Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic heart disease.

Abstract

Thromboembolism is a prominent but poorly understood feature of eosinophilic, or Loeffler's, endocarditis. Eosinophil (EO) specific granule proteins, in particular major basic protein (MBP), accumulate on endocardial surfaces in the course of this disease. We hypothesized that these unusually cationic proteins promote thrombosis by binding to the anionic endothelial protein thrombomodulin (TM) and impairing its anticoagulant activities. We find that MBP potently (IC5, of 1-2 gM) inhibits the capacity of endothelial cell surface TM to generate the natural anticoagulant activated protein C (APC). MBP also inhibits APC generation by purified soluble rabbit TM with an IC50 of 100 nM without altering its apparent Kd for thrombin or Km for protein C. This inhibition is reversed by polyanions such as chondroitin sulfate E and heparin. A TM polypeptide fragment comprising the extracellular domain that includes its naturally occurring anionic glycosaminoglycan (GAG) moiety (TMD-105) is strongly inhibited by MBP, whereas its counterpart lacking the GAG moiety (TMD-75) is not. MBP also curtails the capacity ofTMD-105 but not TMD-75 to prolong the thrombin clotting time. Thus, EO cationic proteins potently inhibit anticoagulant activities of the glycosylated form of TM, thereby suggesting a potential mechanism for thromboembolism in hypereosinophilic heart disease. (J.

Eosinophil count is positively correlated with coronary artery calcification

“…In addition, major basic protein or eosinophil cationic protein, which is an eosinophil granule protein, activates platelets and promotes thrombus formation by inhibiting the function of thrombomodulin in hypereosinophic syndrome or allergic disease. 16,17 Rohrbach et al 18 reported that major basic protein and eosinophilic peroxidase activate platelets. Emanuele et al 19 suggested that increased eotaxin levels, an eosinophil-specific chemoattractant, are associated with the presence of coronary artery disease and that circulating levels of this chemokine may reflect the extent of coronary atherosclerosis.…”

Platelet factor 4 enhances generation of activated protein C in vitro and in vivo

“…[6][7][8] The existence of these anionic domains has prompted interest in potential interactions of cationic compounds with the TM/protein C system. Polybrene 6 and the cationic polypeptides polylysine, 9 eosinophil major basic protein, 10 and eosinophil peroxidase 10 all strongly inhibit both the proteolytic conversion of protein C to APC by the thrombin/TM complex (ie, the protein C-activating cofactor activity of TM) and the ability of TM to prolong the thrombin clotting time (ie, the "direct anticoagulant" action of TM). Thus, these cationic proteins impair the anticoagulant functions of TM and may therefore produce a thrombotic phenotype in vivo.…”

Eosinophils May Be Involved in Thrombus Growth in Acute Coronary Syndrome Histologic Examination of Aspiration Samples

“…3,4,[13][14][15][16] In addition, major basic protein or eosinophilic cationic protein, which is an eosinophil granule protein, activates platelets and promotes thrombus formation by inhibiting the function of thrombomodulin in hypereosinophilic syndrome or allergic diseases. 8,9) Rohrbach et al 7) reported that major basic protein and eosinophil peroxidase activate platelets. In the present study, eosinophils were most frequently observed near the boundary of white thrombus and red thrombus, which develops after white thrombus.…”

“…3,6) In addition, granule proteins of eosinophils may also promote thrombus formation and growth. [7][8][9] The recent development of thrombus aspiration therapy has allowed for the investigation of thrombi and atheroma fragments. However, histologic evaluation of inflammatory cells involved in ACS has not been sufficiently thorough.…”