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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 2

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Time-course of platelet-rich microthrombi in wild-type mouse lungs follo...
Time-course of platelet-rich microthrombi in wild-type mouse lungs following a single injection of mucin. (a) Typical representations of in vivo platelet-rich microthrombi in lung sections observed using fluorescently labeled Ab against the platelet marker, CD41. (b) Quantitative histologic determination, quantitating average number of CD41-positive pixels per 200× view field (mean value of 20 random fields). Each bar represents the mean ± SEM. *P < 0.001 compared with PBS-injected mice, n = 7; **P < 0.05, n = 5.

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