(Circulation. 1996;93:208-209.)
© 1996 American Heart Association, Inc.
Articles |
From the Divisions of Hematology and Medical Oncology, Departments of Medicine and Pathology, Department of Veterans Affairs Medical Center and Cornell University Medical College, New York, NY.
Correspondence to Aaron J. Marcus, MD and M. Johan Broekman, PhD, Thrombosis Research Laboratory, Room 13028W, Cornell University Medical College and Department of Veterans Affairs Medical Center, 423 E 23rd St, New York, NY 10010-5050. E-mail mjbroek@med.cornell.edu.
Key Words: Editorials hemoglobin endothelium-derived factors thrombosis
| Introduction |
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Utilization of cell-free hemoglobin as an erythrocyte substitute was initially hampered by nephrotoxicity and an affinity for oxygen that prevented efficient oxygen delivery to tissues.2 These disadvantages were overcome when Bunn and Jandl3 chemically cross-linked the hemoglobin molecule to produce stable hemoglobin oligomers that do not pass through the glomerular filtrate. In addition, Benesch and Benesch4 developed reagents that modified the 2,3-diphosphoglycerate binding site of hemoglobin, thereby reducing its oxygen affinity.
Administration of cell-free hemoglobin solutions results in systemic vasoconstriction in research animals.5 This is thought to be a consequence of the high avidity of hemoglobin for nitric oxide (NO, endothelium-derived relaxing factor [EDRF]), which it binds and inactivates. The NO-hemoglobin interaction results in rapid formation of nitrite/nitrate and methemoglobin. This blocks vasodilation induced by NO via activation of vascular smooth muscle cell guanylate cyclase.5 6 7
Removal of NO by hemoglobin will also reduce activity of
platelet guanylate cyclase. This increases platelet
reactivity, resulting in platelet deposition on prothrombotic
surfaces such as injured vessel wall. This phenomenon was indeed
demonstrated by the experiments of Olsen et al8 as
reported in this issue of Circulation. Using a rat
microsurgical carotid endarterectomy model, the
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