Abstract 20151: Hyperlipidemia Increases Microparticle Tissue Factor and the Activation of Coagulation: A Tale of Mice and Monkeys
Objective: Oxidized lipids induce tissue factor (TF) expression in monocytes. We previously demonstrated that prolonged hyperlipidemia in mice increased microparticle (MP) TF activity (7.4 fold, P < 0.001), and activation of coagulation, as measured by plasma thrombin-antithrombin (TAT) (10 fold, P < 0.001) compared to controls. Our objective was to determine if monocytes were the source of TF-positive MPs and if TF expression required toll-like receptor 4 (TLR4).
Methods and Results: Bone marrow cells from either low TF (1% of wild-type TF) or TF+/− (n=10 each) mice were transplanted into male low-density lipoprotein receptor deficient (LDLr−/−) mice (8 weeks old). After a 4 week engraftment period, chimeric mice were fed a fat-enriched diet (42% milk fat, 0.2% cholesterol) for 12 weeks. Mice were then euthanized and plasma collected. LDLr−/− (low TF donor) mice had significantly attenuated levels of plasma MP TF activity (85% decreased), TAT (70% decreased), and D-dimer (73% decreased) compared with controls (TF+/− donor, P < 0.001). To determine if hyperlipidemic induction of TF was mediated via activation of TLR4, male LDLr−/− mice, that were either TLR4+/+ (n=19) or TLR4−/− (n=12), were fed a fat-enriched diet for 12 weeks. TLR4 deficiency significantly reduced plasma MP TF activity (93% decreased), TAT (72% decreased), and D-dimer (91% decreased) compared with TLR4+/+ controls (P < 0.001). To verify this effect in a non-human primate (NHP) model, male African Green Vervet monkeys (Chlorocebus aethiops) were fed a fat and cholesterol enriched diet (37% fat, 0.3 mg/kcal cholesterol) for a period of 8 weeks (n=12). The enriched diet significantly increased plasma MP TF activity (10 fold), TAT (17 fold), and D-dimer (7 fold) compared to baseline plasma taken pre-feeding (P < 0.001).
Conclusions: These data indicate that TLR4 mediates hyperlipidemic-induction of coagulation and that hematopoietic cells are the major source of hyperlipidemia-induced TF expression in mice. Further, the NHP model displayed a similar induction of MP TF activity and activation of coagulation. Together, this data suggests TF-positive MPs may be a biomarker to detect a hypercoagulable state in hyperlipidemic patients.
- © 2010 by American Heart Association, Inc.