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Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas
Mark Wahrenbrock, … , Nissi Varki, Ajit Varki
Mark Wahrenbrock, … , Nissi Varki, Ajit Varki
Published September 15, 2003
Citation Information: J Clin Invest. 2003;112(6):853-862. https://doi.org/10.1172/JCI18882.
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Article Hematology

Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas

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Abstract

Trousseau described spontaneous, recurrent superficial migratory thrombophlebitis associated with occult cancers, and this was later correlated with disseminated microangiopathy (platelet-rich clots in small blood vessels). Trousseau syndrome often occurs with mucinous adenocarcinomas, which secrete abnormally glycosylated mucins and mucin fragments into the bloodstream. Since carcinoma mucins can have binding sites for selectins, we hypothesized that selectin-mucin interactions might trigger this syndrome. When highly purified, tissue-factor free carcinoma mucin preparations were intravenously injected into mice, platelet-rich microthrombi were rapidly generated. This pathology was markedly diminished in P- or L-selectin–deficient mice. Heparin (an antithrombin-potentiating agent that can also block P- and L-selectin recognition of ligands) ameliorated this platelet aggregation, but had no additional effect in P- or L-selectin–deficient mice. Inhibition of endogenous thrombin by recombinant hirudin also did not block platelet aggregation. Mucins generated platelet aggregation in vitro in hirudinized whole blood, but not in platelet-rich leukocyte-free plasma nor in whole blood from L-selectin–deficient mice. Thus, Trousseau syndrome is likely triggered by interactions of circulating carcinoma mucins with leukocyte L-selectin and platelet P-selectin without requiring accompanying thrombin generation. These data may also explain why heparin ameliorates Trousseau syndrome, while vitamin K antagonists that merely depress thrombin production do not.

Authors

Mark Wahrenbrock, Lubor Borsig, Dzung Le, Nissi Varki, Ajit Varki

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Figure 1

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Purified mucin preparations are large and retain calcium-dependent bindi...
Purified mucin preparations are large and retain calcium-dependent binding sites for all three selectins. (a) A 4% SDS-PAGE gel with detection of carbohydrates by PAS reagent. (b) ELISA in which immobilized mucin preparations are probed with recombinant soluble murine selectins. Values represent mean ± SEM; n = 5 individual mucin preparations. P, P-selectin; L, L-selectin; E, E-selectin.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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