Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation ?+N1p (10-APR-05) Generation Definitions   Donating Investigator Denisa Wagner,   Center for Blood Research

Description
Mice that are homozygous null for the Vwf gene are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No Vwf protein product is detected in platelets, plasma, heart or lung endothelium. Null mice exhibit defects in hemostasis characterized by prolonged bleeding times in all mice with spontaneous bleeding events observed in ten percent of neonates. Intravital microscopic analysis indicates a complete absence of thrombus formation following vascular injury. Observed levels of factor VIII are reduced to twenty percent of that seen in wild type mice. Although heterozygous mice carrying a single null allele exhibit no defects in hemostasis, they do have reduced levels of factor VIII (57 percent that of wildtype) making them a suitable model for type 1 von Willebrand disease. Characteristics displayed by homozygous null animals qualify them as an appropriate model for severe (type 3) von Willebrand disease.

Development
A targeting vector containing a neomycin resistance gene driven by a mouse phosphoglycerate kinase promoter flanked by two herpes simplex virus thymidine kinase cassettes was used to disrupt exons four and five of the Vwf gene. The construct was introduced into 129S2/SvPas-derived D3 embryonic stem (ES) cells by electroporation. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric male animals were backcrossed to C57BL/6J females.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Von Willebrand Disease - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Vwf^tm1Wgr/Vwf⁺

        involves: 129S2/SvPas * C57BL/6J

• homeostasis/metabolism phenotype
• abnormal blood coagulation (MGI Ref ID J:49083)
  • in heterozygotes, the activity level of coagulation FVIII was reduced to 57% of wild-type level

Vwf^tm1Wgr/Vwf^tm1Wgr

        involves: 129S2/SvPas * C57BL/6J

• cardiovascular system phenotype
• internal hemorrhage (MGI Ref ID J:49083)
  • ~10% of newborn homozygotes displayed spontaneous intra-abdominal bleeding
  • in some cases, bleeding was massive and proved fatal
  • after the neonatal period, no obvious spontaneous bleeding was observed, and females survived pregnancy and delivery of normal size litters
• homeostasis/metabolism phenotype
• abnormal blood coagulation (MGI Ref ID J:49083)
  • in homozygotes, the activity level of coagulation FVIII was reduced to 20% of wild-type level
  • consistent with a reduction in FVIII, the activated partial thromboplastin time (aPTT) was also prolonged while prothrombin time was not changed
  • however, platelet, red cell and white cell counts, hematocrit, and hemoglobin were all within normal range
• abnormal platelet physiology (MGI Ref ID J:49083)
  • at 10 min after ferric chloride-induced injury, most mutant arterioles (66.6%) showed very few, if any, platelet interactions with the vessel wall, whereas all of wild-type arterioles exhibited either complete occlusion (25%) or numerous platelet interactions with the vessel wall, including formation of thrombi
• increased bleeding time (MGI Ref ID J:49083)
  • following amputation of a tail segment, homozygotes exhibited a significantly prolonged bleeding time relative to wild-type mice (499 ± 33.4 sec versus 69.7 ± 5.2 sec, respectively)
  • only 5 of 21 homozygotes managed to control their blood loss without cauterization
  • in addition, 2 anesthetized animals that were not cauterized were never able to control their bleeding
• digestive/alimentary phenotype
• melena (MGI Ref ID J:49083)
  • 7.2% of adult homozygotes displayed the presence of fecal occult blood
• hematopoietic system phenotype
• abnormal platelet physiology (MGI Ref ID J:49083)
  • at 10 min after ferric chloride-induced injury, most mutant arterioles (66.6%) showed very few, if any, platelet interactions with the vessel wall, whereas all of wild-type arterioles exhibited either complete occlusion (25%) or numerous platelet interactions with the vessel wall, including formation of thrombi

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Vwf^tm1Wgr related

Hematological Research
Clotting Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Vwftm1Wgr
Allele Name		targeted mutation 1, Denisa D Wagner
Allele Type		Targeted (knock-out)
Common Name(s)		vWf-;
Mutation Made By		Cecile Denis,   Center for Blood Research
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Vwf, Von Willebrand factor homolog
Chromosome		6
Gene Common Name(s)		6820430P06Rik; AI551257; B130011O06Rik; F8VWF; RIKEN cDNA 6820430P06 gene; RIKEN cDNA B130011O06 gene; VWD; expressed sequence AI551257;
Molecular Note		A neomycin cassette was inserted into intron 5. Northern blot analysis revealed that no normal transcripts were present in homozygous mice, and immunofluorescence experiments demonstrated that the protein was not present in blood smears of homozygous mice. [MGI Ref ID J:49083]

Genotyping

Genotyping Information

Genotyping Protocols

Vwf^tm1Wgr, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References

Additional References

Denis CV; Kwack K; Saffaripour S; Maganti S; Andre P; Schaub RG; Wagner DD. 2001. Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models. Blood 97(2):465-72. [PubMed: 11154224]  [MGI Ref ID J:66963]

Ni H; Denis CV; Subbarao S; Degen JL; Sato TN; Hynes RO; Wagner DD. 2000. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 106(3):385-92. [PubMed: 10930441]  [MGI Ref ID J:63750]

Vwf^tm1Wgr related

Andre P; Denis CV; Ware J; Saffaripour S; Hynes RO; Ruggeri ZM; Wagner DD. 2000. Platelets adhere to and translocate on von willebrand factor presented by endothelium in stimulated veins Blood 96(10):3322-8. [PubMed: 11071623]  [MGI Ref ID J:65812]

Chauhan AK; Kisucka J; Brill A; Walsh MT; Scheiflinger F; Wagner DD. 2008. ADAMTS13: a new link between thrombosis and inflammation. J Exp Med 205(9):2065-74. [PubMed: 18695007]  [MGI Ref ID J:142125]

Chauhan AK; Kisucka J; Lamb CB; Bergmeier W; Wagner DD. 2007. von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins. Blood 109(6):2424-9. [PubMed: 17119108]  [MGI Ref ID J:145354]

Chauhan AK; Walsh MT; Zhu G; Ginsburg D; Wagner DD; Motto DG. 2008. The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis. Blood 111(7):3452-7. [PubMed: 18083848]  [MGI Ref ID J:133469]

Denis C; Methia N; Frenette PS; Rayburn H; Ullman-Cullere M ; Hynes RO ; Wagner DD. 1998. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci U S A 95(16):9524-9. [PubMed: 9689113]  [MGI Ref ID J:49083]

Denis CV; Kwack K; Saffaripour S; Maganti S; Andre P; Schaub RG; Wagner DD. 2001. Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models. Blood 97(2):465-72. [PubMed: 11154224]  [MGI Ref ID J:66963]

Dole VS; Bergmeier W; Mitchell HA; Eichenberger SC; Wagner DD. 2005. Activated platelets induce Weibel-Palade-body secretion and leukocyte rolling in vivo: role of P-selectin. Blood 106(7):2334-9. [PubMed: 15956287]  [MGI Ref ID J:119376]

Dubois C; Panicot-Dubois L; Gainor JF; Furie BC; Furie B. 2007. Thrombin-initiated platelet activation in vivo is vWF independent during thrombus formation in a laser injury model. J Clin Invest 117(4):953-60. [PubMed: 17380206]  [MGI Ref ID J:121278]

Frederix K; Chauhan AK; Kisucka J; Zhao BQ; Hoff EI; Spronk HM; Ten Cate H; Wagner DD. 2007. Platelet adhesion receptors do not modulate infarct volume after a photochemically induced stroke in mice. Brain Res 1185:239-45. [PubMed: 17996853]  [MGI Ref ID J:130124]

Goerge T; Ho-Tin-Noe B; Carbo C; Benarafa C; Remold-O'Donnell E; Zhao BQ; Cifuni SM; Wagner DD. 2008. Inflammation induces hemorrhage in thrombocytopenia. Blood 111(10):4958-64. [PubMed: 18256319]  [MGI Ref ID J:135316]

Hoffmeister KM; Felbinger TW; Falet H; Denis CV; Bergmeier W; Mayadas TN; von Andrian UH; Wagner DD; Stossel TP; Hartwig JH. 2003. The clearance mechanism of chilled blood platelets. Cell 112(1):87-97. [PubMed: 12526796]  [MGI Ref ID J:107707]

Holmback K; Danton MJ; Suh TT; Daugherty CC; Degen JL. 1996. Impaired platelet aggregation and sustained bleeding in mice lacking the fibrinogen motif bound by integrin alpha IIb beta 3. EMBO J 15(21):5760-71. [PubMed: 8918453]  [MGI Ref ID J:36873]

Kleinschnitz C; De Meyer SF; Schwarz T; Austinat M; Vanhoorelbeke K; Nieswandt B; Deckmyn H; Stoll G. 2009. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood 113(15):3600-3. [PubMed: 19182208]  [MGI Ref ID J:148295]

Marx I; Christophe OD; Lenting PJ; Rupin A; Vallez MO; Verbeuren TJ; Denis CV. 2008. Altered thrombus formation in von Willebrand factor-deficient mice expressing von Willebrand factor variants with defective binding to collagen or GPIIbIIIa. Blood 112(3):603-9. [PubMed: 18487513]  [MGI Ref ID J:138441]

Methia N; Andre P; Denis CV; Economopoulos M; Wagner DD. 2001. Localized reduction of atherosclerosis in von Willebrand factor-deficient mice. Blood 98(5):1424-8. [PubMed: 11520791]  [MGI Ref ID J:106677]

Ni H; Denis CV; Subbarao S; Degen JL; Sato TN; Hynes RO; Wagner DD. 2000. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 106(3):385-92. [PubMed: 10930441]  [MGI Ref ID J:63750]

Noubade R; del Rio R; McElvany B; Zachary JF; Millward JM; Wagner DD; Offner H; Blankenhorn EP; Teuscher C. 2008. von-Willebrand factor influences blood brain barrier permeability and brain inflammation in experimental allergic encephalomyelitis. Am J Pathol 173(3):892-900. [PubMed: 18688020]  [MGI Ref ID J:140334]

Othman M; Labelle A; Mazzetti I; Elbatarny HS; Lillicrap D. 2007. Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance. Blood 109(7):2832-9. [PubMed: 17148587]  [MGI Ref ID J:145348]

Reheman A; Yang H; Zhu G; Jin W; He F; Spring CM; Bai X; Gross PL; Freedman J; Ni H. 2009. Plasma fibronectin depletion enhances platelet aggregation and thrombus formation in mice lacking fibrinogen and von Willebrand factor. Blood 113(8):1809-17. [PubMed: 19036705]  [MGI Ref ID J:145550]

Schwarz HP; Lenting PJ; Binder B; Mihaly J; Denis C; Dorner F; Turecek PL. 2000. Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice. Blood 95(5):1703-8. [PubMed: 10688827]  [MGI Ref ID J:60764]

Shi Q; Wilcox DA; Fahs SA; Weiler H; Wells CW; Cooley BC; Desai D; Morateck PA; Gorski J; Montgomery RR. 2006. Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J Clin Invest 116(7):1974-82. [PubMed: 16823491]  [MGI Ref ID J:111741]

Yang H; Lang S; Zhai Z; Li L; Kahr WH; Chen P; Brkic J; Spring CM; Flick MJ; Degen JL; Freedman J; Ni H. 2009. Fibrinogen is required for maintenance of platelet intracellular and cell-surface P-selectin expression. Blood 114(2):425-36. [PubMed: 19332769]  [MGI Ref ID J:150774]

Yang H; Reheman A; Chen P; Zhu G; Hynes RO; Freedman J; Wagner DD; Ni H. 2006. Fibrinogen and von Willebrand factor-independent platelet aggregation in vitro and in vivo. J Thromb Haemost 4(10):2230-7. [PubMed: 16824188]  [MGI Ref ID J:129287]

Yarovoi H; Nurden AT; Montgomery RR; Nurden P; Poncz M. 2005. Intracellular interaction of von Willebrand factor and factor VIII depends on cellular context: lessons from platelet-expressed factor VIII. Blood 105(12):4674-6. [PubMed: 15731176]  [MGI Ref ID J:107451]

Zhao BQ; Chauhan AK; Canault M; Patten IS; Yang JJ; Dockal M; Scheiflinger F; Wagner DD. 2009. von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke. Blood 114(15):3329-34. [PubMed: 19687510]  [MGI Ref ID J:153541]

van Schooten CJ; Shahbazi S; Groot E; Oortwijn BD; van den Berg HM; Denis CV; Lenting PJ. 2008. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood 112(5):1704-12. [PubMed: 18559674]  [MGI Ref ID J:138724]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129S2 background and has been backcrossed to C57BL/6J for at least seven generations before it was made homozygous. When held in a live colony, this strain is maintained by homozygous matings.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. The total number of animals provided, their gender and genotype will vary. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 13 and 16 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location). This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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