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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2141-2145.
Prepublished online as a Blood First Edition Paper on November 18, 2004; DOI 10.1182/blood-2004-04-1578.
 Previous Article | Next Article 
Submitted April 26, 2004
Accepted October 1, 2004
Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors
Frans L Willekens, Jan M Werre*, J K Kruijt, Bregt Roerdinkholder-Stoelwinder, Yvonne A Groenen-Dopp, Annegeet G van den Bos, Giel J Bosman, and Theo J van Berkel
Department of Clinical Chemistry, Rijnstate Hospital, Arnhem, The Netherlands
Department of Blood Transfusion and Transplantation Immunology, Nijmegen Center for Molecular Life Sciences, University Medical Center, Nijmegen, The Netherlands
Division of Biopharmaceutics, Leiden University, Leiden, The Netherlands
Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, University Medical Center, Nijmegen, The Netherlands
* Corresponding author; email: werredehaas{at}planet.nl.
Previous studies have shown that during the life span of red blood cells (RBCs) 20% of hemoglobin is lost by shedding of hemoglobin-containing vesicles. However, the fate of these vesicles is unknown. In order to study this fate we used a rat model, after having established that rat RBCs lose hemoglobin in the same way as human RBCs, and that RBC-derived vesicles are preferentially labeled by Na251CrO4. Such labeled vesicles were injected into recipient rats. Within five minutes, 80% of the radioactivity was cleared from the circulation with a concomitant uptake by the liver of 55% of the injected dose. After 30 minutes Kupffer cells contained considerable amounts of hemoglobin, and were shown to be responsible for 92% of the liver uptake. Vesicle clearance from the blood as well as liver uptake were significantly inhibited by pre-injection of the scavenger receptor ligands polyinosinic acid and phosphatidylserine.
We conclude that in rats Kupffer cells rapidly remove RBC-derived vesicles from the circulation, mainly by scavenger receptors. The same mechanism is likely to be responsible for the elimination of human RBC vesicles, thereby constituting an important pathway for the breakdown of RBCs in man.
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