Genetic strain differences in platelet aggregation and thrombus formation of laboratory rats

Summary

Rats are employed to investigate the role of platelets in thrombus formation under flow conditions in vivo and to evaluate the pre-clinical potential of antiplatelet drugs. While Wistar and Sprague-Dawley (SD) strains are commonly used in thrombosis models, a number of rat strains have been established. Each strain possesses genetically unique characteristics such as hypertension, hyperglycemia or hyperlipidemia. The appropriate selection of a strain might have advantages for physiological and pharmacological studies. Comparative investigation of platelet aggregation among laboratory strains of rats is useful for the development of thrombosis models. In the present study, platelet aggregation response in eight laboratory rat strains, ACI, Brown Norway (BN), Donryu, Fischer 344 (F344), LEW, SD, Wistar and WKAH, were compared. Considerable strain differences were observed in ADP-, collagen- and TRAP-induced platelet aggregation. SD and BN are high-platelet-aggregation strains, while F344 and ACI are low-response strains. In the arteriovenous shunt thrombosis model, SD formed larger thrombi than F344 andWistar rats. In the FeCl 3 -induced thrombosis model with the carotid artery, the time to occlusion of SD was significantly shorter than of F344 and ACI rats. F344 and ACI rats had significantly increased bleeding times compared with SD rat. The present study demonstrates that there are considerable strain differences in platelet aggregation among laboratory rats, which reflect thrombus formation.

Keywords

Platelet aggregation - rat - strain difference - thrombus formation

• References

• 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
• 2 Jackson SP, Schoenwaelder SM. Antiplatelet therapy: in search of the 'magic bullet'. Nat Rev Drug Discov 2003; 2: 775-789.
• 3 Ni H, Denis CV, Subbarao S. et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 2000; 106: 385-392.
• 4 Yang H, Reheman A, Chen P. et al. Fibrinogen and von Willebrand factor-independent platelet aggregation in vitro and in vivo. J Thromb Haemost 2006; 4: 2230-2237.
• 5 Nieswandt B, Aktas B, Moers A. et al. Platelets in atherothrombosis: lessons from mouse models. J Thromb Haemost 2005; 3: 1725-1736.
• 6 Abott A. Laboratory animals: the renaissance rat. Nature 2004; 428: 464-466.
• 7 Kurz KD, Main BW, Sandusky GE. Rat model of arterial thrombosis induced by ferric chloride. Thromb Res 1990; 60: 269-280.
• 8 Dietrich WD, Watson BD, Busto R. et al. Photochemically induced cerebral infarction. I. Early microvascular alterations. Acta Neuropathol 1987; 72: 315-325.
• 9 Hladovec J. Experimental arterial thrombosis in rats with continuous registration. Thromb Diath Haemorrh 1971; 26: 407-410.
• 10 Umetsu T, Sanai K. Effect of 1-methyl-2-mercapto- 5-(3-pyridyl)-imidazole (KC-6141), an anti-aggregating compound, on experimental thrombosis in rats. Thromb Haemost 1978; 28: 74-83.
• 11 Lindsey JR. Historical foundations. In: The Laboratory Rat. Vol. 1. Biology and Diseases. 1979. Academic Press; 2-36.
• 12 Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J 1963; 27: 282-293.
• 13 Okamoto K, Yamori Y, Nagaoka A. Establishment of the stroke-prone spontaneously hypertension rat (SHR). Circ Res 1974; 34: 143-153@@. 34 Suppl
• 14 Kawano K, Hirashima T, Mori S. et al. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992; 41: 1422-1428.
• 15 Harmon KJ, Couper LL, Lindner V. Strain-dependent vascular remodeling phenotypes in inbred mice. Am J Pathol 2000; 156: 1741-1748.
• 16 Korshunov VA, Berk BC. Strain-dependent vascular remodeling: the "Glagov phenomenon" is genetically determined. Circulation 2004; 110: 220-226.
• 17 Kuhel DG, Zhu B, Witte DP. et al. Distinction in genetic determinants for injury-induced neointimal hyperplasia and diet-induced atherosclerosis in inbred mice. Arterioscler Thromb Vasc Biol 2002; 22: 955-960.
• 18 Sindermann JR, Kobbert C, Skaletz-Rorowski A. et al. Vascular injury response in mice is dependent on genetic background. Am J Physiol Heart Circ Physiol 2006; 290: H1307-1310.
• 19 Helisch A, Wagner S, Khan N. et al. Impact of mouse strain differences in innate hindlimb collateral vasculature. Arterioscler Thromb Vasc Biol 2006; 26: 520-526.
• 20 Assadnia S, Rapp JP, Nestor AL. et al. Strain differences in neointimal hyperplasia in the rat. Circ Res 1999; 84: 1252-1257.
• 21 Tanase H, Yamori Y, Hansen CT. et al. Heart size in inbred strains of rats. Part 1. Genetic determination of the development of cardiovascular enlargement in rats. Hypertension 1982; 4: 864-872.
• 22 Sudo T, Ito H, Kimura Y. Genetic strain differences in platelet aggregation of laboratory mice. Thromb Haemost 2006; 95: 159-165.
• 23 Li TT, Larrucea S, Souza S. et al. Genetic v responsible for mouse strain differences in integrin α 2 expression is associated with altered platelet responses to collagen. Blood 2004; 103: 3396-3402.
• 24 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.
• 25 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: 239-246.
• 26 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: 1396-1404.
• 27 Rat Genome Sequencing Project Consortium. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 2004; 428: 493-521.
• 28 Pravenec M, Kunes J, Zicha J. et al. Platelet aggregation in spontaneous hypertension: genetic determination and correlation analysis. J Hypertens 1992; 10: 1453-1456.
• 29 Klinger MHF. Inflamation. In: Platelets. 2002. San Diego: Academic Press; 459-467.
• 30 Tanaka S, Tamaya N, Matsuzawa K. et al. Differences in survivability among F344 rats. Exp Anim 2000; 49: 141-145.
• 31 Sonaka I, Futami Y, Kobayashi T. et al. Effects of dietary protein restriction on nitrogen balance and cardiovascular functions in aged rats. J Gerontol 1993; 48: B145-150.
• 32 Sugidachi A, Asai F, Oshima T. et al. Intracellular Ca2+ mobilization and aggregatory response to ADP and thrombin in aged rat platelets. Platelets 1995; 6: 388-393.
• 33 Levy AE, Alexander JW. Administration of intragraft interleukin-4 prolongs cardiac allograft survival in rats treated with donor-specific transfusion/cyclosporine. Transplantation 1995; 60: 405-406.
• 34 Tchervenkov I J, Cofer BR, Davies C. et al. Indefinite allograft survival induced by the combination of multiple donor-specific transfusions, cyclosporine, and an anti-T cell monoclonal antibody in a protocol relevant to cadaveric organ transplantation. The importance of prolonged posttransplant cyclosporine coverage. Transplantation 1995; 59: 821-824.
• 35 Maffrand JP, Bernat A, Delebassee D. et al. ADP plays a key role in thrombogenesis in rats. Thromb Haemost 1988; 59: 225-230.
• 36 Sugidachi A, Asai F, Ogawa T. et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129: 1439-1446.
• 37 Freund M, Mantz F, Nicolini P. et al. Experimental thrombosis on a collagen coated arterioarterial shunt in rats: a pharmacological model to study antithrombotic agents inhibiting thrombin formation and platelet deposition. Thromb Haemost 1993; 69: 515-521.
• 38 Berry CN, Visconte C, Lecoffre C. et al. Activity of a sub-cutaneously administered novel mixed micellar formulation of argatroban in rat and rabbit models of venous thrombosis. Thromb Haemost 2000; 84: 286-290.
• 39 Cook NS, Zerwes H, Tapparelli C. et al. Platelet aggregation and fibrinogen binding in human, rhesus monkey, guinea-pig, hamster and rat blood: activation by ADP and a thrombin receptor peptide and inhibition by glycoprotein IIb/IIIa antagonists. Thromb Haemost 1993; 70: 531-539.
• 40 Kurata M, Ishizuka N, Matsuzawa M. et al. A comparative study of whole-blood platelet aggregation in laboratory animals: its species differences and comparison with turbidimetric method. Comp Biochem Physiol 1995; 112C@@ 359-365.
• 41 Mattig S, Knoefler R, Deussen A. Modulation of adenine nucleotide concentrations in human plasma by erythrocytes and endothelial cells. Thromb Res 2003; 110: 195-202.
• 42 Heptinstall S, Johnson A, Glenn JR. et al. Adenine nucleotide metabolism in human blood – important roles for leukocytes and erythrocytes. J Thromb Haemost 2005; 3: 2331-2339.
• 43 Emms H, Lewis GP. The effect of ovarian hormones on an in vivo model of thrombosis in the rat. Br J Pharmacol 1985; 84: 243-248.
• 44 Emms H, Lewis GP. Sex and hormonal influences on platelet sensitivity and coagulation in the rat. Br J Pharmacol 1985; 86: 557-563.
• 45 Morikawa M, Kojima T, Inoue M. et al. Sex difference in the effect of aspirin on rat platelet aggregation and arachidonic acid metabolism. Jpn J Pharmacol 1985; 37: 317-323.