Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life
Paul R. Hess, … , Lijun Xia, Mark L. Kahn
Paul R. Hess, … , Lijun Xia, Mark L. Kahn
Published December 2, 2013
Citation Information: J Clin Invest. 2014;124(1):273-284. https://doi.org/10.1172/JCI70422.
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Research Article Hematology

Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life

Abstract

Mammals transport blood through a high-pressure, closed vascular network and lymph through a low-pressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life.

Authors

Paul R. Hess, David R. Rawnsley, Zoltán Jakus, Yiqing Yang, Daniel T. Sweet, Jianxin Fu, Brett Herzog, MinMin Lu, Bernhard Nieswandt, Guillermo Oliver, Taija Makinen, Lijun Xia, Mark L. Kahn

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Figure 2

Blood enters lymphatic vessels of the intestine via backflow from mesenteric-collecting lymphatics in Clec2–/– animals.

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Blood enters lymphatic vessels of the intestine via backflow from mesent...
(A) Normal anatomy of the mesentery and intestine at P6. Lymphatic vessels of the intestine and mesentery are white due to the presence of chyle. Shown are a mesenteric LN and a schematic of the lymphatic network at this site. (B–D) 3 patterns of blood-filled lymphatics were observed between P5 and P7 after anti-CLEC2 antibody injection at P1: (B) blood only in mesenteric LNs; (C) blood in mesenteric LNs and mesenteric lymphatic vessels, but not intestinal lymphatics; and (D) blood in mesenteric LNs, mesenteric lymphatics, and intestinal lymphatics. Dotted outline in B denotes LN; arrows in D indicate lymphatic vessels. (E) Lta–/– neonates lacked mesenteric LNs. Images were obtained at P1. (F) Clec2–/– animals developed blood-filled lymphatics in the intestine on Lta–/– and Rorc–/– backgrounds. Images were obtained at P1. (G) Lta–/– and Rorc–/– neonates developed blood-filled lymphatics after injection of anti-CLEC2 antibody. Antibody was injected at P1 and P5, and images were obtained at P9. (H) Lta–/– and Rorc–/– mature animals developed blood-filled lymphatics after reconstitution with Clec2–/– hematopoietic cells. Images were obtained 8 weeks after transplantation. (I) Lta or Rorc deficiency does not prevent blood from entering the intestines of Clec2–/– animals.