title: Hemostasis and coagulation at a hematocrit level of 0.85: functional consequences of erythrocytosis.
abstract: We have generated a transgenic mouse line that reaches a hematocrit concentration 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 (eg, 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 thromboelastography revealed that thrombus formation was reduced with increasing age from 1 to 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.
authors.affiliation: Department of Anesthesiology, University of Lübeck, Lübeck, Germany.
authors.forename: Junpei
authors.initials: J
authors.lastname: Shibata
authors.forename: Jo
authors.initials: J
authors.lastname: Hasegawa
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Siemens
authors.forename: Eva
authors.initials: E
authors.lastname: Wolber
authors.forename: Leif
authors.initials: L
authors.lastname: Dibbelt
authors.forename: Dechun
authors.initials: D
authors.lastname: Li
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jelkmann
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Wagner
mesh_terms: D000367:Age Factors; D000818:Animals; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006400:Hematocrit; D006487:Hemostasis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000097:blood; D011086:Polycythemia / Q000150:complications / Q000209:etiology / Q000503:physiopathology*; D013923:Thromboembolism / Q000517:prevention & control
chemical_list: D004921:Erythropoietin; D009569:Nitric Oxide