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The “Other”Circulatory System

Kahn JCI image graphic Jan 14Blood is the life force of animals. But behind the more well-known system of veins, arteries, and capillaries functions the mop-up crew, the  vascular network called the lymph system.

Mammals transport blood through a high-pressure, closed vascular network while lymph, composed primarily of interstitial fluid and immune cells, is transported in an open, low-pressure system. The lymphatic system is one-way, starting at the capillaries where the connections between endothelial cells are loose to allow easy entry into the system. Fluid, cells, and proteins accumulate in the interstitial spaces among the tiniest of blood vessels where a small pressure gradient builds up, allowing lymph to passively and slowly flow into lymphatic vessels.

The blood and lymph networks must remain separate to function properly, yet they must also connect in order for lymph and immune cells to be returned to the blood. Valves safeguard this connection.  

In humans, lympho-venous valves (LVVs) are present where these two networks connect, that is where the largest lymphatic vessel in the body -- the thoracic duct, in the abdomen -- merges with the subclavian vein. At the lympho-venous junction, lymph drains slowly into blood and the LVVs are thought to prevent the backflow of blood into lymphatic vessels, thereby protecting the lymphatic vascular network.

Ten years ago, the lab of Mark L. Kahn, M.D., professor of Medicine, Perelman School of Medicine, reported in Science that loss of a blood-cell signaling pathway resulted in failure to separate the blood and lymphatic vascular networks and death of newborn mice due to lymphatic vascular dysfunction. For the next decade his lab struggled to understand the biology to explain these findings. A first break in the story came when the Kahn lab used genetic studies in mice to discover that loss of platelet activation by lymphatic endothelial cells was the cause of the breakdown in separation between the blood and lymph systems.

Collectively, these studies established the cellular players in this pathway, but what exactly did platelets do to protect the lymphatic vascular network? Platelets are only found in blood and not lymph, and their primary function is to form clots at sites of blood-vessel injury.  What’s more, platelets have many adaptations to enable clotting under high-shear, high-flow conditions – “physical attributes that hardly seemed appropriate for a role in lymphatic vessels,” says Kahn. 

In a recently published paper in the Journal of Clinical Investigation, Kahn and first author Paul Hess, an M.D., Ph.D student, solve this mystery and describe an essential role for platelets in the formation of clots at the lympho-venous junction that regulate lymphatic flow. Such clots, or thrombi, form throughout life in normal animals when blood enters the lymphatic network, despite the presence of the valves.

This clotting mechanism is stimulated when platelet CLEC2 receptors are activated by Podoplanin, a cell surface protein expressed by the endothelial cells that line lymphatic, but not blood, vessels. Loss of this pathway, either due to platelet loss of CLEC2 function or lymphatic endothelial loss of Podoplanin function, resulted in lethal backflow of blood into the thoracic duct and lymphatic network in both newborn and mature mice.

Why are platelet clots needed if there are valves to prevent blood backflow?  To investigate this question the team examined mice with either abnormal valves or abnormal platelet function. Defective valves resulted in more extensive clot formation in the lymphatic network, while even partially defective platelets resulted in the presence of blood in the lymphatic network. These findings revealed that both of these protective mechanisms – valves and clots -- are needed to safeguard this fragile connection and maintain normal lymphatic function.

“They are both needed to keep the plumbing working,” says Kahn. “The fact that you need platelet clots to maintain normal lymph flow is a bizarre, and in many ways counter-intuitive observation, but one that we think has important clinical implications.”

One such implication lies in the treatment of patients with chronic heart disease. These patients often develop congestive heart failure, and preliminary studies by the Kahn group in collaboration with Drs. Julio Chirinos and Sarah Kohnstamm at the Philadelphia VA Medical Center and Dr. Marcus Seeger in Kiel, Germany, suggest that high venous pressures associated with this disease impair LVV function. 

The mouse studies in the JCI and earlier papers suggest that impaired valves would increase the importance of platelet-mediated lymph-vein clotting to protect the lymphatic network, but most of these patients have coronary artery disease and are treated with anti-platelet agents to prevent recurrent heart attacks. Whether anti-platelet treatment worsens lymphatic function in these patients is one of many questions the Kahn lab plans to address.

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