Role of fibrinogen- and platelet-mediated hemostasis in mouse embryogenesis and reproduction.
Studies of mice with genetic deficits in specific coagulation factors have shown that many, but not all, components of the hemostatic system serve an essential role in mouse embryogenesis and pregnancy. Although the developmental failures observed in these mice are typically associated with severe hemorrhage, it is uncertain whether the role of coagulation factors in embryogenesis and reproduction is specifically tied to their function in thrombus formation and prevention of blood loss (i.e. hemostasis). Here, we show (i) that a complete loss of fibrinogen- and platelet-dependent hemostatic capacity does not reproduce the developmental defects occurring in mice with either deficits in thrombin generation or unfettered thrombin consumption; (ii) that the essential role of fibrinogen in the maintenance of pregnancy does not involve interaction with platelets; and (iii) that the previously described in utero growth retardation of gene-targeted mice lacking NF-E2, a transcription factor critical for megakaryopoieis, is not caused by a loss of platelet-dependent hemostatic function. In addition, we demonstrate (iv) that fibrinogen can confer physiologically relevant hemostatic function in the absence of platelets, but that a complete loss of hemostatic capacity results if a combined absence of these components is genetically imposed. These findings support the notion that the function of coagulation factors for in utero development and pregnancy is mechanistically distinct from their ability to mediate the formation of hemostatic platelet-fibrin(ogen) aggregates.
Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
J S
JS
Palumbo
M
M
Zogg
K E
KE
Talmage
J L
JL
Degen
H
H
Weiler
B H
BH
Isermann
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics; D004622:Embryo, Mammalian / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D005838:Genotype; D006487:Hemostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; D010920:Placenta / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012098:Reproduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D019076:Transgenes; D015017:Yolk Sac / Q000378:metabolism
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; D014157:Transcription Factors; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D003094:Collagen; D043802:GTP-Binding Protein alpha Subunits, Gq-G11