Changes in Plasma Levels of Protease and Fibrinolytic Inhibitors Induced by Treatment in Acute Myeloid Leukemia

Summary

We have studied the main protease inhibitors of leukocytes, alpha-1-protease (α₁-PI), alpha- 1-antichymotrypsin (α₁-Achy) and alpha-2-macroglobulin (α₂-M), as well as different parameters of coagulation and fibrinolysis in 21 cases of acute nonlymphoblastic leukemia (ANLL) before, during and after therapy.

Nine of the patients presented signs of DIC, 8 of whom belonged to subtype M3 and to subtype 1 M₁.

The initial α₁-PI and α₁-Achy levels, which were elevated, increased during the treatment period. There was no significant difference between patients with and without DIC. However, those leukemic patients with DIC showed a significant decrease in plasminogen (p <0.005) and fast antiplasmin (p <0.01) only during the treatment compared with DIC free patients. All DIC cases demonstrated circulating plasmin-antiplasmin complex (P-AP) both before and during treatment.

Independent of a possible proteolytic action of leukocyte enzymes on clotting factors in the clinical course of ANLL (mainly M₃ subtype), our results suggest an activation of plasminmediated fibrinolysis related to the activation of plasminogen by leukocytes, reactive DIC or both.

Keywords

Leukocyte proteases - ANLL - DIC - Fibrinolytic inhibitors - P-AP complex

• References

• 1 Rosenthal RL. Acute promyelocytic leukemia associated with hypofibrinogenemia. Blood 1963; 21: 495-508
• 2 Didisheim P, Thrombold JS, Vandervoort LE, Mibashan RS. Acute promyelocytic leukemia with fibrinogen and factor V deficiencies. Blood 1964; 23: 717-728
• 3 Gralnick HR, Tan KH. Acute promyelocytic leukemia. Hum Pathol 1974; 5: 661-673
• 4 Gralnick HR, Sultan C. Acute promyelocytic leukemia: haemorrhagic manifestation and morphologic criteria. Br J Haematol 1975; 29: 373-376
• 5 Plow EF, Edgington TS. An alternative pathway for fibrinolysis. The cleavage of fibrinogen by leukocytes proteases at physiologic pH J Clin Invest 1975; 58: 30-38
• 6 Egbring R, Schmidt W, Fuchs G, Havemann K. Demonstration of granulocytic proteases in plasma of patients with acute leukemia and septicemia with coagulation defects. Blood 1977; 49: 219-231
• 7 Bennett JM, Catosvky D, Daniel MT, Flandrin G, Galton DA G, Gralnick HR, Sultan C. Proposals classification of the acute leukemias. Br J Haematol 1976; 33: 451-458
• 8 Gamba G, Fornasari P, Montanini N, Biancardi M, Grignani G, Ascari E. Plasma levels of protease inhibitors in acute myeloid leukemia at the onset of the disease and during antiblastic therapy. Thromb Res 1980; 17: 41-53
• 9 Miralles J, Felez J, Ramirez de Arellano R, Velasco F, Fontcuberta J, Borrell M, Rutilant ML. Metodo rapido y simple de extraction de heparina y sulfato de protamina del plasma humano. Metodologia Biol Clin Hematol 1980; 2: 19-23
• 10 Caen J, Larrieu M, Samama M. L’Hémostase. Méthodes d’exploration et diagnostic practique. L’Expansion Scientifique 1975
• 11 Laurell CM. Quantitative estimation of protein by electrophoresis in agarose gel containing antibodies. Anal Biochem 1966; 15: 45-52
• 12 ødegård OR, Lie M, Abildgaard U. Heparin cofactor activity measured with an amidolytic methods. Thromb Res 1975; 6: 287-294
• 13 Friberger P, Knös M, Gustavsson S, Aurell L, Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-145
• 14 Teger-Nilsson AC, Friberger P, Gyzander E. Determination of a new rapid plasma inhibitor in human blood by means of plasma specific tripeptide substrate. Scand J Clin Lab Invest 1977; 37: 403-404
• 15 Ganrot PO. Crossed Immunoelectrophoresis. Scand J Clin Lab Invest 1972; (Suppl. 29) Suppl 124-139
• 16 Collen D. On the regulation and control of fibrinolysis. Thromb Haemostas 1980; 43: 77-89
• 17 Felez J, Borrell M, Fontcuberta J, Rutllant ML. Determinacion del complejo plasmina-antiplasmina en sujetos normales y en el curso del tratamiento fibrinolitico. Biol Clin Hematol 1979; 2: 153-158
• 18 Velasco F, Torres A, Andres P, Duran M. Functional activities and concentrations of plasmin inhibitors in normal subjects and DIC patients. Thromb Haemostas 1982; 47: 275-277
• 19 Shipper HG, Kalhe LH, Jenkins CS P, Ten Cate JW. Antithrombin III transfusion in disseminated intravascular coagulation. Lancet 1978; 2: 854
• 20 Vellenga E, Mulder NH. Normal levels of antithrombin III in acute leukemia complicated by coagulopathy. Acta Haematol 1980; 63: 336-338
• 21 Trobisch H. Hämostatische. Dt Med Wschr 1976; 101: 1420-1433
• 22 Denson KW E. The ratio of factor VIII-related antigen and factor VIII biological activity as an index of hypercoagulability and intravascular clotting. Thromb Res 1977; 10: 107-119
• 23 Kopec M, Bykowska K, Lopaciuk S, Jelenska M, Kaczanowska J, Sopata I, Wojtecka E. Effects of neutral proteases from leukocytes on structure and biological properties of human factor VIII. Thromb Haemostas 1980; 43: 211-217
• 24 Kopec M, Kaczanowska J, Stachurska J, Tomczak Z, Wojteckalukasik E, Bykowska K, Lopaciuk S. Effects of granulocytic neutral protease on some clotting factors. In: Progress in fibrinolysis. Davidson JF, Nilsson IM, Asted B. (eds) Churchill Livingstone; New York: 1981. 5 75-77
• 25 Moroz LA. Nonplasmin-mediated fibrinolysis. Semin Thromb Haemostas 1984; 10: 80-86
• 26 Graeff H, Hafter R. Subunit structure of circulating fibrin. In: Progress in fibrinolysis. Davidson JF, Nilsson IM, Asted B. (eds) Churchill Livingstone; New York: 1981. 5 393-398
• 27 Pizzo SV, Schwartz ML, Hill RL, Mckee PA. The effect of plasmin on the subunic structure of human fibrinogen. J Biol Chem 1972; 247: 636-645
• 28 McDonald JA, Braun BJ, Rosenberg DM, Kelman JA, Brin SC, Crystal RG. Destruction of major extracellular adhesive glycoprotein (fibronectin) of human fibroblast by neutral protease from polymorphonuclear leukocyte granules. Lab Invest 1979; 40: 350-357
• 29 Gramse M, Bingenheimer C, Schmidt W. Degradation products of fibrinogen by elastase-like neutral protease from human granulocytes. Characterization and effects on blood coagulation in vitro J Clin Invest 1978; 61: 1027-1033
• 30 Ohlsson K, Akersson V. α₁-Antichymotrypsin interaction with cationic proteins from granulocytes. Clin Chim Acta 1976; 73: 285
• 31 Venge P, Ohlsson I, Odebery H. Cationic proteins of human granulocytes. Interaction with plasma protease inhibitors Scand J Clin Lab Invest 1975; 35: 737-744
• 32 Morse JO. Alpha-1-antitrypsin deficiency. N Eng J Med 1978; 299: 1045-1048
• 33 Brower MS, Harper PC. Alpha-l-antitrypsin-human leukocyte elastase complexes in blood: quantification by an enzyme-linked differential antibody immunosorbent assay and comparison with alpha-2-plasmin inhibitor-plasmin complexes. Blood 1983; 61: 841-849
• 34 Plow EF, Edgington TS. Comparative immunochemical characterization of products of plasmin and leukocyte protease cleavage of human fibrinogen. Thromb Res 1978; 12: 653-665