Deficiency of LRP8 in mice is associated with altered platelet function and prolonged time for in vivo thrombosis

Introduction: Our group has previously reported genetic studies associating polymorphisms in the low density lipoprotein receptor related protein 8 (LRP8) gene with myocardial infarction. The aim of this study was to define the role of platelet surface LRP8 in thrombosis. Materials and Methods: Flow cytometry, aggregometry, intravital microscopy and tail bleeding assays were used to examine platelet function and hemostasis in LRP8-deficient mice and littermate controls. Results: We demonstrated that activation of platelets from both LRP8(+/-) and LRP8(-/-) mice was reduced in vitro in response to either ADP or thrombin. In vivo, LRP8-hemizygous and LRP8(-/-) mice demonstrated 200% and 68% increased time for carotid occlusion in response to FeCl3 injury, respectively. Moreover, lipidated apoE3, a tigand for LRP8, inhibited platelet activation in a dose-dependent fashion. This inhibition was markedly attenuated in LRP8(-/-) but not LRP8(+/-) mice and did not result from membrane cholesterol efflux or a nitric oxide dependent pathway. Tail bleeding times were unaffected in both genotypes. Conclusions: Our results suggest that LRP8 is capable of altering thrombosis without affecting normal hemostasis through mechanisms both dependent on and independent of apoE. This suggests a means whereby clot formation could be affected in humans with LRP8 gene variants. (c) 2008 Elsevier Ltd. All rights reserved.