Download PDF
Thromb Haemost 2013; 110(03): 399-407
DOI: 10.1160/TH13-03-0258
Theme Issue Article
Schattauer GmbH

Plasma kallikrein: the bradykinin-producing enzyme

Jenny Björkqvist
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2   Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
,
Anne Jämsä
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2   Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
,
Thomas Renné
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2   Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
3   Institute of Clinical Chemistry, University Hospital Hamburg-Eppendorf, Hamburg, Germany
› Author Affiliations
Further Information

Publication History

Received: 02 April 2013

Accepted after minor revision: 04 June 2013

Publication Date:
22 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein (PK) and circulates in plasma bound to high molecular weight kininogen. The zymogen is converted to PK by activated factor XII. PK drives multiple proteolytic reaction cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system and the alternative complement pathway. Here, we review the biochemistry and cell biology of PK and focus on recent in vivo studies that have established important functions of the protease in procoagulant and proinflammatory disease states. Targeting PK offers novel strategies not previously appreciated to interfere with thrombosis and vascular inflammation in a broad variety of diseases.

 

  • References

  • 1 Renne T. The procoagulant and proinflammatory plasma contact system. Semin Immunopathol 2012; 34: 31-41.
    CrossrefPubMedGoogle Scholar
  • 2 Renne T, Schmaier AH, Nickel KF. et al. In vivo roles of factor XII. Blood 2012; 22: 4296-4303.
    PubMedGoogle Scholar
  • 3 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-3843.
    PubMedGoogle Scholar
  • 4 Chung DW, Fujikawa K, McMullen BA. et al. Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats. Biochemistry 1986; 25: 2410-2417.
    CrossrefPubMedGoogle Scholar
  • 5 Renne T, Gailani D, Meijers JC. et al. Characterisation of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein. J Biol Chem 2002; 277: 4892-4899.
    CrossrefPubMedGoogle Scholar
  • 6 Herwald H, Jahnen-Dechent W, Alla SA. et al. Mapping of the high molecular weight kininogen binding site of prekallikrein. Evidence for a discontinuous epitope formed by distinct segments of the prekallikrein heavy chain. J Biol Chem 1993; 268: 14527-14535.
    PubMedGoogle Scholar
  • 7 Renne T, Dedio J, Meijers JC. et al. Mapping of the discontinuous H-kininogen binding site of plasma prekallikrein. Evidence for a critical role of apple domain-2. J Biol Chem 1999; 274: 25777-25784.
    CrossrefPubMedGoogle Scholar
  • 8 Colman RW, Wachtfogel YT, Kucich U. et al. Effect of cleavage of the heavy chain of human plasma kallikrein on its functional properties. Blood 1985; 65: 311-318.
    PubMedGoogle Scholar
  • 9 Neth P, Arnhold M, Sidarovich V. et al. Expression of the plasma prekallikrein gene: utilisation of multiple transcription start sites and alternative promoter regions. Biol Chem 2005; 386: 101-109.
    PubMedGoogle Scholar
  • 10 Fujikawa K, Chung DW, Hendrickson LE. et al. Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein. Biochemistry 1986; 25: 2417-2424.
    CrossrefPubMedGoogle Scholar
  • 11 Tordai H, Banyai L, Patthy L. The PAN module: the N-terminal domains of plasminogen and hepatocyte growth factor are homologous with the apple domains of the prekallikrein family and with a novel domain found in numerous nematode proteins. FEBS Lett 1999; 461: 63-67.
    CrossrefPubMedGoogle Scholar
  • 12 Ponczek MB, Gailani D, Doolittle RF. Evolution of the contact phase of vertebrate blood coagulation. J Thromb Haemost 2008; 06: 1876-1883.
    CrossrefPubMedGoogle Scholar
  • 13 Girolami A, Scarparo P, Candeo N. et al. Congenital prekallikrein deficiency. Expert Rev Hematol 2010; 03: 685-695.
    CrossrefPubMedGoogle Scholar
  • 14 Revenko AS, Gao D, Crosby JR. et al. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood 2011; 118: 5302-5311.
    CrossrefPubMedGoogle Scholar
  • 15 Wuepper KD. Prekallikrein deficiency in man. J Exp Med 1973; 138: 1345-1355.
    CrossrefPubMedGoogle Scholar
  • 16 Abildgaard CF, Harrison J. Fletcher factor deficiency: family study and detection. Blood 1974; 43: 641-644.
    PubMedGoogle Scholar
  • 17 LaDuca FM, Tourbaf KD. Fletcher factor deficiency, source of variations of the activated partial thromboplastin time test. Am J Clin Pathol 1981; 75: 626-628.
    CrossrefPubMedGoogle Scholar
  • 18 Revak SD, Cochrane CG, Johnston AR. et al. Structural changes accompanying enzymatic activation of human Hageman factor. J Clin Invest 1974; 54: 619-627.
    CrossrefPubMedGoogle Scholar
  • 19 Fujikawa K, Heimark RL, Kurachi K. et al. Activation of bovine factor XII (Hageman factor) by plasma kallikrein. Biochemistry 1980; 19: 1322-1330.
    CrossrefPubMedGoogle Scholar
  • 20 Revak SD, Cochrane CG, Griffin JH. The binding and cleavage characteristics of human Hageman factor during contact activation. A comparison of normal plasma with plasmas deficient in factor XI, prekallikrein, or high molecular weight kininogen. J Clin Invest 1977; 59: 1167-1175.
    CrossrefPubMedGoogle Scholar
  • 21 Cochrane CG, Griffin JH. Molecular assembly in the contact phase of the Hageman factor system. Am J Med 1979; 67: 657-664.
    CrossrefPubMedGoogle Scholar
  • 22 Tans G, Rosing J, Berrettini M. et al. Autoactivation of human plasma prekallikrein. J Biol Chem 1987; 262: 11308-11314.
    PubMedGoogle Scholar
  • 23 van der Graaf F, Koedam JA, Bouma BN. Inactivation of kallikrein in human plasma. J Clin Invest 1983; 71: 149-158.
    CrossrefPubMedGoogle Scholar
  • 24 Berrettini M, Schleef RR, Espana F. et al. Interaction of type 1 plasminogen activator inhibitor with the enzymes of the contact activation system. J Biol Chem 1989; 264: 11738-11743.
    PubMedGoogle Scholar
  • 25 Meijers JC, Kanters DH, Vlooswijk RA. et al. Inactivation of human plasma kallikrein and factor XIa by protein C inhibitor. Biochemistry 1988; 27: 4231-4237.
    CrossrefPubMedGoogle Scholar
  • 26 Reddigari SR, Shibayama Y, Brunnee T. et al. Human Hageman factor (factor XII) and high molecular weight kininogen compete for the same binding site on human umbilical vein endothelial cells. J Biol Chem 1993; 268: 11982-11987.
    PubMedGoogle Scholar
  • 27 Motta G, Rojkjaer R, Hasan AA. et al. High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells: a novel mechanism for contact activation. Blood 1998; 91: 516-528.
    PubMedGoogle Scholar
  • 28 Meloni FJ, Gustafson EJ, Schmaier AH. High molecular weight kininogen binds to platelets by its heavy and light chains and when bound has altered susceptibility to kallikrein cleavage. Blood 1992; 79: 1233-1244.
    PubMedGoogle Scholar
  • 29 Gustafson EJ, Schmaier AH, Wachtfogel YT. et al. Human neutrophils contain and bind high molecular weight kininogen. J Clin Invest 1989; 84: 28-35.
    CrossrefPubMedGoogle Scholar
  • 30 Renne T, Dedio J, David G. et al. High molecular weight kininogen utilises heparan sulfate proteoglycans for accumulation on endothelial cells. J Biol Chem 2000; 275: 33688-33696.
    CrossrefPubMedGoogle Scholar
  • 31 Renne T, Muller-Esterl W. Cell surface-associated chondroitin sulfate proteoglycans bind contact phase factor H-kininogen. FEBS Lett 2001; 500: 36-40.
    CrossrefPubMedGoogle Scholar
  • 32 Renne T, Schuh K, Muller-Esterl W. Local bradykinin formation is controlled by glycosaminoglycans. J Immunol 2005; 175: 3377-3385.
    CrossrefPubMedGoogle Scholar
  • 33 Joseph K, Ghebrehiwet B, Peerschke EI. et al. Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular “heads” of C1q (gC1q-R). Proc Natl Acad Sci USA 1996; 93: 8552-8557.
    CrossrefPubMedGoogle Scholar
  • 34 Mahdi F, Madar ZS, Figueroa CD. et al. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood 2002; 99: 3585-3596.
    CrossrefPubMedGoogle Scholar
  • 35 Dembitzer FR, Kinoshita Y, Burstein D. et al. gC1qR expression in normal and pathologic human tissues: differential expression in tissues of epithelial and mesenchymal origin. J Histochem Cytochem 2012; 60: 467-474.
    CrossrefPubMedGoogle Scholar
  • 36 Dedio J, Jahnen-Dechent W, Bachmann M. et al. The multiligand-binding protein gC1qR, putative C1q receptor, is a mitochondrial protein. J Immunol 1998; 160: 3534-3542.
    PubMedGoogle Scholar
  • 37 Maas C, Renne T. Regulatory mechanisms of the plasma contact system. Thromb Res 2012; 129 (Suppl. 02) S73-S76.
    CrossrefPubMedGoogle Scholar
  • 38 Maas C, Oschatz C, Renne T. The plasma contact system 2.0. Semin Thromb Hemost 2011; 37: 375-381.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Muller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
    CrossrefPubMedGoogle Scholar
  • 40 Oschatz C, Maas C, Lecher B. et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity 2011; 34: 258-268.
    CrossrefPubMedGoogle Scholar
  • 41 Maas C, Govers-Riemslag JW, Bouma B. et al. Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. J Clin Invest 2008; 118: 3208-3218.
    PubMedGoogle Scholar
  • 42 Muller F, Renne T. Platelet polyphosphates: The nexus of primary and secondary hemostasis. Scand J Clin Lab Invest 2011; 71: 82-86.
    CrossrefPubMedGoogle Scholar
  • 43 Moreno-Sanchez D, Hernandez-Ruiz L, Ruiz FA. et al. Polyphosphate is a novel pro-inflammatory regulator of mast cells and is located in acidocalcisomes. J Biol Chem 2012; 287: 28435-28444.
    CrossrefPubMedGoogle Scholar
  • 44 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
    CrossrefPubMedGoogle Scholar
  • 45 Frick IM, Bjorck L, Herwald H. The dual role of the contact system in bacterial infectious disease. Thromb Haemost 2007; 98: 497-502.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Soisson SM, Patel SB, Abeywickrema PD. et al. Structural definition and substrate specificity of the S28 protease family: the crystal structure of human prolylcarboxypeptidase. BMC Struct Biol 2010; 10: 16
    CrossrefPubMedGoogle Scholar
  • 47 Shariat-Madar Z, Mahdi F, Schmaier AH. Identification and characterisation of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem 2002; 277: 17962-17969.
    CrossrefPubMedGoogle Scholar
  • 48 Joseph K, Tholanikunnel BG, Kaplan AP. Heat shock protein 90 catalyses activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci USA 2002; 99: 896-900.
    CrossrefPubMedGoogle Scholar
  • 49 Goetzl EJ, Austen KF. Stimulation of human neutrophil leukocyte aerobic glucose metabolism by purified chemotactic factors. J Clin Invest 1974; 53: 591-599.
    CrossrefPubMedGoogle Scholar
  • 50 Becker CG, Dubin T, Glenn F. Induction of acute cholecystitis by activation of factor XII. J Exp Med 1980; 151: 81-90.
    CrossrefPubMedGoogle Scholar
  • 51 Leeb-Lundberg LM, Marceau F, Muller-Esterl W. et al. International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2005; 57: 27-77.
    CrossrefPubMedGoogle Scholar
  • 52 Schapira M, Despland E, Scott CF. et al. Purified human plasma kallikrein aggregates human blood neutrophils. J Clin Invest 1982; 69: 1199-1202.
    CrossrefPubMedGoogle Scholar
  • 53 Benz PM, Blume C, Seifert S. et al. Differential VASP phosphorylation controls remodeling of the actin cytoskeleton. J Cell Sci 2009; 122: 3954-3965.
    CrossrefPubMedGoogle Scholar
  • 54 Blume C, Benz PM, Walter U. et al. AMP-activated protein kinase impairs endothelial actin cytoskeleton assembly by phosphorylating vasodilator-stimulated phosphoprotein. J Biol Chem 2007; 282: 4601-4612.
    CrossrefPubMedGoogle Scholar
  • 55 Benz PM, Blume C, Moebius J. et al. Cytoskeleton assembly at endothelial cell-cell contacts is regulated by alphaII-spectrin-VASP complexes. J Cell Biol 2008; 180: 205-219.
    CrossrefPubMedGoogle Scholar
  • 56 Tiruppathi C, Ahmmed GU, Vogel SM. et al. Ca2+ signalling, TRP channels, and endothelial permeability. Microcirculation 2006; 13: 693-708.
    CrossrefPubMedGoogle Scholar
  • 57 Busse R, Fleming I. Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol Sci 2003; 24: 24-29.
    CrossrefPubMedGoogle Scholar
  • 58 Lindsay SL, Ramsey S, Aitchison M. et al. Modulation of lamellipodial structure and dynamics by NO-dependent phosphorylation of VASP Ser239. J Cell Sci 2007; 120: 3011-3021.
    CrossrefPubMedGoogle Scholar
  • 59 Wojciak-Stothard B, Torondel B, Zhao L. et al. Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function. Mol Biol Cell 2009; 20: 33-42.
    CrossrefPubMedGoogle Scholar
  • 60 Shigematsu S, Ishida S, Gute DC. et al. Bradykinin-induced proinflammatory signalling mechanisms. Am J Physiol Heart Circ Physiol 2002; 283: H2676-H2686.
    CrossrefPubMedGoogle Scholar
  • 61 Bjorkqvist J, Sala-Cunill A, Renne T. Hereditary angioedema: a bradykinin-mediated swelling disorder. Thromb Haemost 2013; 109: 368-374.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Gailani D, Renne T. Intrinsic pathway of coagulation and arterial thrombosis. Arterioscler Thromb Vasc Biol 2007; 27: 2507-2513.
    CrossrefPubMedGoogle Scholar
  • 63 Gailani D, Broze Jr. GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253: 909-912.
    CrossrefPubMedGoogle Scholar
  • 64 Colman RW. Activation of plasminogen by human plasma kallikrein. Biochem Biophys Res Commun 1969; 35: 273-279.
    CrossrefPubMedGoogle Scholar
  • 65 Jorg M, Binder BR. Kinetic analysis of plasminogen activation by purified plasma kallikrein. Thromb Res 1985; 39: 323-331.
    CrossrefPubMedGoogle Scholar
  • 66 Derkx FH, Bouma BN, Schalekamp MP. et al. An intrinsic factor XII- prekallikrein-dependent pathway activates the human plasma renin-angiotensin system. Nature 1979; 280: 315-316.
    CrossrefPubMedGoogle Scholar
  • 67 Sealey JE, Atlas SA, Laragh JH. et al. Activation of a prorenin-like substance in human plasma by trypsin and by urinary kallikrein. Hypertension 1979; 01: 179-189.
    CrossrefPubMedGoogle Scholar
  • 68 Kaplan AP, Ghebrehiwet B, Silverberg M. et al. The intrinsic coagulation-kinin pathway, complement cascades, plasma renin-angiotensin system, and their interrelationships. Crit Rev Immunol 1981; 03: 75-93.
    PubMedGoogle Scholar
  • 69 DiScipio RG. The activation of the alternative pathway C3 convertase by human plasma kallikrein. Immunology 1982; 45: 587-595.
    PubMedGoogle Scholar
  • 70 Davis 3rd AE. Hereditary angioedema: a current state-of-the-artreview III: mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol 2008; 100 (01) (Suppl. 02) S7-S12.
    CrossrefPubMedGoogle Scholar
  • 71 Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 2008; 359: 1027-1036.
    CrossrefPubMedGoogle Scholar
  • 72 Cichon S, Martin L, Hennies HC. et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 2006; 79: 1098-1104.
    CrossrefPubMedGoogle Scholar
  • 73 Han ED, MacFarlane RC, Mulligan AN. et al. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002; 109: 1057-1063.
    CrossrefPubMedGoogle Scholar
  • 74 Cugno M, Cicardi M, Bottasso B. et al. Activation of the coagulation cascade in C1-inhibitor deficiencies. Blood 1997; 89: 3213-3218.
    CrossrefPubMedGoogle Scholar
  • 75 Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med 2002; 347: 621-622.
    CrossrefPubMedGoogle Scholar
  • 76 Cicardi M, Levy RJ, McNeil DL. et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010; 363: 523-531.
    CrossrefPubMedGoogle Scholar
  • 77 Gao BB, Clermont A, Rook S. et al. Extracellular carbonic anhydrase mediates haemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 2007; 13: 181-188.
    CrossrefPubMedGoogle Scholar
  • 78 Gao BB, Chen X, Timothy N. et al. Characterisation of the vitreous proteome in diabetes without diabetic retinopathy and diabetes with proliferative diabetic retinopathy. J Proteome Res 2008; 07: 2516-2525.
    CrossrefPubMedGoogle Scholar
  • 79 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
    CrossrefPubMedGoogle Scholar
  • 80 Liu J, Gao BB, Clermont AC. et al. Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. Nat Med 2011; 17: 206-210.
    CrossrefPubMedGoogle Scholar
  • 81 Kleinschnitz C, Stoll G, Bendszus M. et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 2006; 203: 513-518.
    CrossrefPubMedGoogle Scholar
  • 82 Bird JE, Smith PL, Wang X. et al. Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: murine ortholog of the Fletcher trait. Thromb Haemost 2012; 107: 1141-1150.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 83 Renne T, Pozgajova M, Gruner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-281.
    CrossrefPubMedGoogle Scholar
  • 84 Merkulov S, Zhang WM, Komar AA. et al. Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis. Blood 2008; 111: 1274-1281.
    PubMedGoogle Scholar
  • 85 Muller F, Gailani D, Renne T. Factor XI and XII as antithrombotic targets. Curr Opin Hematol 2011; 18: 349-355.
    CrossrefPubMedGoogle Scholar
  • 86 Zuraw BL, Busse PJ, White M. et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010; 363: 513-522.
    CrossrefPubMedGoogle Scholar
  • 87 Fergusson DA, Hebert PC, Mazer CD. et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358: 2319-2331.
    CrossrefPubMedGoogle Scholar
  • 88 Williams A, Baird LG. DX-88 and HAE: a developmental perspective. Transfus Apher Sci 2003; 29: 255-258.
    CrossrefPubMedGoogle Scholar
  • 89 Hathaway WE, Belhasen LP, Hathaway HS. Evidence for a new plasma thromboplastin factor I. Case report, coagulation studies physicochemical properties. Blood 1965; 26: 521-532.
    PubMedGoogle Scholar