Mouse Genome Informatics
hm1
    Thbdtm2Rdr/Thbdtm2Rdr
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• homozygotes are completely resorbed by E9.5

embryogenesis
• at E8.5, homozygotes contain a reduced number of diploid ectoplacental trophoblast cells (63.5% of wild-type), as a result of reduced cell proliferation
• anti-coagulation therapy with heparin or warfarin does not overcome the growth defect in the ectoplacental cone
• growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors by coagulation factors
• at E8.5, BrdU incorporation is marginally lower in mutant polyploid giant trophoblast cells, but is significantly reduced in diploid trophoblast cells of the ectoplacental cone
• at E8.5, all homozygotes exhibit a significant increase in TUNEL+ giant trophoblast cells but only rarely in ectoplacental cone cells, indicating selective cell death of giant trophoblast cells
• at E8.5, BrdU incorporation is only marginally reduced in mutant polyploid giant trophoblast cells
• anti-coagulation treatment of pregnant mothers with heparin or warfarin inhibits cell death of giant trophoblast cells
• death of giant trophoblast cells is caused by conversion of the thrombin substrate fibrinogen to fibrin and subsequent formation of fibrin degradation products
• homozygotes exhibit an overall growth retardation at E8.5, followed by rapid resorption within the next 10-12 hrs (J:74855)
• anti-coagulation treatment of pregnant mothers with heparin or warfarin does not overcome the growth defect, with E9.5 homozygotes resembling E8.5 wild-type mice (J:82224)


Mouse Genome Informatics
ht2
    Thbdtm1Wlr/Thbdtm2Rdr
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• fibrin deposition is increased 10- to 20-fold compared to in wild-type mice (J:47676)
• fibrin deposition is increased compared to in wild-type mice (J:111502)

immune system
• fibrin deposition is increased 10- to 20-fold compared to in wild-type mice (J:47676)
• fibrin deposition is increased compared to in wild-type mice (J:111502)

respiratory system
• fibrin deposition is increased 10- to 20-fold compared to in wild-type mice (J:47676)
• fibrin deposition is increased compared to in wild-type mice (J:111502)

homeostasis/metabolism
• plasma thrombin-antithrombin (TAT) and D-dimer are increased compared to in wild-type mice
• under hypoxic conditions, mice exhibit a 10-fold increase in fibrin depositions in the lung compared with a 4- to 5-fold increase in similarly treated wild-type mice (J:47676)
• after FeCl3-induced injury mice exhibit accelerated arterial thrombus growth compared with wild-type mice (J:111502)

hematopoietic system
• fibrin deposition is increased 10- to 20-fold compared to in wild-type mice (J:47676)
• fibrin deposition is increased compared to in wild-type mice (J:111502)


Mouse Genome Informatics
cn3
    Tg(Tek-cre)1Ywa/0
Thbdtm2Rdr/Thbdtm2Wlr

involves: 129S2/SvPas * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Venous and arterial thrombi and extravascular fibrinogen deposition in the lungs of Thbdtm2Rdr/Thbdtm2Wlr Tg(Tek-cre)1Ywa/0 mice

mortality/aging
• by 25 weeks of age, most mice die secondary to consumptive coagulopathy or progressive thrombosis, hemorrhage/necrosis of individual digits, extremities, skin, ears, tongue, or priapism
• male mice exhibit shorter life spans compared with female mice (100% at 20 and 30 weeks, respectively)
• unlike wild-type mice, some mice develop lethal cerebral or intrathoracic hemorrhaging that cannot be prevented by warfarin treatment
• however, gonadectomized mice do not display any gender-specific difference in life span
• 40% of mice die around E10.5
• although present in Mendelian ratios at E9.5 and E10.5, fewer than expected mice are present at E14.5 and E16.5

reproductive system
• in 8% of male mice and occasionally associated with necrosis of testis (J:71269)

cardiovascular system
• at 5 to 8 weeks
• beginning at 3 weeks of age
• at 8 weeks, mice develop multifoci myocardial fibrosis unlike wild-type mice
• some mice exhibit lethal intrathoracic hemorrhaging unlike wild-type mice
• warfarin treatment fails to improve overall survival in these mice
• in 10% of mice
• in 8% of mice
• some mice exhibit lethal cerebral hemorrhaging unlike wild-type mice
• warfarin treatment fail to improve overall survival in these mice
• early skin lesions on extremities, hindlimbs, the perianal region, abdominal skin, and ears consist of small hemorrhagic lesions that increase in size and become necrotic
• 67% of mice exhibit subcutaneous hemorrhage unlike wild-type mice
• however, treatment with warfarin between 3 and 11 weeks prevents development of hemorrhagic or necrotic skin lesions
• due to increased resistance in the pulmonary vascular bed as a consequence of recurrent embolic and/or vascular lung injury

homeostasis/metabolism
• in older mice due to widespread organ damage
• in terminal mice, whole-blood clotting time is prolonged compared to in wild-type mice and 6 mice fail to form clots within 60 minutes
• plasma levels of thrombin-antithrombin (TAT) complexes and D-Dimer are increased at 3, 5, and 8 weeks compared to in wild-type mice
• at E10.5, 36% of mice exhibit pallor or placenta thrombosis unlike wild-type mice
• mice develop age- and gender-dependent progression of thrombosis that leads to lethal consumptive coagulopathy
• mice exhibit multiple venous and arterial thrombi that are fibrin-rich with few cellular components
• however, no thrombi occur in the cardiac atria and treatment with warfarin between 3 and 11 weeks prevents thrombosis
• fibrinogen deposits in the lungs are increased compared to in wild-type mice
• at 3 weeks, mice exhibit increased consumption of fibrinogen compared to wild-type mice
• however, fibrinogen levels increased in older mice due to compensation
• in 1% of mice

respiratory system
• some mice exhibit lethal intrathoracic hemorrhaging unlike wild-type mice
• warfarin treatment fails to improve overall survival in these mice
• in 10% of mice
• at 3 weeks, lungs have increased extravascular fibrinogen depositions compared to in wild-type mice associated with increased extracellular matrix and a disruption of the tissue architecture resulting in distention of terminal airways and alveoli, destruction of the alveolar septa, and, in severe cases, formation of bullae

hematopoietic system
• at 3 weeks, mice exhibit lower than normal platelet counts
• however, platelet counts are normalized in older mice due to compensation
• at 8 weeks, the number of megakaryocytes per splenocytes is increased compared to in wild-type mice
• at 8 weeks, mice exhibit increased spleen weight compared to in wild-type mice
• however, treatment with warfarin between 3 and 11 weeks prevents increased spleen weight

immune system
• at 8 weeks, mice exhibit increased spleen weight compared to in wild-type mice
• however, treatment with warfarin between 3 and 11 weeks prevents increased spleen weight
• in older mice due to widespread organ damage
• fibrinogen deposits in the lungs are increased compared to in wild-type mice
• at 3 weeks, mice exhibit increased consumption of fibrinogen compared to wild-type mice
• however, fibrinogen levels increased in older mice due to compensation

growth/size
• after weaning, 14% of mice are runted
• from the first week after birth through 8 weeks post-weaning, mice exhibit decreased body weight
• however, treatment with warfarin between 3 and 11 weeks prevents reduced body weight
• over the 8 weeks following weaning

liver/biliary system
• 36% of mice exhibit liver lesions consisting of liver infarcts or hemorrhagic liver swellings unlike wild-type mice

renal/urinary system
• in 1% of mice

digestive/alimentary system
• in 8% of mice

integument
• early skin lesions on extremities, hindlimbs, the perianal region, abdominal skin, and ears consist of small hemorrhagic lesions that increase in size and become necrotic
• 67% of mice exhibit subcutaneous hemorrhage unlike wild-type mice
• however, treatment with warfarin between 3 and 11 weeks prevents development of hemorrhagic or necrotic skin lesions
• at E10.5, 36% of mice exhibit pallor or placenta thrombosis unlike wild-type mice

nervous system
• some mice exhibit lethal cerebral hemorrhaging unlike wild-type mice
• warfarin treatment fail to improve overall survival in these mice


Mouse Genome Informatics
cx4
    F3tm1Dco/F3tm1Dco
Thbdtm2Rdr/Thbdtm2Rdr
Tg(F3)1Nmk/0

involves: 129/Sv * 129S2/SvPas * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• mutant embryos develop normally beyond E10.5 and are viable to birth (J:82224)

cardiovascular system
• at E10.5, mutant embryos exhibit bleeding in the placental labyrinth, not caused by thrombomodulin deficiency but characteristic of embryos with low F3 activity


Mouse Genome Informatics
cx5
    Fgatm1Jld/Fgatm1Jld
Thbdtm2Rdr/Thbdtm2Rdr

involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• unlike Thbdtm2Rdr homozygotes which are completely resorbed by E9.5, double homozygotes are recovered as late as E10.5

embryogenesis
• double homozygotes display a proliferation defect in trophoblast cells of the ectoplacental cone
• similarly, inhibition of fibrinolysis with tranexamic acid fails to augment proliferation of ectoplacental trophoblast cells
• in contrast, both the absence of fibrinogen and inhibition of fibrinolysis prevents DNA fragmentation in trophoblast giant cells, as detected by TUNEL assay
• double homozygotes exhibit embryonic growth arrest at E8.5
• inhibition of fibrinolysis with tranexamic acid has the same effect as complete elimination of fibrinogen and results in recovery of growth-arrested embryos at E9.5


Mouse Genome Informatics
cx6
    Plautm1Mlg/Plautm1Mlg
Thbdtm2Rdr/Thbdtm2Rdr

involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging


Mouse Genome Informatics
cx7
    Plattm1Mlg/Plattm1Mlg
Thbdtm2Rdr/Thbdtm2Rdr

involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging


Mouse Genome Informatics
cx8
    F3tm1Dco/F3tm1Dco
Thbdtm2Rdr/Thbdtm2Rdr

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• unlike Thbdtm2Rdr homozygotes which are completely resorbed by E9.5, double homozygotes develop normally until E9.5 but become necrotic by E10.5 due to defective yolk sac vasculature

embryogenesis
• by E10.5, double homozygotes display defective vitelline vasculature with free blood pools in the yolk sac cavity
• by E10.5, double mutant yolk sacs lack blood-filled larger vitelline vessels

cardiovascular system
• by E10.5, double homozygotes display defective vitelline vasculature with free blood pools in the yolk sac cavity
• by E10.5, double mutant yolk sacs lack blood-filled larger vitelline vessels
• by E10.5, double homozygotes exhibit an enlarged pericardial cavity, similar to F3tm1Dco homozygotes