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Sluka, S.H.M.* ; Stämpfli, S.F.* ; Akhmedov, A.* ; Klein-Rodewald, T. ; Sanz-Moreno, A. ; Horsch, M. ; Grest, P.* ; Rothmeier, A.S.* ; Rathkolb, B. ; Schrewe, A. ; Beckers, J. ; Neff, F. ; Wolf, E.* ; Camici, G.G.* ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Lüscher, T.F.* ; Ruf, W.* ; Tanner, F.C.*

Murine tissue actor disulfide mutation causes a bleeding phenotype with sex specific organ pathology and lethality.

Haematologica 105, 2484-2495 (2019)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
T issue factor (TF) is highly expressed in sub-endothelial tissue. The extracellular allosteric disulfide bond Cys186-Cys209 of human TF shows high evolutionary conservation and in vitro evidence suggests that it significantly contributes to TF procoagulant activity. To investigate the role of this allosteric disulfide bond in vivo, we generated a C213G mutant Tf mouse by replacing Cys213 of the corresponding disulfide Cys190-Cys213 in murine Tf A bleeding phenotype was prominent in homozygous C213G Tf mice. Pre-natal lethality of one third of homozygous offspring was observed between embryonic (E) day E9.5 and E14.5 associated with placental hemorrhages. After birth, homozygous mice suffered from bleedings in different organs and reduced survival. Homozygous C213G Tf male mice showed higher incidence of lung bleedings and lower survival rates than females. In both sexes, C213G mutation evoked a reduced protein expression (about 10-fold) and severely reduced pro-coagulant activity (at least 100-fold). Protein glycosylation was impaired and cell membrane exposure decreased in macrophages in vivo. Single housing of homozygous C213G Tf males reduced the occurrence of severe bleeding and significantly improved survival, suggesting that inter-male aggressiveness might significantly account for the sex differences. These experiments show that the TF allosteric disulfide bond is of crucial importance for normal in vivo expression, post-translational processing and activity of murine TF. Although C213G Tf mice do not display the severe embryonic lethality of Tf knock-out mice, their postnatal bleeding phenotype emphasizes the importance of fully functional TF for hemostasis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Arterial Thrombosis; Blood Coagulation and Fibrinolysis; Disorders of Coagulation and Fibrinolysis; Pulmonary Hemorrhage; Alveolar Hemorrhage; Thrombin Receptor; Factor Activation; Cardiac Fibrosis; Hemostasis; Deficiency; Mice; Coagulation; Complement
ISSN (print) / ISBN 0390-6078
e-ISSN 1592-8721
Quellenangaben Band: 105, Heft: 10, Seiten: 2484-2495 Artikelnummer: , Supplement: ,
Verlag Ferrata Storti Foundation
Verlagsort Via Giuseppe Belli 4, 27100 Pavia, Italy
Begutachtungsstatus Peer reviewed
Förderungen Swiss Heart Foundation
National Heart Lung Blood Institute
German Federal Ministry of Education and Research