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Factor (Factor XII) by Complement Subcomponent C1q

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Factor (Factor XII) by Complement Subcomponent C1q Inhibition of the activation of Hageman factor (factor XII) by complement subcomponent C1q. E H Rehmus, … , B A Everson, O D Ratnoff J Clin Invest. 1987;80(2):516-521. https://doi.org/10.1172/JCI113100. Research Article Hageman factor (HF, Factor XII) is activated by glass, collagen, and ellagic acid, and initiates blood coagulation via the intrinsic pathway. C1q inhibits collagen-induced platelet aggregation and adherence of platelets to glass, effects attributable to the collagen-like region of C1q. We examined the actions of C1q on HF activation. Incubation of C1q with HF before addition of HF-deficient plasma extended the activated partial thromboplastin time. Similarly, when glass tubes were coated with C1q before testing, the partial thromboplastin time of normal plasma was increased. C1q reduced the activation of HF by ellagic acid, as measured by the release of p-nitroaniline from the synthetic substrate H-D-prolyl-L- phenylalanyl-L-arginine-p-nitroanilide dihydrochloride, an effect inhibited by monoclonal anti-human C1q murine IgG and by digestion of C1q by collagenase. Thus, C1q inhibits activation of HF in vitro in clot-promoting and amidolytic assays and suggests a regulatory mechanism for the inhibition of coagulation. Find the latest version: https://jci.me/113100/pdf Inhibition of the Activation of Hageman Factor (Factor XII) by Complement Subcomponent Clq Esther H. Rehmus, Bruce M. Greene, Barbara A. Everson, and Oscar D. Ratnoff Department ofMedicine, Case Western Reserve University School ofMedicine and University Hospitals of Cleveland, Cleveland, Ohio 44106 Abstract Methods Hageman factor (HF, Factor XII) is activated by glass, collagen, Plasmas. Pooled human serum and frozen citrated (acid citrate dextrose) and ellagic acid, and initiates blood coagulation via the intrinsic plasma were obtained from normal human volunteers. A pool of 24 pathway. Clq inhibits collagen-induced platelet aggregation and normal human plasmas was prepared from venous blood to which one- adherence of platelets to glass, effects attributable to the collagen- fiftieth volume of 0.5 M sodium citrate buffer (pH 5.0) had been added, like region of Clq. We examined the actions of Clq on HF and stored at -70'C as previously described (14). Human HF-deficient ac- plasma was similarly prepared and stored. Venepuncture was performed tivation. Incubation of Clq with HF before addition of HF-de- after informed consent with the approval of the Institutional Review ficient plasma extended the activated partial thromboplastin time. Board for Human Investigation, University Hospitals of Cleveland. The Similarly, when glass tubes were coated with Clq before testing, pooled normal plasma was arbitrarily said to contain 1 U of HF/ml, as the partial thromboplastin time of normal plasma was increased. measured in a coagulant assay. Clq reduced the activation of HF by ellagic acid, as measured Clq preparation. Clq was isolated from pooled human serum or by the release of p-nitroaniline from the synthetic substrate H- frozen citrated plasma by successive chromatography upon columns of D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochlo- Bio-Rex 70 and Bio-Gel A5M (Bio-Rad Laboratories, Richmond, CA), ride, an effect inhibited by monoclonal anti-human Clq murine using a minor modification of the method of Tenner et al. (15) in which IgG and by digestion of C1q by collagenase. Thus, Clq inhibits 102 mM sodium chloride was substituted for 82 mM sodium chloride in the initial buffer used for the equilibration of the Bio-Rex 70 column activation of HF in vitro in clot-promoting and amidolytic assays (Bio-Rad Laboratories). The presence of Clq in the Clq preparation and suggests a regulatory mechanism for the inhibition of co- was established by Ouchterlony gel diffusion against polyclonal anti- agulation. human Clq goat antibody (Atlantic Antibodies, Scarborough, ME or Boehringer-Mannheim Biochemicals, Indianapolis, IN). The purity of Introduction Clq was assessed by sodium dodecyl sulfate-polyacrylamide gel electro- phoresis (SDS-PAGE), which demonstrated homogeneous subunits of Clq. The apparent molecular weights ofthe reduced samples were 35,000, The initial step of the intrinsic pathway of thrombin formation 32,000, and 28,000, as previously described (16). Digestion of the col- is the activation of Hageman factor (HF,' Factor XII) by neg- lagenous portion ofClq was performed by a modification ofthe method atively charged agents, a process that can be inhibited by posi- of Pacques (17) by heating the Clq solution at 540C in a water bath for tively charged substances (1). Some fractions of normal plasma 10 min and then adding 0.037 ml collagenase (Clostridium histolyticum, are known to block the activation of HF, but neither the identity 10 mg/ml, 689 U/mg; Cooper Biomedical, Malvern, PA). The sample nor mode of action of the inhibitory agents in these fractions was immediately removed from the water bath and freed of traces of has been clarified (2). precipitate by centrifugation at 900 g for 10 min at 20C. The sample Cl q, a subcomponent of the first component of complement was then precipitated at 4VC overnight by addition of (NH4)2SO4 to one- third saturation. The precipitate was collected by centrifugation, dissolved (C1), has amino acid sequences resembling those of collagen in barbital-saline buffer (BS), and dialyzed against the buffer for 1 h. A and can inhibit collagen-induced platelet aggregation and the control sample was treated in a similar manner, omitting the addition adherence of platelets to glass (3, 4). Both glass and some forms of collagenase. SDS-PAGE of reduced and unreduced samples of the of collagen activate HF (1, 5, 6), although the effect of collagen collagenase-treated Clq preparation exhibited homogeneous subunits; on HF is controversial (6-13). The possibility was examined the apparent molecular weights of the subunits in the reduced sample that, similar to its effect on platelets, C lq might block the acti- were 25,000, 19,000, and 18,000, similar to those previously described vation of HF. The experiments to be described demonstrate that for this digestion ( 17). Clq can inhibit the activation of HF by glass or ellagic acid. The HF preparation. Purified human HF, depleted of other detectable biological significance of this observation is yet to be determined. clotting factors (coagulant titer 2.56 U/ml; specific activity 58 U/mg protein) was prepared by a method described elsewhere (18) and stored at -700C. Antibody preparation. Murine monoclonal anti-human Clq antibody Address reprint requests to Dr. Ratnoff. (Genzyme, Boston, MA) was filtered through Affi-gel Blue IgG purifi- Received for publication 5 September 1986 and in revised form 8 cation gel (Bio-Rad Laboratories) that had been equilibrated with 70 ml January 1987. 0.02 M KH2PO4, pH 8.0; similarly prepared monoclonal antibody against von Willebrand factor (Factor VIII:vWF) was used as a control (19). For 1. Abbreviations used in this paper: BS, barbital-saline buffer, HF, Hage- use in these experiments the protein contents ofthe filtered samples were man factor, HPPAN, H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide adjusted to 20 ttg/ml with BS. dihydrochloride; p-NA, p-nitroaniline; P1T, partial thromboplastin time. Reagents and buffers. Ellagic acid, synthesized by Dr. Miklos Bod- anzky, Case Western Reserve University, was dissolved at a concentration J. Clin. Invest. of 10-4 M in BS using a motorized Teflon pestle fitted to a glass mortar. © The American Society for Clinical Investigation, Inc. The solution was filtered through No. 1 paper (Whatman, Inc., Clifton, 0021-9738/87/08/0516/06 $2.00 NJ) and diluted in the same buffer to 2 X 10- M. Ellagic acid solutions Volume 80, August 1987, 516-521 were used freshly prepared. 516 E. H. Rehmus, B. M. Greene, B. A. Everson, and 0. D. Ratnoff H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochloride Table L Inhibitory Effect of Clq on the Clot-promoting (HPPAN, S2302; Helena Laboratories, Beaumont, TX) was dissolved Property of Glass-activated HF at a concentration of l0-3 M in water and diluted to 5 X 10-' M with an equal part of Tris-imidazole-saline buffer. Crystallized bovine serum Incubation mixture* IYTT albumin (BSA; Pentex Div., Miles Laboratories, Elkhart, IN) was dis- S solved in BS at a concentration of 0.25 g/100 ml. Crude soybean phos- phatides (Centrolex-P; a gift from Central Soya Co., Chicago, IL) were HF and BS 118.9 suspended at a concentration of 0.1% in 0.15 M sodium chloride. HF and lx 10-'M C1q 126.9 Tris-imidazole buffer (pH 8.2) was 0.025 M tris (hydroxymethyl) HF and X lo0- M Clq 135.4 aminomethane (Sigma Chemical Co., St. Louis, MO), 0.25 M imidazole BS >400 (Matheson, Coleman and Bell, Norwood, OH), and sufficient sodium chloride to provide an ionic strength of 0.15 (20). BS, pH 7.5, was 0.025 M sodium barbital in 0.125 M sodium chloride. * 0.1 1 ml each of HF (0.05 U/mI in 0.25% BSA in BS) and test mate- Coagulation studies. The coagulant activity of glass-activated HF rial (Clq or BS) were incubated for 10 min at 370C in a polystyrene was tested by a modified partial thromboplastin time (PTT) technique, tube. A volume of 0.2 ml of this mixture was transferred to a glass incubating 0.1 ml of HF (0.05 U/ml in 0.25% BSA in BS) with or without tube and the PTT was then measured (see Methods). Clq with 0.1 ml Centrolex-P in 10 X 75-mm glass tubes at 370C for 2 min. Thereafter, 0.1 ml of HF-deficient plasma was added, incubation was continued for 8 min, 0.1 ml of 0.025 M CaCl2, prewarmed to 370C, pooled normal plasma was used as the coating substance, the was then added, and the PTT was measured.
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