Transgenic animals having a modified glycoprotein V gene

1. A transgenic mouse comprising a modified glycoprotein V (GP V) gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NQ:12 and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene.

2. Platelets isolated from blood plasma of the mouse of claim 1 .

3. A method of preparing a transgenic mouse comprising a modified glycoprotein V gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12, said method comprising:

a) introducing into embryonic stem cells a nucleic acid molecule a comprising a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12;

b) generating a transgenic mouse from the cells resulting from step a);

c) breeding the transgenic mouse to obtain a transgenic mouse homozygous for the modified GP V gene; and

d) determining that platelets from the homozygotic transgenic mouse have an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the GP V gene.

4. A method of preparing a transgenic mouse is genome comprising a nonfunctional glycoprotein V gene, wherein the mouse has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12, said method comprising:

a) introducing into embryonic stem cells a nucleic acid molecule comprising a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12 and a selectable marker;

b) identifying and selecting transformed cells;

c) injecting the transformed cells from step b) into blastocysts;

d) generating a transgenic mouse from the blastocysts of step c), wherein the generated transgenic mouse is chimeric for the nonfunctional GP V gene and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene;

e) breeding the chimeric mouse with a wild-type mouse to produce a mouse heterozygotic for the nonfunctional GP V gene;

f) crossing a heterozygotic mouse produced in step e) with a mouse which is chimeric or heterozygotic for the nonfunctional GP V gene; and

g) selecting a mouse homozygotic for the nonfunctional GP V gene from the resulting progeny.

5. A method to identify an agent that modulates a thrombotic response of a transgenic mouse whose genome has a modified GP V gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12 and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene, comprising the step of exposing the mouse to the agent and determining whether the agent modulates the thrombotic response.

6. A method of determining the effect of an agent on a characteristic of a mouse that is attributable to the expression of the GP V gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12 and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene, and wherein said characteristic is platelet function, said method comprising;

a) administering said agent to the mouse of claim 1 ;

b) maintaining said mouse for a desired period of time after said administration; and,

c) determining whether the characteristic of said mouse that is attributable to the expression of the modified GP V gene has been affected by the administration of said agent.

7. A cell isolated from a transgenic mouse that comprises a transgene stably integrated into the mouse's genome, said transgene encoding a modified glycoprotein V gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12 and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene.

8. The mouse of claim 1 , wherein said mouse is fertile and transmits the modified GP V gene to its offspring.

9. A method of determining the effect of an agent on a characteristic of a mouse that is attributable to the expression of the GP V gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NQ:12 and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene, and wherein said characteristic is hemostasis, said method comprising;

a) administering said agent to the mouse of claim 1 ;

b) maintaining said mouse for a desired period of time after said administration; and,

c) determining whether the characteristic of said mouse that is attributable to the expression of the modified GP V gene has been affected by the administration of said agent.

10. A method of determining the effect of an agent on a characteristic of a mouse that is attributable to the expression of the GP V gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12 and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene, and wherein said characteristic is coagulation, said method comprising;

a) administering said agent to the mouse of claim 1 ;

b) maintaining said mouse for a desired period of time after said administration; and,

c) determining whether the characteristic of said mouse that is attributable to the expression of the modified GP V gene has been affected by the administration of said agent.

11. A method of determining the effect of an agent on a characteristic of a mouse that is attributable to the expression of the GP V gene, wherein the mouse is genome has a homozygous modification with a construct which removes a sequence of GP V gene comprising nucleotides encoding Met 1 to Leu 389 of SEQ ID NO:12 and wherein said mouse has platelets with an increased aggregation response to a low concentration of thrombin compared to platelets from a mouse homozygous for the wild type GP V gene, and wherein said characteristic is thrombosis, said method comprising;

a) administering said agent to the mouse of claim 1 ;

b) maintaining said mouse for a desired period of time after said administration; and,

c) determining whether the characteristic of said mouse that is attributable to the expression of the modified GP V gene has been affected by the administration of said agent.