Thromb Haemost 2006; 95(01): 159-165
DOI: 10.1160/TH05-05-0322
Animal Models
Schattauer GmbH

Genetic strain differences in platelet aggregation of laboratory mice

Toshiki Sudo
1   First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
,
Hideki Ito
1   First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
,
Yukio Kimura
1   First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
› Author Affiliations
Further Information

Publication History

Received 09 May 2005

Accepted after resubmission 23 November 2005

Publication Date:
28 November 2017 (online)

Summary

To investigate the physiological role of novel genes and proteins in platelet activation, various knockout mice have been produced. A number of standard inbred mouse strains each possessing genetically unique characters such as high tumor generation, hyperglycemia or hyperlipidemia, have been bred. In breeding knockout mice for investigation of specific physiological functions, appropriate selection of parental or backcross strains is necessary. Thus, examination of strain-specific platelet characteristics is important. In the present study, platelet aggregation responses of 13 laboratory mouse strains, 129/Sv, A, AKR, BALB/c, C3H/He, C57BL/6J, CBA, DBA/1, DBA/2, ddY, FVB, ICR, and NZW, and the diabetic strain C57BL/KsJ db/db, were compared. Marked strain differences were observed inADP- and collagen-induced platelet aggregation. The highest responses with both were seen in AKR/J and NZW/N, whereas the lowest were seen in DBA/2 and DBA/1.There was a 5-fold difference in the platelet aggregation threshold index (PATI) for ADP-induced PRP aggregation between AKR/J (0.6 µM) and DBA/2 (3.0 µM). With whole blood aggregation, the highest response was seen in AKR, whereas the lowest was seen in DBA/2 and DBA/1. The present study demonstrated that there is considerable strain difference in platelet aggregation among laboratory mice, which should be taken into account in backcrossing knockout strains.

 
  • References

  • 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-34.
  • 2 Moers A, Nieswandt B, Massberg S. et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat Med 2003; 09: 1418-22.
  • 3 Watanabe N, Nakajima H, Suzuki H. et al. Functional phenotype of phosphoinositide 3-kinase p85α-null platelets characterized by an impaired response to GPVI stimulation. Blood 2003; 102: 541-8.
  • 4 Woulfe D, Jiang H, Morgans A. et al. Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2. J Clin Invest 2004; 113: 441-50.
  • 5 Angelillo-Scherrer A, de Frutos P, Aparicio C. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med 2001; 07: 215-21.
  • 6 Senis YA, Sangrar W, Zirngibl RA. et al. Fps/Fes and Fer non-receptor protein-tyrosine kinases regulate collagen- and ADP-induced platelet aggregation. J Thromb Haemost 2003; 01: 1062-70.
  • 7 Auger JM, Best D, Snell DC. et al. c-Cbl negatively regulates platelet activation by glycoprotein VI. J Thromb Haemost 2003; 01: 2419-26.
  • 8 Montagutelli X. Effect of the genetic background on the phenotype of mouse mutations. J Am Soc Nephrol 2000; 11: S101-5.
  • 9 Coleman DL, Hummel KP. The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 1973; 09: 287-93.
  • 10 Hummel KP, Coleman DL, Lane PW. The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL-KsJ and C57BL-6J strains. Biochem Genet 1972; 07: 1-13.
  • 11 Cho H, Mu J, Kim JK. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001; 292: 1728-31.
  • 12 Garofalo RS, Orena SJ, Rafidi K. et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 2003; 112: 197-208.
  • 13 Staats J. Standardized nomenclature for inbred strains of mice: fourth listing. Cancer Res 1968; 28: 391-420.
  • 14 Schadt EE, Monks SA, Drake TA. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 2003; 422: 297-302.
  • 15 Schwarz M, Davis DL, Vick BR. et al. Genetic analysis of cholesterol accumulation in inbred mice. J Lipid Res 2001; 42: 1812-9.
  • 16 Nishina PM, Wang J, Toyofuku W. et al. Atherosclerosis and plasma and liver lipids in nine inbred strains of mice. Lipids 1993; 28: 599-605.
  • 17 Harmon KJ, Couper LL, Lindner V. Strain-dependent vascular remodeling phenotypes in inbred mice. Am J Pathol 2000; 156: 1741-8.
  • 18 Tsakiris DA, Scudder L, Hodivala-Dilke K. et al. Hemostasis in the mouse (Mus musculus): a review. Thromb Haemost 1999; 81: 177-88.
  • 19 Mackman N. Mouse models in haemostasis and thrombosis. Thromb Haemost 2004; 92: 440-3.
  • 20 Ware J. Dysfunctional platelet membrane receptors: from human to mice. Thromb Haemost 2004; 92: 478-85.
  • 21 Day SM, Reeve JL, Myers DD. et al. Murine thrombosis models. Thromb Haemost 2004; 92: 486-94.
  • 22 Paigen B, Kovats SE, Chapman MH. et al. Characterization of a genetic difference in the platelet aggregation response of two inbred mouse strains, C57BL/6 and C3H/He. Atherosclerosis 1987; 64: 181-90.
  • 23 Zumbach A, Marbet GA, Tsakiris DA. Influence of the genetic background on platelet function, microparticle and thrombin generation in the common laboratory mouse. Platelets 2001; 12: 496-502.
  • 24 Li TT, Larrucea S, Souza S. et al. Genetic variation responsible for mouse strain differences in integrin ?2 expression is associated with altered platelet responses to collagen. Blood 2004; 103: 3396-402.
  • 25 Sudo T, Ito H. Genetic strain differences of platelet aggregation in laboratory mice. Platelets 2004; 15: 387-8 (abstract).
  • 26 Ozeki Y, Sudo T, Toga K. et al. Characterization of whole blood aggregation with a new type of aggregometer by a screen filtration pressure method. Thromb Res 2001; 101: 65-72.
  • 27 Sudo T, Tachibana K, Toga K. et al. Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem Pharmacol 2000; 59: 347-56.
  • 28 Sudo T, Ito H, Kimura Y. Characterization of platelet aggregation in whole blood of laboratory animals by a screen filtration pressure method. Platelets 2003; 14: 239-46.
  • 29 Sudo T, Ito H, Ozeki Y. et al. Estimation of anti-platelet drugs on human platelet aggregation with a novel whole blood aggregometer by a screen filtration pressure method. Br J Pharmacol 2001; 133: 1396-404.
  • 30 Taylor BA. Genetic relationships between inbred strains of mice. J Hered 1972; 63: 83-6.
  • 31 Brodsky I. Thrombocytopenia, a prelymphoid leukaemic sign in AKR mice. Nature 1969; 223: 198-9.
  • 32 Gross L. “Spontaneous” leukemia developing in C3H mice following inoculation in infancy, with AKleukemic extracts, or AK-embrvos. Proc Soc Exp Biol Med 1951; 76: 27-32.
  • 33 Storer JB. Longevity and gross pathology at death in 22 inbred mouse strains. J Gerontol 1966; 21: 404-9.
  • 34 Festing MFW, Blackmore DK. Life span of specified-pathogen-free (MRC category 4) mice and rats. Lab Anim 1971; 05: 179-92.
  • 35 Brodsky I, Dimitrov NV. Platelet kinetics and adenosine triphosphatase activity in AKR mice. J Natl Cancer Inst 1973; 50: 997-1001.
  • 36 Stafford NP, Pink AE, White AE. et al. Mechanisms involved in adenosine triphosphate-induced platelet aggregation in whole blood. Arterioscler Thromb Vasc Biol 2003; 23: 1928-33.
  • 37 Rosenblum WI, El-Sabban F, Loria RM. Platelet aggregation in the cerebral and mesenteric microcirculation of mice with genetically determined diabetes. Diabetes 1981; 30: 89-92.
  • 38 Konstantinides S, Schäfer K, Koschnick S. et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-40.
  • 39 Nakata M, Yada T, Soejima N. et al. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 426-9.
  • 40 Born GVR, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-95.
  • 41 Swank RL. Alteration of blood on storage: measurement of adhesiveness of “aging” platelets and leukocytes and their removal by filtration. New Engl J Med 1961; 265: 728-33.
  • 42 Swank RL, Roth JG, Jansen J. Screen filtration pressure method and adhesiveness and aggregation of blood cells. J Appl Physiol 1964; 19: 340-6.
  • 43 Aihara KI, Azuma H, Akaike M. et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004; 279: 35798-802.
  • 44 Arakawa K, Takeyoshi I, Muraoka M. et al. Measuring platelet aggregation to estimate small intestinal ischemia-reperfusion injury. J Surg Res 2004; 122: 195-200.
  • 45 Yokoyama S, Ikeda H, Haramaki N. et al. Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates. J Am Coll Cardiol 2005; 45: 1280-6.
  • 46 Qi R, Yatomi Y, Ozaki Y. Effects of incubation time, temperature, and anticoagulants on platelet aggregation in whole blood. Thromb Res 2001; 101: 139-44.
  • 47 Inoue T, Hayashi M, Uchida T. et al. Significance of platelet aggregability immediately after blood sampling and effect of cigarette smoking. Platelets 2001; 12: 415-8.
  • 48 Kohro S, Yamakage M, Sato K. et al. Intermittent pneumatic foot compression can activate blood fibrinolysis without changes in blood coagulability and platelet activation. Acta Anaesthesiol Scand 2005; 49: 660-4.
  • 49 Santos MT, Vallés J, Aznar J. et al. Role of red blood cells in the early stages of platelet activation by collagen. Thromb Haemost 1986; 56: 376-81.
  • 50 Setiabudy-Dharma R, Funahara Y. Enhancement of collagen induced aggregation of platelets in whole blood. Thromb Res 1986; 42: 621-34.
  • 51 Vallés J, Santos M T, Aznar J. et al. Platelet-erythrocyte interactions enhance αIIbβ3 integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood 2002; 99: 3978-84.