Genetic Models of Hemostasis and Thrombosis

Living reference work entry

Abstract

The genes encoding the coagulation factor proteins were among the first human genes to be characterized. Since then significant progress has been made in the application of this information, such as in the case of hemophilia A and B as well as the genetic variations in key coagulation factors. Additionally, the drug metabolizing enzyme (CYPs) variations and the resulting changes in the pharmacokinetic and the pharmacodynamic profiles of the active anticoagulant or antiplatelet moieties can be monitored to determine the unit dose required for optimal efficacy and safety. For various coagulation disorders and pharmacotherapy, genetic characterization of the disease-causing mutations (pharmacogenetics) and pharmacogenomics are currently incorporated into the standard of care for the risk stratification of treatment complications.

Keywords

Tissue Factor Pathway Inhibitor Thrombin Receptor Prolonged Bleeding Time Glanzmann Thrombasthenia Tissue Factor Pathway Inhibitor Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Further Reading

  1. Bi L, Sarkar R, Naas T et al (1996) Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies. Blood 88:3446–3450Google Scholar
  2. Bugge TH, Suh TT, Flick MJ et al (1995) The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Bio Chem 270:16886–16894Google Scholar
  3. Bugge TH, Xiao Q, Kombrinck KW et al (1996) Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci USA 93:6258–6263Google Scholar
  4. Carmeliet P, Stassen JM, Schoonjans L et al (1993) Plasminogen activator inhibitor-1 gene-deficient mice. J Clin Invest 92:2756–2760Google Scholar
  5. Carmeliet P, Schoonjans L, Kieckens L et al (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368:419–424Google Scholar
  6. Connolly AJ, Ishihara H, Kahn ML et al (1996) Role of the thrombin receptor in development and evidence for a second receptor. Nature 381:516–519Google Scholar
  7. Cui J, O’Shea KS, Purkayastha A et al (1996) Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 384:66–68Google Scholar
  8. Denis C, Methia N, Frenette PS et al (1998) A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci USA 95:9524–9529Google Scholar
  9. Dewerchin M, van Nuffelen A, Wallays G et al (1996) Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 97:870–878Google Scholar
  10. Dewerchin M, Liang Z, Moons L et al (2000) Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 83:185–190Google Scholar
  11. Gailani D, Lasky NM, Broze GJ (1997) A murine model of factor XI deficiency. Blood Coagul Fibrinolysis 8:134–144Google Scholar
  12. Healy AM, Rayburn HB, Rosenberg RD, Weiler H (1995) Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci USA 92:850–854Google Scholar
  13. Hodivala-Dilke KM, McHugh KP, Tsakiris DA et al (1999) β 3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103:229–238Google Scholar
  14. Huang ZF, Higuchi D, Lasky N, Broze GJJ (1997) Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 90:944–951Google Scholar
  15. Jalbert LR, Rosen ED, Moons L et al (1998) Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest 102:1481–1488Google Scholar
  16. Kahn ML, Zheng YW, Huang W et al (1998) A dual thrombin receptor system for platelet activation. Nature 394:690–694Google Scholar
  17. Law DA, DeGuzman FR, Heiser P et al (1999) Integrin cytoplasmic tyrosine motif is required for outside-in αllbβ3 signalling and platelet function. Nature 401:808–811Google Scholar
  18. Leon C, Hechler B, Freund M et al (1999) Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor-null mice. J Clin Invest 104:1731–1737Google Scholar
  19. Offermans S, Toombs CF, Hu YH, Simon MI (1997) Defective platelet activation in G alpha(q)-deficient mice. Nature 389:183–186Google Scholar
  20. Ploplis VA, Carmeliet P, Vazirzadeh S et al (1995) Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 92:2585–2593Google Scholar
  21. Rosen ED, Chan JCY, Idusogie E et al (1997) Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Nature 390:290–294Google Scholar
  22. Subramaniam M, Frenette PS, Saffaripour S et al (1996) Defects in hemostasis in P-selectin-deficient mice. Blood 87:1238–1242Google Scholar
  23. Suh TT, Holmback K, Jensen NJ et al (1995) Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 9:2020–2033Google Scholar
  24. Sun WY, Witte DP, Degen JL et al (1998) Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proc Natl Acad Sci USA 95:7597–7602Google Scholar
  25. Thomas DW, Mannon RB, Mannon PJ et al (1998) Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. J Clin Invest 102:1994–2001Google Scholar
  26. Toomey JR, Kratzer KE, Lasky NM et al (1996) Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 88:1583–1587Google Scholar
  27. Wang L, Zoppè M, Hackeng TM et al (1997) A factor IX-deficient mouse model for hemophilia B gene therapy. Proc Natl Acad Sci USA 94:11563–11566Google Scholar
  28. Xu J, Wu Q, Westfield L et al (1998) Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice. Proc Natl Acad Sci USA 95:7603–7607Google Scholar

Genetic Models of Hemostasis and Thrombosis

  1. Bi L, Sarkar R, Naas T et al (1996) Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies. Blood 88:3446–3450Google Scholar
  2. Bugge TH, Suh TT, Flick MJ et al (1995) The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Bio Chem 270:16886–16894Google Scholar
  3. Bugge TH, Xiao Q, Kombrinck KW et al (1996) Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci USA 93:6258–6263Google Scholar
  4. Carmeliet P, Collen D (1999) New developments in the molecular biology of coagulation and fibrinolysis. In: Handbook of experimental pharmacology, vol 132, Antithrombotics. Springer, Berlin, pp 41–76Google Scholar
  5. Carmeliet P, Stassen JM, Schoonjans L et al (1993) Plasminogen activator inhibitor-1 gene-deficient mice. J Clin Invest 92:2756–2760Google Scholar
  6. Carmeliet P, Schoonjans L, Kieckens L et al (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368:419–424Google Scholar
  7. Carmeliet P, Mackman N, Moons L et al (1996) Role of tissue factor in embryonic blood vessel development. Nature 383:73–75Google Scholar
  8. Christie PD, Edelberg JM, Picard MH et al (1999) A murine model of myocardial thrombosis. J Clin Invest 104:533–539Google Scholar
  9. Connolly AJ, Ishihara H, Kahn ML et al (1996) Role of the thrombin receptor in development and evidence for a second receptor. Nature 381:516–519Google Scholar
  10. Cui J, O’Shea KS, Purkayastha A et al (1996) Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 384:66–68Google Scholar
  11. Denis C, Methia N, Frenette PS et al (1998) A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci USA 95:9524–9529Google Scholar
  12. Evans JP, Brinkhous KM, Brayer GD et al (1989) Canine hemophilia B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci U S A 86:10095–10099CrossRefPubMedCentralPubMedGoogle Scholar
  13. Healy AM, Rayburn HB, Rosenberg RD, Weiler H (1995) Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci USA 92:850–854Google Scholar
  14. Herzog RW, Yang EY, Couto LB et al (1999) Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med 5:56–63CrossRefPubMedGoogle Scholar
  15. Hodivala-Dilke KM, McHugh KP, Tsakiris DA et al (1999) β 3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103:229–238Google Scholar
  16. Huang ZF, Higuchi D, Lasky N, Broze GJJ (1997) Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 90:944–951Google Scholar
  17. Kahn ML, Zheng YW, Huang W et al (1998) A dual thrombin receptor system for platelet activation. Nature 394:690–694Google Scholar
  18. Kay MA, Manno CS, Ragni MV et al (2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients with an AAV vector. Nat Genet 24:257–261CrossRefPubMedGoogle Scholar
  19. Kung J, Hagstrom J, Cass D et al (1998) Human FIX corrects bleeding diathesis of mice with hemophilia B. Blood 91:784–790PubMedGoogle Scholar
  20. Law DA, DeGuzman FR, Heiser P et al (1999) Integrin cytoplasmic tyrosine motif is required for outside-in αllbβ3 signalling and platelet function. Nature 401:808–811Google Scholar
  21. Leon C, Hechler B, Freund M et al (1999) Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor-null mice. J Clin Invest 104:1731–1737Google Scholar
  22. Lin HF, Maeda N, Sithies O et al (1997) A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 90:3962–3966PubMedGoogle Scholar
  23. Offermanns S, Toombs CF, Hu YH, Simon MI (1997) Defective platelet activation in Gα q-deficient mice. Nature 389:183–186CrossRefPubMedGoogle Scholar
  24. Pearson JM, Ginsburg D (1999) Use of transgenic mice in the study of thrombosis and hemostasis. In: Handbook of experimental pharmacology, vol 132, Antithrombotics. Springer, Berlin, pp 157–174Google Scholar
  25. Ploplis VA, Carmeliet P, Vazirzadeh S et al (1995) Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 92:2585–2593Google Scholar
  26. Subramaniam M, Frenette PS, Saffaripour S et al (1996) Defects in hemostasis in P-selectin-deficient mice. Blood 87:1238–1242Google Scholar
  27. Thomas DW, Mannon RB, Mannon PJ et al (1998) Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. J Clin Invest 102:1994–2001Google Scholar
  28. Toomey JR, Kratzer KE, Lasky NM et al (1996) Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 88:1583–1587Google Scholar
  29. Vassalli G, Dichek DA (1997) Gene therapy for arterial thrombosis. Cardiovasc Res 35:459–469CrossRefPubMedGoogle Scholar
  30. Wang L, Zoppè M, Hackeng TM et al (1997) A factor IX-deficient mouse model for hemophilia B gene therapy. Proc Natl Acad Sci USA 94:11563–11566Google Scholar
  31. Waugh JM, Yuksel E, Li J et al (1999a) Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. Circ Res 84:84–92CrossRefPubMedGoogle Scholar
  32. Waugh JM, Kattash M, Li J et al (1999b) Gene therapy to promote thromboresistance: local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. Proc Natl Acad Sci U S A 96:1065–1070CrossRefPubMedCentralPubMedGoogle Scholar
  33. Zoldhelyi P, McNatt J, Shelat HS et al (2000) Thromboresistance of balloon-injured porcine carotid arteries after local gene transfer of human tissue factor pathway inhibitor. Circulation 101:289–295CrossRefPubMedGoogle Scholar

Knock-Out Mice: Factor I (Fibrinogen)

  1. Suh TT, Holmback K, Jensen NJ et al (1995) Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 9:2020–2033Google Scholar

Knock-Out Mice: Factor II (Prothrombin)

  1. Sun WY, Witte DP, Degen JL et al (1998) Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proc Natl Acad Sci USA 95:7597–7602Google Scholar
  2. Xu J, Wu Q, Westfield L et al (1998) Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice. Proc Natl Acad Sci USA 95:7603–7607Google Scholar

Knock-Out Mice: Factor V

  1. Cui J, O’Shea KS, Purkayastha A et al (1996) Fatal hemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 384:66–68Google Scholar
  2. Yang TL, Cui J, Taylor JM et al (2000) Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level transgene expression. Thromb Haemost 83:70–77Google Scholar

Knock-Out Mice: Factor VII

  1. Rosen ED, Chan JCY, Idusogie E et al (1997) Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Nature 390:290–294Google Scholar

Knock-Out Mice: Factor VIII

  1. Bi L, Lawler AM, Antonarakis SE et al (1995) Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet 10:119–121CrossRefPubMedGoogle Scholar

Knock-Out Mice: Factor IX

  1. Kundu RK, Sangiorgi F, Wu LY et al (1998) Targeted inactivation of the coagulation factor IX gene causes hemophilia B in mice. Blood 92:168–174PubMedGoogle Scholar
  2. Wang L, Zoppè M, Hackeng TM et al (1997) A factor IX-deficient mouse model for hemophilia B gene therapy. Proc Natl Acad Sci USA 94:11563–11566Google Scholar

Knock-Out Mice: Factor X

  1. Dewerchin M, Liang Z, Moons L et al (2000) Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 83:185–190Google Scholar

Knock-Out Mice: Factor XI

  1. Gailani D, Lasky NM, Broze GJ (1997) A murine model of factor XI deficiency. Blood Coagul Fibrinolysis 8:134–144Google Scholar

Knock-Out Mice: TF (Tissue Factor)

  1. Bugge TH, Xiao Q, Kombrinck KW et al (1996) Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci USA 93:6258–6263Google Scholar
  2. Carmeliet P, Mackman N, Moons L et al (1996) Role of tissue factor in embryonic blood vessel development. Nature 383:73–75Google Scholar
  3. Toomey JR, Kratzer KE, Lasky NM et al (1996) Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 88:1583–1587Google Scholar
  4. Toomey JR, Kratzer KE, Lasky NM, Broze GJ (1997) Effect of tissue factor deficiency on mouse and tumor development. Proc Natl Acad Sci U S A 94:6922–6926CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: TFPI (Tissue Factor Pathway Inhibitor)

  1. Huang ZF, Higuchi D, Lasky N, Broze GJJ (1997) Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 90:944–951Google Scholar

Knock-Out Mice: Thrombin Receptor

  1. Connolly AJ, Ishihara H, Kahn ML et al (1996) Role of the thrombin receptor in development and evidence for a second receptor. Nature 381:516–519Google Scholar
  2. Darrow AL, Fung-Leung WP, Ye RD et al (1996) Biological consequences of thrombin receptor deficiency in mice. Thromb Haemost 76:860–866PubMedGoogle Scholar

Knock-Out Mice: Thrombomodulin

  1. Christie PD, Edelberg JM, Picard MH et al (1999) A murine model of myocardial microvascular thrombosis. J Clin Invest 104:533–539Google Scholar
  2. Healy AM, Rayburn HB, Rosenberg RD, Weiler H (1995) Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci USA 92:850–854Google Scholar
  3. Healy AM, Hancock WW, Christie PD et al (1998) Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition. Blood 92:4188–4197PubMedGoogle Scholar
  4. Weiler-Guettler H, Christie PD, Beeler DL et al (1998) A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state. J Clin Invest 101:1983–1991CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Protein C

  1. Jalbert LR, Rosen ED, Moons L et al (1998) Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest 102:1481–1488Google Scholar

Knock-Out Mice: Plasminogen

  1. Bugge TH, Flick MJ, Daugherty CC, Degen JL (1995) Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 9:794–807Google Scholar
  2. Ploplis VA, Carmeliet P, Vazirzadeh S et al (1995) Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 92:2585–2593Google Scholar

Knock-Out Mice: Alpha2-Antiplasmin

  1. Lijnen HR, Okada K, Matsuo O et al (1999) Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. Blood 93:2274–2281PubMedGoogle Scholar

Knock-Out Mice: T-PA (Tissue-type Plasminogen Activator)

  1. Carmeliet P, Schoonjans L, Kieckens L et al (1998) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368:419–424Google Scholar
  2. Christie PD, Edelberg JM, Picard MH et al (1999) A murine model of myocardial microvascular thrombosis. J Clin Invest 104:533–539Google Scholar

Knock-Out Mice: PAI-1 (Plasminogen Activator Inhibitor-1)

  1. Carmeliet P, Stassen JM, Schoonjans L et al (1993) Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 92:2756–2760Google Scholar
  2. Eitzman DT, McCoy RD, Zheng X et al (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97:232–237CrossRefPubMedCentralPubMedGoogle Scholar
  3. Erickson LA, Fici GJ, Lund JE et al (1990) Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 346:74–76CrossRefPubMedGoogle Scholar
  4. Kawasaki T, Dewerchin M, Lijnen HR et al (2000) Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice. Blood 96:153–160PubMedGoogle Scholar
  5. Pinsky DJ, Liao H, Lawson CA et al (1998) Coordinated induction of plasminogen activator inhibitor-1(PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 102:919–928CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Vitronectin

  1. Eitzman DT, Westrick RJ, Nabel EG, Ginsburg D (2000) Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. Blood 95:577–580PubMedGoogle Scholar
  2. Zheng X, Saunders TL, Camper SA et al (1995) Vitronectin is not essential for normal mammalian development and fertility. Proc Natl Acad Sci U S A 92:12426–12430CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Urokinase, U-PA (Urinary-Type Plasminogen Activator)

  1. Carmeliet P, Schoonjans L, Kieckens L et al (1998) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368:419–424Google Scholar
  2. Heckel JL, Sandgren EP, Degen JL et al (1990) Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell 62:447–456CrossRefPubMedGoogle Scholar

Knock-Out Mice: uPAR (Urinary-Type Plasminogen Activator Receptor)

  1. Bugge TH, Suh TT, Flick MJ et al (1995) The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Bio Chem 270:16886–16894Google Scholar
  2. Bugge TH, Flick MJ, Danton MJ et al (1996) Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 93:5899–5904Google Scholar
  3. Dewerchin M, van Nuffelen A, Wallays G et al (1996) Generation and characterization of urokinase receptor deficient mice. J Clin Invest 97:870–878Google Scholar
  4. Piguet PF, Da-Laperrousaz C, Vesin C et al (2000) Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice. Infect Immun 68:3822–3829CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Gas 6 (Growth Arrest-Specific Gene 6 Product)

  1. Angelillo-Scherrer A, DeFrutos PG, Aparicio C et al (2001) Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med 7:215–221CrossRefPubMedGoogle Scholar

Knock-Out Mice: GPIbalpha (Glycoprotein Ib Alpha, Part of the GP Ib-V–IX Complex)

  1. Ware J, Russell S, Ruggeri ZM (2000) Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc Natl Acad Sci U S A 97:2803–2808CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: GPV (Glycoprotein V, Part of the GP Ib-V–IX Complex)

  1. Ramakrishnan V, Reeves PS, DeGuzman F et al (1999) Increased thrombin responsiveness in platelets from mice lacking glycoprotein V. Proc Natl Acad Sci U S A 96:13336–13341CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: GPIIb (Integrin Alpha IIb, Glycoprotein IIb, Part of the GP IIb–IIIa Complex)

  1. Tronik-Le Roux D, Roullot V, Poujol C et al (2000) Thrombasthenic mice generated by replacement of the integrin alphaIIb gene: demonstration that transcriptional activation of this megakaryocytic locus precedes lineage commitment. Blood 96:1399–1408PubMedGoogle Scholar

Knock-Out Mice: GP IIIa (Integrin Beta3, Glycoprotein IIIa, Part of the GP IIb–IIIa Complex)

  1. Hodivala-Dilke KM, McHugh KP, Tsakiris DA et al (1999) Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103:229–238Google Scholar
  2. McHugh KP, Hodivala-Dilke K, Zheng MH et al (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105:433–440CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: GP IIa (Glycoprotein IIa, Integrin Beta 1, Part of the GP Ia–IIa Complex)

  1. Nieswandt B, Brakebusch C, Bergmeier W et al (2001) Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. EMBO J 20:2120–2130CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: vWF (von Willebrand Factor)

  1. Denis C, Methia N, Frenette PS et al (1998) A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci USA 95:9524–9529Google Scholar
  2. Ni H, Denis CV, Subbarao S et al (2000) Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 106:385–392CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Thromboxane A2 Receptor (TXA2r)

  1. Thomas DW, Mannon RB, Mannon PJ et al (1998) Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. J Clin Invest 102:1994–2001Google Scholar

Knock-Out Mice: Prostacyclin Receptor (PGI2r)

  1. Murata T, Ushikubi F, Matsuoka T et al (1997) Altered pain reception and inflammatory response in mice lacking prostacyclin receptor. Nature 388:678–682CrossRefPubMedGoogle Scholar

Knock-Out Mice: PECAM (Platelet: Endothelial Cell Adhesion Molecule)

  1. Duncan GS, Andrew DP, Takimoto H et al (1999) Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1) CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J Immunol 162:3022–3030PubMedGoogle Scholar
  2. Mahooti S, Graesser D, Patil S et al (2000) PECAM-1 (CD 31) expression modulates bleeding tome in vivo. Am J Pathol 157:75–81CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Pallid (Pa)

  1. Huang L, Kuo YM, Gitschier J (1999) The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency. Nat Genet 23:329–332CrossRefPubMedGoogle Scholar

Knock-Out Mice: G Alpha (q) (Guanyl Nucleotide Binding Protein G Alpha q)

  1. Offermans S, Toombs CF, Hu YH, Simon MI (1997) Defective platelet activation in G alpha(q)-deficient mice. Nature 389:183–186Google Scholar
  2. Ohlmann P, Eckly A, Freund M et al (2000) ADP induces partial platelet aggregation without shape change and potentiates collagen-induced aggregation in the absence of Galphaq. Blood 96:2134–2139PubMedGoogle Scholar

Knock-Out Mice: G z (Member of the Gi Family of G Proteins)

  1. Yang J, Wu J, Kowalska MA et al (2000) Loss of signaling through G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs. Proc Natl Acad Sci USA 97:9984–9989Google Scholar

Knock-Out Mice: Phospholipase C Gamma

  1. Wang D, Feng J, Wen R et al (2000) Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 13:25–35CrossRefPubMedGoogle Scholar

Knock-Out Mice: CD39 (Vascular Adenosine Triphosphate Diphosphohydrolase)

  1. Enjyoji K, Sevigny J, Lin Y et al (1999) Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med 5:1010–1017CrossRefPubMedGoogle Scholar

Knock-Out Mice: Protein Kinase, cGMP-Dependent

  1. Massberg S, Sausbier M, Klatt P et al (1999) Increased adhesion and aggregation of platelets lacking cyclic guanosine 3′,5′-monophosphate kinase I. J Exp Med 189:1255–1264CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Vasodilator-Stimulated Phosphoprotein (VASP)

  1. Aszodi A, Pfeifer A, Ahmad M et al (1999) The vasodilator-stimulated phosphoprotein (VASP) is involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function. EMBO J 18:37–48CrossRefPubMedCentralPubMedGoogle Scholar
  2. Hauser W, Knobeloch KP, Eigenthaler M et al (1999) Megakaryocyte hyperplasia and enhanced agonist-induced platelet activation in vasodilator-stimulated phosphoprotein knockout mice. Proc Natl Acad Sci U S A 96:8120–8125CrossRefPubMedCentralPubMedGoogle Scholar

Knock-Out Mice: Arachidonate 12-Lipoxygenase (P-12LO)

  1. Chen XS, Sheller JR, Johnson EN, Funk CD (1994) Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature 372:179–182Google Scholar
  2. Johnson EN, Brass LF, Funk CD (1998) Increased platelet sensitivity to ADP in mice lacking platelet-type 12-lipoxygenase. Proc Natl Acad Sci USA 95:3100–3105Google Scholar

Knock-Out Mice: Arachidonate 5-Lipoxygenase (P-5LO)

  1. Chen XS, Sheller JR, Johnson EN, Funk CD (1994) Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature 372:179–182Google Scholar
  2. Johnson EN, Brass LF, Funk CD (1998) Increased platelet sensitivity to ADP in mice lacking platelet-type 12-lipoxygenase. Proc Natl Acad Sci USA 95:3100–3105Google Scholar

Knock-Out Mice: Thrombopoietin

  1. Lawler J, Sunday M, Thibert V et al (1998) Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 101:982–992Google Scholar

Knock-Out Mice: Thrombospondin-1

  1. Lawler J, Sunday M, Thibert V et al (1998) Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 101:982–992Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.The Pharmaceutical Research InstituteAlbany College of Pharmacy and Health SciencesAlbanyUSA

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