Top

Published in:

Open Access 01-12-2015 | Research

Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1-inhibitor deficiency

Authors: Dorottya Csuka, Nóra Veszeli, Éva Imreh, Zsuzsanna Zotter, Judit Skopál, Zoltán Prohászka, Lilian Varga, Henriette Farkas

Published in: Orphanet Journal of Rare Diseases | Issue 1/2015

Abstract

Background

The activation of plasma enzyme systems contributes to hereditary angioedema attacks. We aimed to study the activation markers of the fibrinolytic, coagulation, and contact systems in a larger number of paired samples obtained from the same C1-INH-HAE patients in symptom-free periods and during attacks.

Methods

Eleven parameters (Factors XI, XII, and C1-inhibitor activity; the concentrations of the D-dimer, prothrombin fragments 1 + 2, plasminogen, plasminogen activator inhibitor-1 [PAI-1], thrombin-anti-thrombin III [TAT] complex, fibrinogen) were measured along with prothrombin time and activated partial thromboplastin time (aPTT), using commercial kits. We compared these markers in samples obtained from the same 39 patients during attack-free periods and during 62 edematous episodes. Forty healthy subjects of matching sex and age served as controls.

Results

Compared with the healthy controls, significantly higher FXI and FXII activity (p = 0.0007, p = 0.005), as well as D-dimer (p < 0.0001), prothrombin fragments 1 + 2 (p < 0.0001), and TAT (p = 0.0303) levels were ascertained in the patients during symptom-free periods. The evaluation of samples from symptom-free periods or obtained during attacks revealed the increase of FXII activity, as well as of the concentration of D-dimer, prothrombin fragments 1 + 2, and TAT during edematous episodes. PAI-1 level, prothrombin time, and aPTT decreased significantly during attacks, compared with symptom-free periods. D-dimer level was significantly higher during multiple- vs. single-site attacks.

Conclusions

Comparing a large number of paired samples from symptom-free periods or from edematous episodes allowed accurate appraisal of the changes occurring during attacks. Moreover, our study pointed out that individual episodes may be characterized by different marker patterns.

Zeerleder S. C1-inhibitor: more than a serine protease inhibitor. Semin Thromb Hemost. 2011;37(4):362–74. doi:10.1055/s-0031-1276585.CrossRefPubMed

Forbes CD, Pensky J, Ratnoff OD. Inhibition of activated Hageman factor and activated plasma thromboplastin antecedent by purified serum C1 inactivator. J Lab Clin Med. 1970;76(5):809–15.PubMed

van der Graaf F, Keus JF, Koedam JA, Rietveld A, Bouma BN. Prekallikrein activation and kallikrein inactivation in human plasma. Adv Exp Med Biol. 1983;156:143–8.PubMed

Wuillemin WA, Minnema M, Meijers JC, Roem D, Eerenberg AJ, Nuijens JH, et al. Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor. Blood. 1995;85(6):1517–26.PubMed

Pixley RA, Schapira M, Colman RW. The regulation of human factor XIIa by plasma proteinase inhibitors. J Biol Chem. 1985;260(3):1723–9.PubMed

Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A. 2007;104(15):6388–93. doi:10.1073/pnas.0608647104.PubMedCentralCrossRefPubMed

Maas C, Govers-Riemslag JW, Bouma B, Schiks B, Hazenberg BP, Lokhorst HM, et al. Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. J Clin Invest. 2008;118(9):3208–18. doi:10.1172/JCI35424.PubMedCentralPubMed

Smith SA, Choi SH, Davis-Harrison R, Huyck J, Boettcher J, Rienstra CM, et al. Polyphosphate exerts differential effects on blood clotting, depending on polymer size. Blood. 2010;116(20):4353–9. doi:10.1182/blood-2010-01-266791.PubMedCentralCrossRefPubMed

Muller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM, et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell. 2009;139(6):1143–56. doi:10.1016/j.cell.2009.11.001.PubMedCentralCrossRefPubMed

10.

Herwald H, Morgelin M, Olsen A, Rhen M, Dahlback B, Muller-Esterl W, et al. Activation of the contact-phase system on bacterial surfaces--a clue to serious complications in infectious diseases. Nat Med. 1998;4(3):298–302.CrossRefPubMed

11.

Joseph K, Shibayama Y, Ghebrehiwet B, Kaplan AP. Factor XII-dependent contact activation on endothelial cells and binding proteins gC1qR and cytokeratin 1. Thromb Haemost. 2001;85(1):119–24.PubMed

12.

Zotter Z, Csuka D, Szabo E, Czaller I, Nebenfuhrer Z, Temesszentandrasi G, et al. The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis. 2014;9:44. doi:10.1186/1750-1172-9-44.PubMedCentralCrossRefPubMed

13.

Kaplan AP. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy. J Allergy Clin Immunol. 2010;126(5):918–25. doi:10.1016/j.jaci.2010.08.012.CrossRefPubMed

14.

Cugno M, Cicardi M, Bottasso B, Coppola R, Paonessa R, Mannucci PM, et al. Activation of the coagulation cascade in C1-inhibitor deficiencies. Blood. 1997;89(9):3213–8.PubMed

15.

Garcia JG, Pavalko FM, Patterson CE. Vascular endothelial cell activation and permeability responses to thrombin. Blood Coagul Fibrinolysis. 1995;6(7):609–26.CrossRefPubMed

16.

Garcia JG, Siflinger-Birnboim A, Bizios R, Del Vecchio PJ, Fenton 2nd JW, Malik AB. Thrombin-induced increase in albumin permeability across the endothelium. J Cell Physiol. 1986;128(1):96–104. doi:10.1002/jcp.1041280115.CrossRefPubMed

17.

DeMichele MA, Moon DG, Fenton 2nd JW, Minnear FL. Thrombin’s enzymatic activity increases permeability of endothelial cell monolayers. J Appl Physiol. 1990;69(5):1599–606.PubMed

18.

Oschatz C, Maas C, Lecher B, Jansen T, Bjorkqvist J, Tradler T, et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011;34(2):258–68. doi:10.1016/j.immuni.2011.02.008.CrossRefPubMed

19.

Bossi F, Fischetti F, Regoli D, Durigutto P, Frossi B, Gobeil Jr F, et al. Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency. J Allergy Clin Immunol. 2009;124(6):1303–10. doi:10.1016/j.jaci.2009.08.007.PubMedCentralCrossRefPubMed

20.

Brown NJ, Gainer JV, Stein CM, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release in human vasculature. Hypertension. 1999;33(6):1431–5.CrossRefPubMed

21.

Okada H, Watanabe Y, Kikuta T, Kobayashi T, Kanno Y, Sugaya T, et al. Bradykinin decreases plasminogen activator inhibitor-1 expression and facilitates matrix degradation in the renal tubulointerstitium under angiotensin-converting enzyme blockade. J Am Soc Nephrol. 2004;15(9):2404–13. doi:10.1097/01.ASN.0000136132.20189.95.CrossRefPubMed

22.

Colman RW, Bagdasarian A, Talamo RC, Scott CF, Seavey M, Guimaraes JA, et al. Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways. J Clin Invest. 1975;56(6):1650–62. doi:10.1172/JCI108247.PubMedCentralCrossRefPubMed

23.

Ghebrehiwet B, Randazzo BP, Dunn JT, Silverberg M, Kaplan AP. Mechanisms of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest. 1983;71(5):1450–6.PubMedCentralCrossRefPubMed

24.

Schmaier AH. Contact activation: a revision. Thromb Haemost. 1997;78(1):101–7.PubMed

25.

Kaplan AP, Austen KF. A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin. J Exp Med. 1971;133(4):696–712.PubMedCentralCrossRefPubMed

26.

Kleniewski J, Blankenship DT, Cardin AD, Donaldson V. Mechanism of enhanced kinin release from high molecular weight kininogen by plasma kallikrein after its exposure to plasmin. J Lab Clin Med. 1992;120(1):129–39.PubMed

27.

Nielsen EW, Morrissey J, Olsen JO, Osterud B. Factor VIIa in patients with C1-inhibitor deficiency. Thromb Haemost. 1995;74(4):1103–6.PubMed

28.

Joseph K, Tholanikunnel TE, Kaplan AP. Treatment of episodes of hereditary angioedema with C1 inhibitor: serial assessment of observed abnormalities of the plasma bradykinin-forming pathway and fibrinolysis. Ann Allergy Asthma Immunol. 2010;104(1):50–4. doi:10.1016/j.anai.2009.11.014.CrossRefPubMed

29.

Cugno M, Zanichelli A, Bellatorre AG, Griffini S, Cicardi M. Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency. Allergy. 2009;64(2):254–7. doi:10.1111/j.1398-9995.2008.01859.x.CrossRefPubMed

30.

Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6(1):24. doi:10.1186/1710-1492-6-24.PubMedCentralCrossRefPubMed

31.

Clauss A. Rapid physiological coagulation method in determination of fibrinogen. Acta Haematol. 1957;17(4):237–46.CrossRefPubMed

32.

Cugno M, Cicardi M, Coppola R, Agostoni A. Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies. Immunopharmacology. 1996;33(1–3):361–4.CrossRefPubMed

33.

Nielsen EW, Johansen HT, Hogasen K, Wuillemin W, Hack CE, Mollnes TE. Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema. Scand J Immunol. 1996;44(2):185–92.CrossRefPubMed

34.

van Geffen M, Cugno M, Lap P, Loof A, Cicardi M, van Heerde W. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency. Clin Exp Immunol. 2012;167(3):472–8. doi:10.1111/j.1365-2249.2011.04541.x.PubMedCentralCrossRefPubMed

35.

Reshef A, Zanichelli A, Longhurst H, Relan A, Hack CE. Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk. Allergy. 2015;70(5):506–13. doi:10.1111/all.12587.PubMedCentralCrossRefPubMed

36.

Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145(1):24–33. doi:10.1111/j.1365-2141.2009.07600.x.CrossRefPubMed

37.

Bloom AL. Intravascular coagulation and the liver. Br J Haematol. 1975;30(1):1–7.CrossRefPubMed

38.

Pottinger BE, Read RC, Paleolog EM, Higgins PG, Pearson JD. von Willebrand factor is an acute phase reactant in man. Thromb Res. 1989;53(4):387–94.CrossRefPubMed

Title: Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1-inhibitor deficiency
Authors: Dorottya Csuka
Nóra Veszeli
Éva Imreh
Zsuzsanna Zotter
Judit Skopál
Zoltán Prohászka
Lilian Varga
Henriette Farkas
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2015
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-015-0351-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1-inhibitor deficiency

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Unmet needs for healthcare and social support services in patients with Huntington’s disease: a cross-sectional population-based study

Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study

Bone health in phenylketonuria: a systematic review and meta-analysis

Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ß-cyclodextrin

Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype

Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study