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Interactions of the Classical and Alternate Complement Pathway with Endotoxin Lipopolysaccharide EFFECT on PLATELETS and BLOOD COAGULATION

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Interactions of the Classical and Alternate Complement Pathway with Endotoxin Lipopolysaccharide EFFECT on PLATELETS and BLOOD COAGULATION Interactions of the Classical and Alternate Complement Pathway with Endotoxin Lipopolysaccharide EFFECT ON PLATELETS AND BLOOD COAGULATION Michael A. Kane, … , Joseph E. May, Michael M. Frank J Clin Invest. 1973;52(2):370-376. https://doi.org/10.1172/JCI107193. Research Article The contributions of the classical and alternate pathways of complement activation to the biological effects of endotoxin have been examined in the guinea pig, with particular reference to thrombocytopenia, leukopenia, and the development of the hypercoagulable state. Injection of endotoxin into normal guinea pigs led to a 95% fall in the level of circulating platelets within 15 min as well as a fall in circulating granulocytes. C4-deficient guinea pigs, known to have a complete block in the activity of the classical complement pathway, but with the alternate pathway intact, sustained no fall in platelets. The development of granulocytopenia proceeded normally. Endotoxin did activate the alternate complement pathway in C4D guinea pigs, as evidenced by the fall in C3-9 titers. With restoration of serum C4 levels, endotoxin- induced thrombocytopenia was observed in C4D animals. Thus, function of the classical complement pathway was an absolute requirement for the development of thrombocytopenia. Experiments performed in cobra venom factor (CVF)- treated normal guinea pigs, with normal levels of C1, C4, and C2, but with less than 1% of serum C3-9 demonstrated the importance of the late components in the development of thrombocytopenia but not leukopenia. C4-deficient guinea pigs had normal clotting times demonstrating that C4 was not required for normal clotting. In addition, development of the hypercoagulable state, evidenced by a marked shortening of the clotting […] Find the latest version: https://jci.me/107193/pdf Interactions of the Classical and Alternate Complement Pathway with Endotoxin Lipopolysaccharide EFFECT ON PLATELETS AND BLOOD COAGULATION MICHAEL A. KANE, JOSEPH E. MAY, and MICHAEL M. FRANK From the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20014 A B s T R A C T The contributions of the classical and pathway. Again, the importance of the late components alternate pathways of complement activation to the of complement was emphasized by the failure of CVF- biological effects of endotoxin have been examined in treated normal animals to develop hypercoagulability. the guinea pig, with particular reference to thrombo- These results demonstrate that endotoxin is capable of cytopenia, leukopenia, and the development of the hyper- activating both the classical and alternate complement coagulable state. Injection of endotoxin into normal pathways in guinea pigs but that function of the classical guinea pigs led to a 95% fall in the level of circulating pathway is an absolute requirement for the development platelets within 15 min as well as a fall in circulating of thrombocytopenia and the hypercoagulable state. granulocytes. C4-deficient guinea pigs, known to have a complete block in the activity of the classical comple- ment pathway, but with the alternate pathway intact, INTRODUCTION sustained no fall in platelets. The development of granu- For more than 20 years it has been known that thrombo- locytopenia proceeded normally. Endotoxin did activate cytopenia, leukopenia, and hypercoagulability of blood the alternate complement pathway in C4D guinea pigs, occur in many species after the administration of bac- as evidenced by the fall in C3-9 titers. With restoration terial endotoxins (1). The pathophysiologic basis for of serum C4 levels, endotoxin-induced thrombocytopenia the thrombocytopenia has been a matter of controversy. was observed in C4D animals. Thus, function of the Experiments in vitro have demonstrated a requirement classical complement pathway was an absolute require- for divalent cations and heat labile serum factors for ment for the development of thrombocytopenia. Experi- endotoxin-mediated platelet damage (2, 3). Other find- ments performed in cobra venom factor (CVF)-treated ings have suggested that complement is not involved: normal guinea pigs, with normal levels of Cl, C4, and the metal requirements for the endotoxin effects in vitro C2, but with less than 1% of serum C3-9 demonstrated are not those which have been shown to maximize com- the importance of the late components in the development plement-fixation reactions or complement-mediated cyto- of thrombocytopenia but not leukopenia. toxic reactions, and no consumption of whole comple- C4-deficient guinea pigs had normal clotting times ment has been demonstrated in the in vitro reaction (4). demonstrating that C4 was not required for normal Nevertheless, the resemblance between the thrombocyto- clotting. In addition, development of the hypercoagulable penia induced in vivo and the complement-mediated im- state, evidenced by a marked shortening of the clotting mune adherence reaction has been noted by several au- time, was not observed on injection of endotoxin into thors (5, 6). Development of the hypercoagulable state C4D animals. Therefore, development of the hyperco- has been thought to be a consequence of platelet damage agulable state paralleled the development of thrombocv- (7). topenia and required function of the classical complement In this report the role of complement in these reactions has been evaluated with particular reference to the con- Received for publication 10 August 1972 and in revised tribution of the two recently described pathways of com- form 10 October 1972. plement activation. The classical complement pathway 370 The Journal of Clinical Investigation Volume 52 February 1973 proceeds through activation of the early complement ration of optimally sensitized sheep erythrocytes (EA) and components, Cl, C4, and C2, to activation and cleavage of complement cell intermediates, and the method of C3-9 of C3 and the which complex titrations have all been described previously (17, complement proteins act later in 18). Pooled guinea pig serum, obtained from Suburban the sequence. The alternate or properdin pathway acts Serum Laboratory, Silver Spring, Md. was employed as through another series of proteins to enter the comple- the source of C4 given to the homozygous C4D animals, ment sequence at the C3 step (8-11). In defining the and also as the serum complement source for the prepara- role of these two pathways, this study utilized the re- tion of cellular intermediates. C4 titrations were performed utilizing C4D serum as a cently described strain of guinea pigs with a genetically reagent containing all of the components of complement in controlled deficiency in C4 (C4D)' (12). These animals excess except C4. A 0.25 ml aliquot of the sample diluted have an intact alternate pathway but absence of func- in DVBS was added to 0.25 ml EA (1.5 X 108 cells/ml) in tion of the classical pathway due to the deficiency in C4. DVBS. To this mixture was added 0.25 ml C4D serum known to be activators diluted 1: 50 in DVBS, and after incubation for 2 h at Bacterial endotoxins are potent of 37° C, the reaction was stopped by the addition of 2.5 ml the alternate pathway (13, 14) and their effects are ice-cold EDTA buffer to each tube. The degree of lysis was thought to be mediated by the classical pathway only recorded spectrophotometrically at 412 nm, and the C4 in rare circumstances (15). By studying the biological titer expressed as that dilution of serum which would yield consequences of endotoxin administration in C4D ani- one effective C4 site/cell, as calculated from the Poisson distribution and the one hit theory of complement action. A mals it has been possible to establish the importance of detailed rationale for this technique of C4 titration will be the classical complement pathway in mediating these presented elsewhere,2 but results obtained by this method phenomena. By extending these studies to cobra venom are in good agreement with those derived by previously factor (CVF)-treated normal animals it has also been reported procedures. possible to show that activation of the late complement Wlhite blood cell and platelet determiniations. WVhite blood cell (WBC) and platelet counts were made on 1 ml EDTA components is required. anticoagulated retro-orbital blood samples using an elec- tronic particle counter (Coulter Electronics, Inc., Hialeah, METHODS Fla.) and standard techniques (19, 20). 100 cell differen- tial leukocyte counts were done on air-dried, Wright's Endotoxin lipopolysaccharide (LPS). The LPS used for stained smears. all the experiments was a phenol-water extract of Escheri- Clotting time. Cardiac punctures were performed with a chia coli. (0127:B8) obtained from Difco Laboratories (lot 19 gauge small vein infusion set (Abbott Laboratories, 562875), Detroit, Mich. The mean lethal dose (LD50) of North Chicago, Ill.). To avoid contamination with tissue the E. coli endotoxin for NIH multipurpose guinea pigs was fluids, blood for clotting studies was used only when the 1.0 mg/kg and this dose of endotoxin was administered in needle was placed directly into the cardiac chambers with- all studies reported here. out manipulation and blood flow was immediate, rapid, and Experimental animals. "NIH multipurpose" guinea pigs, uninterrupted. 1 ml of blood was withdrawn with a 6 ml the strain from which the C4D guinea pigs were derived, disposable polypropylene syringe and discarded. A fresh were obtained from the NIH animal production section, polypropylene syringe was then attached to the infusion set, and used as the normal guinea pigs. C4D guinea pigs were and an additional 4 ml was withdrawn. 1-ml portions were also obtained from the NIH animal production service, and placed into each of two 13 X 100-ml glass tubes and each screened by a hemolytic assay for the presence or absence of two 13 X 100-mm siliconized glass tubes at 250C. A stop of C4. Sera from 20 representative C4D and NIH animals watch was started when blood was placed in the first tube.
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