Fatalembryonic bleeding eventsinmicelacking tissue factor, thecell-associated initiator ofbloodcoagulation

Tissue factor (TF)isthecellular receptor for coagulation factor VII/VIla andisthemembrane-bound glycoprotein thatisgenerally viewed astheprimary physio- logical initiator ofbloodcoagulation. Todefine ingreater detail thephysiological role ofTFindevelopment andhemo- stasis, theTFgenewasdisrupted inmice. Miceheterozygous fortheinactivated TFallele expressed approximately half the TFactivity ofwild-type micebutwerephenotypically normal. However, homozygous TF-/- pupswerenever bornincrosses between heterozygous mice.Analysis ofmid-gestation em- bryos showed that TF-/- embryos dieinutero between days8.5 and10.5. TF-/-embryos weremorphologically distinct from their TF+/+ andTF+/- littermates after day9.5inthatthey werepale, edematous, andgrowthretarded. Histological studies showedthatearly organogenesis wasnormal. The initial failure inTF-/- embryos appeared tobehemorrhaging, leading totheleakage ofembryonic redcells fromboth extraembryonic andembryonic vessels. Thesestudies indicate thatTFplays anindispensable roleinestablishing and/or maintaining vascular integrity inthedeveloping embryo ata timewhenembryonic andextraembryonic vasculatures are fusing andbloodcirculation begins. Tissue factor (TF)isa47-kDa membrane-bound glycoprotein that functions asthecellular receptor forcoagulation factor VII/VIIa. TF isthought tobetheprimary physiological initiator ofblood coagulation following vascular damage(1). Unlike other coagulation factors, TFneednotbeactivated and isdelivered tothecellsurface asa functional VII/VIla receptor. Factor VIlaboundtoTF atthecell surface effi- ciently catalyzes theproteolytic activation ofcoagulation fac- tors IXandX.Thisultimately leads tolocal thrombin gener- ation andthrombin-catalyzed events suchasfibrin formation andtheactivation offactors V,VIII, XIII, thrombin receptor, andprotein C (1). Thecentral roleofTF inbloodcoagulation invivois supported byseveral compelling, butindirect, observations. First, severe congenital deficiencies infactor VIIcanproduce bleeding problems similar toclassic hemophilias (2). Second, TF-deficient patients haveneverbeenidentified, suggesting that TFdeficiency maybelethal duetoacoagulation disorder. Finally, thenormal distribution ofTFinvivo isconsistent with theviewthat TFprovides ahemostatic "envelope" outside of thevasculature that will initiate local coagulation intheevent ofvessel rupture (3). Although TFisbest understood inthecontext ofhemostasis, thephysiological andpathological roles ofTF maynotbe restricted totheinitiation ofblood coagulation. Notably, the angiogenic ormetastatic properties ofexperimental tumor