Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas.
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.
Wahrenbrock
Mark
M
Department of Medicine,Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687, USA.
Borsig
Lubor
L
Le
Dzung
D
Varki
Nissi
N
Varki
Ajit
A
D002288:Adenocarcinoma, Mucinous / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000933:Antifibrinolytic Agents / Q000627:therapeutic use; D001792:Blood Platelets / Q000378:metabolism; D015897:Comorbidity; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000302:isolation & purification / Q000378:metabolism*; D009368:Neoplasm Transplantation; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D010257:Paraneoplastic Syndromes / Q000378:metabolism*; D015539:Platelet Activation; D013577:Syndrome; D013917:Thrombin / Q000378:metabolism; D013924:Thrombophlebitis / Q000188:drug therapy / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014812:Vitamin K
D000933:Antifibrinolytic Agents; D005343:Fibrinolytic Agents; D009077:Mucins; D019007:P-Selectin; D014812:Vitamin K; D019041:L-Selectin; D006493:Heparin; D013917:Thrombin