α₂ antiplasmin (α₂AP) level (112 ± 11% and 115 ± 16%) and accordingly an obviously prolonged dilute blood clot lysis time (DBCLT). Neither PAI activity and α₂AP level nor DBCLT were significantly different from controls in the 10 patients with hyperlipoproteinemia type IIa. The 18 patients with severe hepatic cirrhosis had low α₂AP level (59 ± 19.7%) and accelerated clot lysis, while mean PAI activity (160 ± 87%) was slightly (p <0.05) increased. In the 17 nephrotic patients α₂AP was increased (115 ±12%) while PAI activity was similar to controls and DBCLT rather shorter. Two liver secretion enzymes, namely serum Cholinesterase and plasma protein C, were found to be decreased in cirrhotic patients, similar to control values in hyperlipoproteinemia type Ha and obviously increased in nephrotic patients as well as in hypertriglyceridemic subjects. The relevance of PAI and α₂AP for clot lysis was considered in relation to data in the literature concerning the behaviour of t-PA and factor XIII. Enhanced hepatic synthesis of protease inhibitors and factor XIII as a possible cause of delayed clot lysis in hypertriglyceridemia was envisaged.

• References

• 1 Aoki N. Hemostasis associated with abnormalities of fibrinolysis. Blood Rev 1989; 3: 1-17
• 2 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Brief Review. Blood 1987; 69: 381-7
• 3 Lijnen HR, Collen D. Congenital and acquired deficiencies of components of the fibrinolytic system and their relation to bleeding or thrombosis. Fibrinolysis 1989; 3: 67-77
• 4 Sakata Y, Aoki N. Crosslinking of α₂ plasmin inhibitor to fibrin stabilizing factor. J Clin Invest 1980; 65: 290-7
• 5 de Fouw NJ, de Jong YP, Hyerkate P, Bertina BM. The influence of thrombin and platelets on fibrin clot lysis rates in vitro: a study using a clot lysis system consisting of purified human proteins. Fibrinolysis 1988; 2: 235-44
• 6 Clouse LN, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314: 1298-304
• 7 Koie K, Kamiya T, Ogata K, Takamatsu J, Kobokura M. α₂ plasmin inhibitor deficiency (Miyasato disease). Lancet 1978; 2: 1334-6
• 8 Schleef RR, Higgins DL, Pilemer E, Lewitt AJ. Bleeding diathesis due to a decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest 1989; 83: 1747-52
• 9 Duckert F. Documentation of the plasma factor XIII deficiency in man. Ann NY Acad Sci 1972; 202: 190-9
• 10 Hamsten A, Wiman B, De Faire U, Blombôck M. Increased plasma level of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63
• 11 Cucuianu M, Stef C, Zdrenghea D, Popescu O. In vitro effect of p-chlormercuribenzoate upon dilute blood clot lysis time in hyperlipemia. Thromb Haemostas 1979; 42: 924-44
• 12 Boks AI, Brommer EIP, Schalm SW, Van Vliet HHDM. Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage. Hepatology 1986; 6: 79-86
• 13 Tran-Thang C, Fasel-Felley J, Pralong G, Hofstetter JR, Bachmann F, Kruithof EKO. Plasminogen activators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or infections hepatitis. Thromb Haemostas 1989; 62: 651-3
• 14 Aoki N, Yamanaka T. The α₂ plasmin inhibitor in liver disease. Clin Chim Acta 1978; 84: 99-105
• 15 Cucuianu M, Rus HG, Cristea A, Niculescu P, Bedeleanu D, Poruțiu D, Roman S. Clinical studies on plasma fibronectin and factor XIII; with special reference to hyperlipoproteinemia. Clin Chim Acta 1985; 147: 273-81
• 16 Cucuianu M, Rus HG, Roman S, Mărcuşu C, Spînu C, Manasia M, Niculescu F. Tissue-type plasminogen activator and dilute blood clot lysis time in nephrotic patients. Thromb Haemostas 1989; 61: 270-4
• 17 Astrup T, Brackman P, Nissen U. The estimation of fibrinogen. A revision. Scand J Clin Lab Invest 1965; 17: 57-65
• 18 Bockendahl H, Ammon R. Cholinesterases. In: Methods of Enzymatic Analysis.. Bergmeyer HU. (ed) Second Edition, Academic Press, New York – London: 1965. pp 771-5
• 19 Mimuro J, Koike Y, Sumi Y, Aoki N. Monoclonal antibodies to discrete regions in α₂ plasmin inhibitor. Blood 1987; 69: 446-53
• 20 Chmielewska J, Wiman B. Determination of tissue plasminogen activator and its "fast" inhibitor in plasma. Clin Chim Acta 1986; 32: 482-5
• 21 Chmielewska J. Studies on human plasminogen activator inhibitor in plasma and cell cultures. Thesis, Karolinska Institutet Stockholm, 1988
• 22 Gallimore MJ, Tyler HM, Shaw JTB. The measurement of fibrinolysis in the rat. Thromb Diathes Haemorrh (Stuttg) 1971; 26: 275-310
• 23 Vigano S, Mannucci PM, Rumi MG, Vigano P, Delninno E, Colombo M, Podda M. The significance of protein C antigen in acute and chronic liver and biliary disease. Am J Clin Pathol 1985; 84: 454-8
• 24 Zurborn KH, Kirch W, Bruhn HD. Immunological and functional determination of the protease inhibitors, protein C and antithrombin III, in liver cirrhosis and in neoplasia. Thromb Res 1988; 52: 325-36
• 25 Goldstein JL, Brown MS. The low density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 1977; 46: 897-930
• 26 Sane T, Nikkilô EA. Very low density lipoprotein triglyceride metabolism in relatives of hypertriglyceridemic probands. Arteriosclerosis 1988; 8: 217-26
• 27 Junah-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationship between plasma insulin, triglyceride, body mass index and plasminogen activator inhibitor-1. Diab-Metabol 1987; 13: 331-6
• 28 Knöbl PN, Fisher P, Kaliman JF, Vukovich ThChr. Plasma levels of protein C and protein S in patients with vasculopathy. Thromb Res 1987; 45: 857-63
• 29 Cucuianu M, Opincaru A, Tapalagă D. Similar behaviour of lecithin: cholesterol acyltransferase and pseudoCholinesterase in liver disease and hyperlipoproteinemia. Clin Chim Acta 1978; 85: 73-9
• 30 Constantino M, Merkey C, Kudzma DJ, Zucker MB. Increased activity of vitamin K-dependent clotting factors in human hyperlipoproteinemia. Association with cholesterol and triglyceride levels. Thromb Haemostas 1977; 38: 465-74
• 31 Cucuianu M, Popescu TA, Roman S, Bedeleanu D, Pais R. Increased plasma level of clotting factors VII and X in hyperlipoproteinemia. Rev Roum Med Interne 1985; 23: 37-43
• 32 Alessi MC, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator by hepatocellular cell line Hep G₂ . Thromb Haemostas 1988; 60: 491-4
• 33 Kooistra T, Bosma PI, Töns HAM, van den Berg AP, Meyer P, Princen HMG. Plasminogen activator inhibitor 1: Biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemostas 1989; 62: 723-8
• 34 Legnani C, Maccaferri M, Tonini P, Cassio A, Cacciari E, Coccheri S. Reduced fibrinolytic response in obese children: association with high baseline activity of the fast acting plasminogen activator inhibitor (PAI-1). Fibrinolysis 1988; 2: 211-4
• 35 Hoffman M, Fuchs HE, Pizzo SV. The macrophage mediated regulation of hepatocyte synthesis of antithrombin III and α₁ proteinase inhibitor. Thromb Res 1986; 41: 707-15
• 36 Appel GB, Blum CB, Chien S, Kunis CL, Appel AS. The hyper-lipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure and viscosity. N Engl J Med 1985; 312: 1544-8
• 37 Pabinger-Fasching I, Lechner K, Niessner H, Schmidt P, Balzar E, Mannhalter Ch. High levels of plasma protein C in nephrotic syndrome. Thromb Haemostas 1985; 53: 5-7
• 38 Edelberg JM, Gonzales-Gronow M, Pizzo SV. Lipoprotein(a) inhibition of plasminogen activation by tissue-type plasminogen activator. Thromb Res 1990; 57: 155-62
• 39 Fletcher AP, Biederman O, Moore O, Alkjaersig N, Sherry S. Abnormal plasminogen-plasmin system activity (fibrinolysis) in patients with hepatic cirrhosis: its cause and consequences. J Clin Invest 1964; 43: 681-95
• 40 Wun TC, Capuano A. Initiation and regulation of fibrinolysis in human plasma at the plasminogen activator level. Blood 1987; 69: 1354-62
• 41 McDonagh RP, McDonagh I, Duckert F. The influence of fibrin crosslinking on the kinetics of urokinase-induced clot lysis. Br J Haematol 1971; 21: 323-32