Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome

Abstract

Trousseau syndrome is classically defined as migratory, heparin-sensitive but warfarin-resistant microthrombi in patients with occult, mucinous adenocarcinomas. Injecting carcinoma mucins into mice generates platelet-rich microthrombi dependent on P-and L-selectin but not thrombin. Heparin prevents mucin binding to P-and L-selectin and mucininduced microthrombi. This model of Trousseau syndrome explains resistance to warfarin, which inhibits fluid-phase coagulation but not selectins. Here we found that carcinoma mucins do not generate microthrombi in mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), the leukocyte ligand for P-and L-selectin. Furthermore, mucins did not activate platelets in blood from PSGL-1-deficient mice. Mucins induced microthrombi in radiation chimeras lacking endothelial P-selectin but not in chimeras lacking platelet Pselectin. Mucins caused leukocytes to release cathepsin G, but only if platelets were present. Mucins failed to generate microthrombi in cathepsin G-deficient mice. Mucins did not activate platelets in blood from mice lacking cathepsin G or protease-activated receptor-4 (PAR4), indicating that cathepsin G activates platelets through PAR4. Using knockout mice and blocking antibodies, we found that mucin-triggered cathepsin G release requires L-selectin and PSGL-1 on neutrophils, P-selectin on platelets, and Src family kinases in both cell types. IntroductionTrousseau syndrome is classically defined as a thrombotic event preceding or appearing concomitantly with a visceral malignancy. 1,2 The hallmarks are venous and arterial microthrombi with secondary microangiopathic hemolytic anemia. Notwithstanding its classic definition, Trousseau syndrome is sometimes used to describe any thrombotic complication associated with cancer. 2 Early studies of Trousseau syndrome emphasized the activation of fluid-phase coagulation. A cysteine protease in carcinoma extracts was reported to directly activate factor X. 3 Many tumors express tissue factor, 4 and tissue factor-bearing microparticles derived from platelets 5 or tumor cells 6,7 have been observed. However, heparin prevents recurrent thrombosis much more effectively than vitamin K antagonists such as warfarin. 1,[8][9][10][11][12][13] Although heparin might block tissue factor-triggered coagulation more effectively than warfarin, its clinical superiority implies that other mechanisms also contribute to Trousseau syndrome. The association of Trousseau syndrome with mucinous adenocarcinomas suggests a pathogenic role for tumor-secreted mucins. 1 Carcinoma cells express higher levels of mucins, 14 and elevated levels of these mucins and their fragments circulate in patients. 15,16 Mucins bearing highly sialylated Oglycans selectively resist clearance and circulate for long periods. 17 During inflammation or injury, interactions of selectins with their glycosylated ligands initiate adhesion of leukocytes to activated platelets and/or endothelial cells. 18 L-selectin is expressed on leukocytes. Thrombin and other agonists cause plat...

Case series of cerebral infarction with Trousseau's syndrome associated with malignant gynecological tumors

“…Moreover, we observed an association between D-dimer level and serum CA-125 level. A significant increase in CA-125 levels has been reported in mucin-producing tumors, and TS is known to occur in association with such tumors (2,6). We observed that tumors with mucin-producing characteristics exhibited an association between the levels of D-dimer and serum CA-125 (parallel change) in TS.…”

Trousseau's syndrome caused by bladder cancer producing granulocyte colony-stimulating factor and parathyroid hormone-related protein: A case report

“…The development of a novel marker to diagnose Trousseau's syndrome is required. Several mechanisms have been proposed to explain the occurrence of hypercoagulation in patients with malignancy, including thromboplastin-like substances, fibrin deposition, direct factor X activation by tumor proteases, tissue factor, cysteine protease, tumor hypoxia, tumor-induced inflammatory cytokines and carcinoma-associated mucins (1,(8)(9)(10). Among them, mucins are thought to trigger this syndrome (9,10).…”

“…Several mechanisms have been proposed to explain the occurrence of hypercoagulation in patients with malignancy, including thromboplastin-like substances, fibrin deposition, direct factor X activation by tumor proteases, tissue factor, cysteine protease, tumor hypoxia, tumor-induced inflammatory cytokines and carcinoma-associated mucins (1,(8)(9)(10). Among them, mucins are thought to trigger this syndrome (9,10). The serum tumor markers CA19-9 (also known as MUC-1/Y), CA125 (also known as MUC-16) and CA15-3 (also known as MUC-1) are well known tumor-associated mucins; these are large, heavily glycosylated molecules that are resistant to denaturation, boiling and proteases (11).…”

Feared complication of malignancy: Venous thromboembolism

“…Bazı akut lösemilerde, over, mide ve böbrek solid tümörlerinde prokoagülan olarak doku faktörünün arttığı ve akciğer, kolon, meme, böbrek kanserlerinde ve lösemilerde prokoagülan olan sistein proteinaz tarafınca direkt faktör X aktivasyonu yapıldığı gösterilmiştir (27,28). Musin sekrete eden adenokarsinomlarda ise sialik asitin faktör X'u aktifleştirdiği ve dolayısıyla akciğer, pankreas, gastrointestinal sistem ve over adenokarsinomlarında venöz tromboz riskinin arttıtığı ortaya konmuştur (29)(30)(31)(32)(33). Diğer bir mekanizma olan damar duvarı hasarında; kanser hücreleri direkt damar invazyonu yaparak endotel bütünlüğünü bozmanın yanı sıra damar geçirgenliğini bozan faktörlerin sentezine yol açarak fibrinojen ve pıhtılaşma proteinlerinin toplanmasına neden olurlar (34).…”