Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life
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
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
View: Text | PDF
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

×

Figure 3

Blood is first observed in the TD after loss of Clec2 in both neonates and mature animals.

Options: View larger image (or click on image) Download as PowerPoint
Blood is first observed in the TD after loss of Clec2 in both neonates a...
(A) Terminal lymphatic network between the intestine and LV junction. Dotted lines denote level of the diaphragm. (B) The TD at P6 was detected adjacent to the vertebral column in the chest by the presence of FITC-dextran after injection into the hindlimb. Boxed regions are shown enlarged at right. (C) Blood was detected in the TD prior to the lymphatics of the mesentery and intestine after loss of CLEC2. Shown are TD (top left) and abdomen (top right) of a P6 wild-type animal injected with anti-CLEC2 antibodies on P1 after FITC-dextran injection. Arrows indicate blood in the TD. Note the absence of blood in lymphatics of the intestine (top) and its presence in the terminal region of the TD near the LV junction (bottom). (D) 12-week-old wild-type mice were lethally irradiated and reconstituted with Clec2–/– hematopoietic cells, and the TD was imaged 3 weeks later. Arrows indicate blood in the TD. Note the absence of blood in lymphatics of the intestine (top right). Blood was first observed in the terminal region of the TD near the LV junction after reconstitution (bottom). (E) Path of blood from the TD to the lymphatics of the mesentery and intestine after induced CLEC2 deficiency. (F) TD after 8 days of fostamatinib treatment of wild-type mice. Blood was not detected in the TD (n = 6).