Activation of kinin-kallikrein and complement pathways by oversulfated-chondroitin-sulfate (OSCS) has been linked with recent heparin-associated adverse clinical events. Given the fact that the majority of patients who received contaminated heparin did not experience an adverse event, it is of particular importance to determine the circumstances that increase the risk of a clinical reaction. In this study, we demonstrated by both the addition and affinity depletion of C1inh from normal human plasma, that the level of C1inh in the plasma has a great impact on the OSCS-induced kallikrein activity and its kinetics. OSCS-induced kallikrein activity was dramatically increased after C1inh was depleted, while the addition of C1inh completely attenuated kallikrein activity. In addition, actual clinical infection can lead to increased C1inh levels. Plasma from patients with sepsis had higher average levels of functional C1inh and decreased OSCS-induced kallikrein activity. Lastly, descriptive data on adverse event reports suggest cases likely to be associated with contaminated heparin are inversely correlated with infection. Our data suggest that low C1inh levels can be a risk factor and high levels can be protective. The identification of risk factors for contact system-mediated adverse events may allow for patient screening and clinical development of prophylaxis and treatments.
References
[1]
Charles SC, Frisch PR (2005) Adverse Events, Stress, and Litigation: A Physician's Guide. New York: Oxford University Press. 288 p.
[2]
Morris JA, Carrillo Y, Jenkins JM, Smith PW, Bledsoe S, et al. (2003) Surgical adverse events, risk management, and malpractice outcome: morbidity and mortality review is not enough. Ann Surg 237: 844–851; discussion 851–842.
[3]
Deis JN, Smith KM, Warren MD, Throop PG, Hickson GB, et al. (2008) Transforming the Morbidity and Mortality Conference into an Instrument for Systemwide Improvement (Vol. 2: Culture and Redesign).
[4]
Blossom DB, Kallen AJ, Patel PR, Elward A, Robinson L, et al. (2008) Outbreak of adverse reactions associated with contaminated heparin. N Engl J Med 359: 2674–2684.
[5]
Guerrini M, Beccati D, Shriver Z, Naggi A, Viswanathan K, et al. (2008) Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events. Nat Biotechnol 26: 669–675.
[6]
Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S, et al. (2008) Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 358: 2457–2467.
[7]
Tami C, Puig M, Reepmeyer JC, Ye H, D'Avignon DA, et al. (2008) Inhibition of Taq polymerase as a method for screening heparin for oversulfated contaminants. Biomaterials 29: 4808–4814.
[8]
McMahon AW, Pratt RG, Hammad TA, Kozlowski S, Zhou E, et al. (2010) Description of hypersensitivity adverse events following administration of heparin that was potentially contaminated with oversulfated chondroitin sulfate in early 2008. Pharmacoepidemiol Drug Saf.
[9]
Kemp SF, deShazo RD (2008) Prevention and treatment of Anaphylaxis. In: Lockey RF, Ledford DK, editors. Allergens and Allergen Immunotherapy Fourth ed. New York: Informa Healthcare USA, Inc. pp. 477–498.
[10]
Schwartz LB (2008) Heparin comes clean. N Engl J Med 358: 2505–2509.
[11]
Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M (2009) C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med 15: 69–78.
[12]
Johnson AM, Alper CA, Rosen FS, Craig JM (1971) C1 inhibitor: evidence for decreased hepatic synthesis in hereditary angioneurotic edema. Science 173: 553–554.
[13]
van der Graaf F, Koedam JA, Griffin JH, Bouma BN (1983) Interaction of human plasma kallikrein and its light chain with C1 inhibitor. Biochemistry 22: 4860–4866.
[14]
Wuillemin WA, te Velthuis H, Lubbers YT, de Ruig CP, Eldering E, et al. (1997) Potentiation of C1 inhibitor by glycosaminoglycans: dextran sulfate species are effective inhibitors of in vitro complement activation in plasma. J Immunol 159: 1953–1960.
[15]
Emonts M, de Jongh CE, Houwing-Duistermaat JJ, van Leeuwen WB, de Groot R, et al. (2007) Association between nasal carriage of Staphylococcus aureus and the human complement cascade activator serine protease C1 inhibitor (C1INH) valine vs. methionine polymorphism at amino acid position 480. FEMS Immunol Med Microbiol 50: 330–332.
[16]
Joseph K, Tholanikunnel BG, Kaplan AP (2009) Factor XII-independent cleavage of high-molecular-weight kininogen by prekallikrein and inhibition by C1 inhibitor. J Allergy Clin Immunol 124: 143–149.
[17]
Kleinschnitz C, Stoll G, Bendszus M, Schuh K, Pauer HU, et al. (2006) Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 203: 513–518.
[18]
Blanch A, Roche O, Urrutia I, Gamboa P, Fontan G, et al. (2006) First case of homozygous C1 inhibitor deficiency. J Allergy Clin Immunol 118: 1330–1335.
[19]
Han ED, MacFarlane RC, Mulligan AN, Scafidi J, Davis AE (2002) Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 109: 1057–1063.
[20]
Cugno M, Zanichelli A, Bellatorre AG, Griffini S, Cicardi M (2009) Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency. Allergy 64: 254–257.
[21]
Levi M, Hack CE, van Oers MH (2006) Rituximab-induced elimination of acquired angioedema due to C1-inhibitor deficiency. Am J Med 119: e3–5.
[22]
Munkvad S, Jespersen J, Gram J, Overgaard K, Ranby M (1990) Effects of methylamine and heparin on a rapid chromogenic assay of C1-esterase inhibitor in plasma. Clin Chem 36: 737–741.
[23]
Nuijens JH, Eerenberg-Belmer AJ, Huijbregts CC, Schreuder WO, Felt-Bersma RJ, et al. (1989) Proteolytic inactivation of plasma C1- inhibitor in sepsis. J Clin Invest 84: 443–450.
[24]
Zhou ZH, Zhang Y, Hu YF, Wahl LM, Cisar JO, et al. (2007) The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies. Cell Host Microbe 1: 51–61.
[25]
Adam A, Montpas N, Keire D, Desormeaux A, Brown NJ, et al. (2010) Bradykinin forming capacity of oversulfated chondroitin sulfate contaminated heparin in vitro. Biomaterials 31: 5741–5748.
[26]
Hagman R, Ronnberg E, Pejler G (2009) Canine uterine bacterial infection induces upregulation of proteolysis-related genes and downregulation of homeobox and zinc finger factors. PLoS One 4: e8039.
[27]
Martinez-Brotons F, Oncins JR, Mestres J, Amargos V, Reynaldo C (1987) Plasma kallikrein-kinin system in patients with uncomplicated sepsis and septic shock–comparison with cardiogenic shock. Thromb Haemost 58: 709–713.
[28]
Aasen AO, Erichsen NS, Gallimore MJ, Amundsen E (1980) Studies on components of the plasma kallikrein-kinin system in plasma samples from normal individuals and patients with septic shock. Adv Shock Res 4: 1–10.
[29]
Kalter ES, Daha MR, ten Cate JW, Verhoef J, Bouma BN (1985) Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bacteremia or bacterial shock. J Infect Dis 151: 1019–1027.
[30]
Bryant JW, Shariat-Madar Z (2009) Human plasma kallikrein-kinin system: physiological and biochemical parameters. Cardiovasc Hematol Agents Med Chem 7: 234–250.
[31]
Li B, Suwan J, Martin JG, Zhang F, Zhang Z, et al. (2009) Oversulfated chondroitin sulfate interaction with heparin-binding proteins: new insights into adverse reactions from contaminated heparins. Biochem Pharmacol 78: 292–300.
[32]
Kaplan AP, Ghebrehiwet B (2010) The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 47: 2161–2169.
[33]
Nikpoor B, Duan QL, Rouleau GA (2005) Acute adverse reactions associated with angiotensin-converting enzyme inhibitors: genetic factors and therapeutic implications. Expert Opin Pharmacother 6: 1851–1856.
[34]
Skidgel RA (1992) Bradykinin-degrading enzymes: structure, function, distribution, and potential roles in cardiovascular pharmacology. J Cardiovasc Pharmacol 20: Suppl 9S4–9.
[35]
Beltrami L, Zingale LC, Carugo S, Cicardi M (2006) Angiotensin-converting enzyme inhibitor-related angioedema: how to deal with it. Expert Opin Drug Saf 5: 643–649.
[36]
Molinaro G, Cugno M, Perez M, Lepage Y, Gervais N, et al. (2002) Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther 303: 232–237.
[37]
Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, et al. (2004) Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 114: S51–131.
[38]
Hack CE, Relan A, van Amersfoort ES, Cicardi M (2012) Target levels of functional C1-inhibitor in hereditary angioedema. Allergy 67: 123–130.
Loescher A, Edmondson HD (1988) Lupus erythematosus–a case of facial swelling. Br J Oral Maxillofac Surg 26: 129–132.
[41]
Lahiri M, Lim AY (2007) Angioedema and systemic lupus erythematosus–a complementary association? Ann Acad Med Singapore 36: 142–145.
[42]
Martinez-Barricarte R, Heurich M, Valdes-Canedo F, Vazquez-Martul E, Torreira E, et al. (2010) Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest 120: 3702–3712.
[43]
Meszaros T, Fust G, Farkas H, Jakab L, Temesszentandrasi G, et al. (2010) C1-inhibitor autoantibodies in SLE. Lupus 19: 634–638.
[44]
McLean-Tooke A, Stroud C, Sampson A, Spickett G (2007) Falsely normal C4 in a case of acquired C1 esterase inhibitor deficiency. J Clin Pathol 60: 565–566.
[45]
Stiller B, Sonntag J, Dahnert I, Alexi-Meskishvili V, Hetzer R, et al. (2001) Capillary leak syndrome in children who undergo cardiopulmonary bypass: clinical outcome in comparison with complement activation and C1 inhibitor. Intensive Care Med 27: 193–200.
