title: 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.forename: Paul R
authors.initials: PR
authors.lastname: Hess
authors.forename: David R
authors.initials: DR
authors.lastname: Rawnsley
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Jakus
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Yang
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Sweet
authors.forename: Jianxin
authors.initials: J
authors.lastname: Fu
authors.forename: Brett
authors.initials: B
authors.lastname: Herzog
authors.forename: MinMin
authors.initials: M
authors.lastname: Lu
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Guillermo
authors.initials: G
authors.lastname: Oliver
authors.forename: Taija
authors.initials: T
authors.lastname: Makinen
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kahn
mesh_terms: D000631:Aminopyridines; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D005337:Fibrin / Q000378:metabolism; D006487:Hemostasis; D007422:Intestines / Q000098:blood supply; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics; D008198:Lymph Nodes / Q000002:abnormalities; D042601:Lymphatic Vessels / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology; D010974:Platelet Aggregation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines; D012039:Regional Blood Flow; D000072377:Syk Kinase; D013897:Thoracic Duct / Q000098:blood supply; D013927:Thrombosis / Q000503:physiopathology; D055422:Venous Valves / Q000502:physiology
chemical_list: D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D005337:Fibrin; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib