In vivo, bromide (Br ؊ ), nitrite (NO 2 ؊ ), and thiocyanate (SCN ؊ ) compete for oxidation by eosinophil peroxidase (EPO) and H 2 O 2 , yielding, respectively, HOBr, NO 2 ⅐ , and HOSCN. We have recently shown that SCN ؊ is the strongly preferred substrate for EPO in vivo and that HOSCN, in contrast with other EPO-generated oxidants and HOCl, is a relatively weak, cellpermeant, sulfhydryl (SH)-reactive oxidant. We here show that HOSCN is a uniquely potent (up to 100-fold) phagocyte oxidant inducer of tissue factor (TF) activity in human umbilical vein endothelial cells (HUVECs). This induction is attributable to transcriptional up-regulation of TF gene expression dependent upon both activation of the p65/c-Rel TF-B transcription factor and activity of the ERK1/2 kinase pathway upstream of Egr-1 and was markedly further enhanced in the presence of wortmannin, an inhibitor of the PI3 kinase/Akt pathway. HOSCN also markedly activates the proinflammatory p65/p50 NF-B pathway. Based on these findings we hypothesize that HOSCN generated by adherent and infiltrating eosinophils may provoke the development of a prothrombotic and proinflammatory endothelial/endocardial phenotype that promotes the pronounced thrombotic diathesis characteristic of the hypereosinophilic syndrome. ( IntroductionEosinophils (EOs) are specialized phagocytes that function to protect the host against metazoan parasites but can also mediate pathologic tissue damage in allergic inflammatory states. Perhaps the most striking example of EO-mediated pathology is the hypereosinophilic syndrome (HES), a systemic hematologic order characterized by multiorgan system involvement, most notably a characteristic, often lethal, form of endocarditis. 1,2 Eosinophilic, or Loeffler, endocarditis is characterized by massive infiltration into the endocardium and myocardium of activated degranulating EOs and mural thrombosis leading to both pulmonary and systemic embolism. HES is also accompanied by a prominent systemic thrombotic diathesis that can manifest as hepatic vein thrombosis, cerebral sinus thrombosis, disseminated intravascular coagulation (DIC), skin microvessel thrombosis, and deep venous thrombosis. [3][4][5][6] The etiology of this thrombotic diathesis is unclear.EO-specific granule proteins are exocytosed and accumulate at sites of EO inflammation. These include the unique eosinophil peroxidase (EPO), a protein that accounts for 40% by weight of the EO-specific granule weight and shares 70% amino acid homology with the better-characterized neutrophil myeloperoxidase (MPO). 7 In addition, EOs are endowed with a highly active NADPH oxidase system capable of sustaining up to 10 times the superoxide anion and H 2 O 2 generation capacity of neutrophils. 8 While it is clear that MPO functions predominantly to utilize H 2 O 2 to oxidize chloride to hypochlorous acid (HOCl), the preferred physiologic substrate for EPO is less certain. Three unusual substrates-bromide (Br Ϫ ), nitrite (NO 2 Ϫ ), and thiocyanate (SCN Ϫ )-compete for oxidation by EPO in physi...

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