|
|
Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-09-2814.
Submitted October 3, 2002
Accepted January 24, 2003
Hemostasis and coagulation at a hematocrit of 0.85: functional consequences of erythrocytosis
Junpei Shibata, Jo Hasegawa, Hans-Joachim Siemens, Eva Wolber, Leif Dibbelt, Dechun Li, Doerthe M Katschinski, Joachim Fandrey, Wolfgang Jelkmann, Max Gassmann, Roland H Wenger, and Klaus F Wagner*
Clinic of Internal Medicine II, University Luebeck, Luebeck, Germany
Department of Clinical Chemistry, University Luebeck, Luebeck, Germany
Institute of Physiology, University Luebeck, Luebeck, Germany
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Institute of Veterinary Physiology, University Zuerich, Zuerich, Switzerland
Institute of Physiolgy, University Essen, Essen, Germany
Carl-Ludwig-Institute of Physiology, University Leipzig, Leipzig, Germany
Department of Anesthesiology, Univversity Luebeck, Luebeck, Germany
* Corresponding author; email: wagner{at}physio.uni-luebeck.de.
We have generated a transgenic mouse line that reaches a hematocrit of 0.85 due to constitutive overexpression of human erythropoietin in an oxygen-independent manner. Unexpectedly, this excessive erythrocytosis did not lead to thrombembolic complications in all investigated organs at any age. Thus, we investigated the mechanisms preventing thrombembolism in this mouse model. Blood analysis revealed an age-dependent elevation of reticulocyte numbers and a marked thrombocytopenia that matched the reduced megakaryocyte numbers in the bone marrow. However, platelet counts were not different from wild type controls, when calculations were based on the distribution (e.g. plasma) volume, thereby explaining why thrombopoietin levels did not increase in transgenic mice. Nevertheless, bleeding time was significantly increased in transgenic animals. A longitudinal investigation using computerized thrombelastography revealed that thrombus formation was reduced with increasing age from 1-8 months in transgenic animals. We observed that increasing erythrocyte concentrations inhibited profoundly and reversibly thrombus formation and prolonged the time of clot development, most likely due to mechanical interference of red blood cells with clot-forming platelets. Transgenic animals showed increased nitric oxide levels in the blood that could inhibit vasoconstriction and platelet activation. Finally, we observed that plasmatic coagulation activity in transgenic animals was significantly decreased. Taken together, our findings suggest that prevention of thrombembolic disease in these erythrocytotic transgenic mice was due to functional consequences inherent to increased erythrocyte concentrations and a reduction of plasmatic coagulation activity, the cause of which remains to be elucidated.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Elevated hematocrit, risk of thrombosis, and polycythemia vera
- Josef T. Prchal
Blood 2003 101: 4229.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
S. S. Adam, N. S. Key, and C. S. Greenberg
D-dimer antigen: current concepts and future prospects
Blood,
March 26, 2009;
113(13):
2878 - 2887.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Lindenblatt, M. D. Menger, E. Klar, and B. Vollmar
Darbepoetin-Alpha Does Not Promote Microvascular Thrombus Formation in Mice: Role of eNOS-Dependent Protection Through Platelet and Endothelial Cell Deactivation
Arterioscler Thromb Vasc Biol,
May 1, 2007;
27(5):
1191 - 1198.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Waskow, G. Terszowski, C. Costa, M. Gassmann, and H.-R. Rodewald
Rescue of lethal c-KitW/W mice by erythropoietin
Blood,
September 15, 2004;
104(6):
1688 - 1695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T Strunk, C Hartel, and C Schultz
Does erythropoietin protect the preterm brain?
Arch. Dis. Child. Fetal Neonatal Ed.,
July 1, 2004;
89(4):
F364 - F366.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Grimm, A. Wenzel, D. Stanescu, M. Samardzija, S. Hotop, M. Groszer, M. Naash, M. Gassmann, and C. Reme
Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration
J. Neurosci.,
June 23, 2004;
24(25):
5651 - 5658.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. R. Gordeuk, A. I. Sergueeva, G. Y. Miasnikova, D. Okhotin, Y. Voloshin, P. L. Choyke, J. A. Butman, K. Jedlickova, J. T. Prchal, and L. A. Polyakova
Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors
Blood,
May 15, 2004;
103(10):
3924 - 3932.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Hasegawa, K. F. Wagner, D. Karp, D. Li, J. Shibata, M. Heringlake, L. Bahlmann, R. Depping, J. Fandrey, P. Schmucker, et al.
Altered Pulmonary Vascular Reactivity in Mice with Excessive Erythrocytosis
Am. J. Respir. Crit. Care Med.,
April 1, 2004;
169(7):
829 - 835.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Deten, J. Shibata, D. Scholz, W. Briest, K. F Wagner, R. H Wenger, and H.-G. Zimmer
Norepinephrine-induced acute heart failure in transgenic mice overexpressing erythropoietin
Cardiovasc Res,
January 1, 2004;
61(1):
105 - 114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Vogel, I. Kiessling, K. Heinicke, T. Stallmach, P. Ossent, O. Vogel, M. Aulmann, T. Frietsch, H. Schmid-Schonbein, W. Kuschinsky, et al.
Transgenic mice overexpressing erythropoietin adapt to excessive erythrocytosis by regulating blood viscosity
Blood,
September 15, 2003;
102(6):
2278 - 2284.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
