A Hypercoagulable State in Myeloperoxidase Deficient Mice

Abstract number: P1208

Spronk¹ HMH, Huugen² D, Frederix¹ K, Loubele¹ S, van Oerle¹ R, ten Cate¹ H, Heeringa² P

¹¹Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, University Maastricht, The Netherlands ²²Department of Clinical and Experimental Immunology, Cardiovascular Research Institute Maastricht, University Maastricht, The Netherlands

Background:  Myeloperoxidase (MPO) is a heme protein mainly stored in polymorphonuclear neutrophils (PMNs). It produces the chlorinating oxidant hypochlorous acid from hydrogen peroxide and chloride, proposed to play a critical role in host defense and tissue damage during inflammation. Also, MPO-derived oxidants induce endothelial tissue factor expression in vitro and inhibit cardiac PAI-1 activity in a mouse model of acute myocardial infarction, thus exerting an effect on coagulation. We determined the role of MPO-deficiency on coagulation using MPO-knockout (KO) mice.

Results:  To study a possible contribution of the coagulation system to the effect of MPO, we determined Tissue Factor (TF) activity and TAT levels in WT and MPO-KO mice. TAT levels in untreated WT and MPO-KO mice were 9.2 ± 2.7 and 38.6 ± 6.4 ng/ml, respectively (P= 0.0005). Tissue factor activity levels in heart, spleen and lung from MPO-KO mice were significantly decreased compared to WT animals, whereas no differences were observed for kidney and liver. LPS-induced (2 mg/kg) endotoxemia resulted in increased tissue factor activity in kidneys of both WT and MPO-KO mice (P < 0.05) and a decreased activity in lungs of WT animals. Also, endotoxemia induced a decrease in heart and spleen TF activity in MPO-KO mice (P < 0.05). The effects of endotoxemia on TF activity were more pronounced in relation to MPO deficiency as indicated by a significant higher TF activity in kidneys from MPO-KO mice compared to controls.

Conclusion:  MPO deficiency induced a decrease in tissue factor activity in organs known to be rich in infiltrating PMNs, e.g. spleen and lung. The increased TAT-levels suggest a systemic hypercoagulabilty induced by MPO deficiency, a state which can not be explained by decreased organ specific tissue factor activity. In ongoing experiments, we are currently aiming to further elucidate possible mechanisms.