Structure, Kinetics, and Function of Human and Rhesus Plasma Prekallikreins Are Similar

Summary

To determine if rhesus monkeys (Macaca mulatta) could serve as a model for studying the role of the contact system in the pathophysiology of human infections, we compared structural, kinetic, and functional characteristics of plasma prekallikrein and its activation products in rhesus and humans. Three prekallikrein variants (85-, 89- and 93-kDa) were revealed in rhesus plasma as compared with the two variants (85- and 88-kDa) in human plasma by immunoblotting with the monoclonal antibody MAb 13G11. The prekallikrein concentration in rhesus plasma was 1.5-fold that in human plasma as determined by computerized immunoblot analyses (CIBA) and amidolytic activity. The electrophoretic mobility of prekallikrein from plasma of both species increased after deglycosylation. Inhibition of prekallikrein activation by MAb 13G11 was 55% (rhesus plasma) and 76% (human plasma), with similar inhibition curves. Immunoblots of activated rhesus plasma showed prekallikrein, complexes of kallikrein with C1 inhibitor, α₂-macroglobulin and ~60-kDa inhibitor(s) (viz. antithrombin III), and 45-kDa fragments, like those in activated human plasma. Concentrations and molecular masses of factor XII and high molecular weight kininogen were similar in rhesus and human plasma. The activated partial thromboplastin time (APTT) and prothrombin time were 20.1 ± 1.6 and 9.7 ± 0.3 s for rhesus and 32.0 ±5.6 and 12 ± 0.5 s for human plasma. Human and rhesus APTTs were similar when prekallikrein concentrations in human and rhesus plasma became alike by adding human purified prekallikrein. We conclude that the contact systems of rhesus and humans are similar in many respects and that rhesus should be a useful model to study the role of the contact system in the pathophysiology of human infectious diseases.

• REFERENCES

• 1 Mandle Jr RJ, Kaplan AP. Human plasma prekallikrein. Mechanism of activation by Hageman factor and participation in Hageman factor-dependent fibrinolysis. J Biol Chem 1977; 252: 6097-6104
• 2 Veloso D, Silver LD, Hahn S, Colman RW. A monoclonal anti-human plasma prekallikrein antibody that inhibits activation of prekallikrein by factor XIIa on a surface. Blood 1987; 70: 1053-1062
• 3 Veloso D, Colman RW. Western blot analyses of prekallikrein and its activation products in human plasma. Thromb Haemostas 1991; 65: 382-388
• 4 Chung DW, Fujikawa K, McMullen BA, Davie EW. Human plasma prekallikrein, a zymogen to a serine protease that contains tandem repeats. Biochemistry 1986; 25: 2410-2417
• 5 Bouma BN, Miles LA, Beretta G, Griffin JH. Human plasma prekallikrein studies of its activation by activated factor XII and its inactivation by diisopropyl phosphofluoridate. Biochemistry 1980; 19: 1151-1160
• 6 Kaplan AP, Silveberg M. The coagulation-kinin pathway of human plasma. Blood 1987; 70: 01-15
• 7 Pierce JV, Webster ME. Purification and some properties of the two different kallidinogens. In: Hypotensive Peptides. Erdos EG, Back N, Sicuteri F. (eds) Springer, New York: 1966. p 130
• 8 Kerbiriou DM, Griffin JH. Human high molecular weight kininogen. Studies of structure-function relationships and of proteolysis of the molecule occurring during contact activation of plasma. J Biol Chem 1979; 254: 12020-12027
• 9 Kaplan AP, Austen KF. A prealbumin activator of prekallikrein. J Immun 1970; 105: 802-811
• 10 Cochrane CG, Wueper KD. The first component of the kinin-forming system in human and rabbit plasma. Its relationship to clotting factor XII (Hageman factor). J Exp Med 1971; 134: 986-994
• 11 Tankersley DL, Finlayson JS. Kinetics of activation and autoactivation of human factor XII. Biochemistry 1984; 23: 273-279
• 12 Harpel PC. Blood proteolytic enzyme inhibitors: their role in modulating blood coagulation and fibrinolytic pathways. In: Hemostasis and Thrombosis. Colman RW, Hirsch J, Marder V, Salzman E. (eds) J. B. Lippincott Company, Philadelphia, PA: 1987. p 219
• 13 Owen MC, Brennan SO, Lewis JH, Carrell RW. Mutation of antitrypsin Pittsburgh (358 Met -» Arg), a fatal bleeding disorder. N Engl J Med 1983; 309: 694-698
• 14 Scott CF, Carrell RW, Claser CB, Kueppers F, Lewis JH, Colman RW. Alpha-1-antitrypsin-Pittsburgh: a potent inhibitor of human plasma factor IXa, kallikrein, and factor Xllf. J Clin Invest 1986; 77: 631-634
• 15 Schapira M, Scott CF, Colman RW. Protection of human plasma, kallikrein from inactivation by Cl-inhibitor and other protease inhibitors. The role of high molecular weight kininogen. Biochemistry 1981; 20: 2738-2745
• 16 van der Graaf F, Koedam JA, Bouma BN. Inactivation of kallikrein in human plasma. J Clin Invest 1983; 71: 149-158
• 17 Saito H, Ratnoff OD, Donaldson VH. Defective activation of clotting, fibrinolytic, and permeability enhancing system in human Fletcher trait plasma. Circ Res 1974; 34: 641-653
• 18 Mandle Jr R, Kaplan AP. Hageman factor substrates. Human plasma prekallikrein: mechanism of activation by Hageman factor-dependent fibrinolysis. J Biol Chem 1977; 252: 6097-6104
• 19 Ichinose A, Fujikawa K, Suyama T. The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986; 261: 3486-3489
• 20 Levi M, Hack CE, de-Boer JP, Brandjes DP, Buller HR, ten Cate JW. Reduction of contact activation related fibrinolytic activity in factor XII deficient patients. Further evidence for the role of the contact system in fibrinolysis in vivo. J Clin Invest 1991; 88: 1155-1160
• 21 Alving BM, Hojima Y, Pisano JJ, Mason BL, Buckingham Jr RE, Mozen MM, Finlayson JS. Hypotension associated with prekallikrein activator (Hageman factor fragments) in plasma protein fraction. N Engl J Med 1978; 299: 66-70
• 22 Lämmle B, Tran TH, Ritz R, Duckert F. Plasma prekallikrein, factor XII, antithrombin III, C1 inhibitor and α₂-macroglobulin in critically ill patients with suspected disseminated intravascular coagulation (DIC). Am J Clin Pathol. 1984; 82: 396-404
• 23 Yamada T, Harber P, Pettit GW, Wing DA, Oster CN. Activation of the kallikrein-kinin system in Rocky Mountain spotted fever. Ann Intern Med 1978; 88: 764-768
• 24 Cosgriff TM. Viruses and Hemostasis. Rev Infect Dis 1989; 11 (Suppl4) S672-S688
• 25 McKee Jr KT, Mahlandt BG, Maiztegui JI, Green DE, Peters CJ. Virus-specific factors in experimental Argentine hemorrhagic fever in rhesus macaques. J Med Virol 1987; 22: 099-111
• 26 Wing DA, Yamada T, Hawley HB, Pettit GW. Model for disseminated intravascular coagulation: Bacterial sepsis in rhesus monkeys. J Lab Clin Med 1978; 92: 239-251
• 27 Cosgriff TM, Morrill JC, Jennings GB, Hodson LA, Slayter PH, Peters CJ. Hemostatic derangement produced by Rift Valley fever virus in rhesus monkeys. Rev Infect Dis 1989; 11 (Suppl4) S807-S814
• 28 Scicli AG, Mindroiu T, Scicli G, Carretero OA. Blood kinins, their concentrations in normal subjects and in patients with congenital deficiency in plasma prekallikrein and kininogen. J Lab Clin Med 1982; 100: 81-93
• 29 Lewin MF, Kaplan AP, Harpel PC. Studies of C1 inactivator-plasma kallikrein complexes in purified system and in plasma. Quantification by an enzyme-linked differential antibody immunosorbent assay. J Biol Chem 1983; 258: 6415-6421
• 30 Harpel PC, Lewin MF, Kaplan AP. Distribution of plasma kallikrein between C1 inactivator and α₂-macroglobulin in plasma utilizing a new assay for α₂-macroglobulin complexes. J Biol Chem. 1985; 260: 4257-4263
• 31 Kaplan AP, Gruber B, Harpel PC. Assessment of Hageman factor activation in human plasma: quantification of activated Hageman factor-Cl inactivator complexes by an enzyme-linked differential antibody immunosorbent assay. Blood 1985; 66: 636-641
• 32 Veloso D, Tseng SY, Craig AR, Colman RW. Binding of a monoclonal anti-human plasma prekallikrein antibody to the complexes of kallikrein with C1 inhibitor and α₂-macroglobulin analyzed by immunoblot and “sandwich” assays. Adv Exp Med Biol. 1989; 247 PT A: 499-505
• 33 Nujens JH, Huijbregts CCM, Eerenberg-Belmer AJM, Abbink JJ, Strack van Schijndel RJM, Felt-Bersma RJF, Thijls LG, Hack CE. Quantification of plasma factor XIIa-Cl inhibitor and kallikrein-Cl inhibitor complexes in sepsis. Blood 1988; 72: 1841-1848
• 34 Abbink JJ, Nuijens JH, Eerenberg AJ, Huijbregts CC, Strack van Schijndel RJ, Thijls LG, Hack CE. Quantification of functional and inactivated alpha-2-macroglobulin in sepsis. Thromb Haemostas 1991; 65: 32-39
• 35 van Deventer SJH, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: Analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520-2526
• 36 Weiss AS, Gallin JI, Kaplan AP. Fletcher factor deficiency. A diminished rate of Hageman factor activation caused by absence of prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic activity, and kinin generation. J Clin Invest 1974; 53: 622-633
• 37 Veloso D. Comparison between prekallikrein in human and rhesus plasma. Thromb Haemostas (Abstr) 1991; 65: 1249
• 38 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature (London) 1970; 227: 680-685
• 39 Burnette WN. “Western Blotting”. Electrophoretic transfer from sodium dodecyl sulfate-polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem 1981; 112: 195-203
• 40 Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proc Natl Acad Sci 1979; 76: 4350-4354
• 41 Fraker PM, Speck Jr JC. Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1, 3, 4, 6-tetrachloro, 3α, 6α-diphenylglycoluril. Biochem Biophys Res Commun 1978; 80: 849-857
• 42 Reddigari S, Kaplan AP. Cleavage of human high-molecular weight kininogen by purified kallikreins and upon contact activation of plasma. Blood 1988; 71: 1334-1340
• 43 Meijers JCM, Kanters DHAJ, Vlooswijk RAA, van Herp HE, Hessing M, Bouma BN. Inactivation of human plasma kallikrein and factor XIa by protein C inhibitor. Biochemistry 1988; 27: 4231-4237
• 44 Reboul A, Prandini M-H, Colomb MG. Proteolysis and deglycosylation of human CT inhibitor. Effect on functional properties. Biochem J 1987; 244: 117-121
• 45 Bock PE, Shore JD, Trans G, Griffin JH. Protein-protein interactions in contact activation of blood coagulation. Binding of high molecular weight kininogen and the 5-(iodoacetamido)fluorescein-labeled kininogen light chain to prekallikrein, kallikrein, and the separated kallikrein heavy and light chains. J Biol Chem 1985; 260: 12434-12443
• 46 Veloso D, Campbell G. Computerized immunoblot analyses of the distribution of prekallikrein and its activation products in normal and C1 inhibitor human plasmas. Thromb Haemostas (Abstr) 1991; 65: 1316
• 47 Vincente V, España F, Tabernero D, Estelles A, Aznar J, Hendl S, Griffin JH. Evidence of activation of the protein C pathway during acute vascular damage induced by Mediterranean spotted fever. Blood 1991; 78: 416-422
• 48 España F, Estelles A, Griffin JH, Aznar J. Interaction of plasma kallikrein with protein C inhibitor in purified mixtures and in plasma. Thromb Haemostas 1991; 65: 46-51
• 49 Lämmle B, Berrettini M, Griffin JH. Immunoblotting studies of coagulation factor XII, plasma prekallikrein and high molecular weight kininogen. Semin Thromb Hemostas 1987; 13: 106-114