Mechanical generation of peri-valvular oscillatory flow to prevent deep venous thrombosis.

Project SummaryDeep venous thrombosisDVTand secondary pulmonary embolismPEaffectof the population and cause approximatelydeaths annually in the USImmobility and lack of muscular activity is the primary risk factor for DVTan effect attributed to reduced venous flowAutopsy studies have identified the venous valve sinus in the leg as the site of origin for DVTbut a molecular and cellular mechanism for this observation has not been identifiedPresent therapies for DVT include systemic anticoagulation pneumatic compression devices designed to augment venous flowOur recent studies reveal that oscillatory shear forces generated in the venous valve sinus by muscular activity are required to stimulated a powerful anti thrombotic endothelial phenotype that prevents venous thrombosisConsistent with this mechanismanalysis of venous valves harvested at autopsy from individuals who died of DVT and fatal PE reveals reversal of the anti thrombotic phenotype in the peri valvular endotheliumThese studies provide a hemodynamiccellular and molecular mechanism for DVT that explains its association with immobility and site of origin at the venous valve sinusand suggests that a mechanical device that restored peri valvular oscillatory flow in high risk patients would effectively prevent DVT by maintaining the natural anti thrombotic phenotype at that siteAnalysis of existing pneumatic devices reveals that they do not drive oscillatory flow at the venous valve sinus of the legBased on physiologic studies performed with human volunteerswe have designed and created a prototype devicetermedOsciflexdesigned to restore oscillatory flow at the venous valves by mimicking the response to active toe curlingThe Osciflex device simultaneously flexes and compresses the footan action that generates a high degree of oscillatory flow when performed manuallyThe goal of this proposal is to perform initial testing and design optimization of the Osciflex prototype in preparation for the creation of final devices to be used for a larger scale clinical trialIn Aimwe will test that ability of newly developed prototype Osciflex devices to drive oscillatory flow in the venous valve sinus in the legs of normal volunteersIn Aimwe will use these data to refine and improve the function of Osciflex to more effectively protect immobile individuals who are at high risk for DVTIf successfulthe Osciflex device represents a novel means of effectively preventing DVT and PE in high risk patients without an increased risk of bleeding Project Narrative Deep venous thrombosisDVTaffects millions of Americans and causes approximatelydeaths each year due to associated pulmonary embolismPresent therapies for DVT include systemic anticoagulation that carries risk of bleeding and pneumatic compression devices that are not based on defined DVT pathophysiologyThe present proposal is to support the development of a novel mechanical device to prevent DVT that is based on our recent finding that oscillatory blood flow in the valve sinus is required to drive an anti thrombotic endothelial cell phenotype that prevents DVT in healthy individuals