VS08. Thoracic Outlet Decompression Surgery: Transaxillary First Rib Resection

Abstract

Objective: Discovery of an antithrombotic therapy that does not cause bleeding would be a transformative advance in the management of arterial thrombosis, including in peripheral artery disease and at sites of artificial surfaces such as stents, balloons, and grafts. One promising approach is inhibition of factor XII (FXII/FXIIa), which has been demonstrated to be thromboprotective in preclinical models. Importantly, severe congenital FXII deficiency is not associated with bleeding, and FXII inhibition does not augment bleeding in animal models. Despite its potential as a therapeutic target, the physiologic mechanisms of FXII recruitment to sites of injury and its activation by platelets remain poorly understood.Methods: To explore the binding and activation of FXII by platelets, we stimulated human platelet-rich plasma and measured thrombin generation in the presence of inhibitory antibodies against FXIIa, tissue factor, and activated factor VII. Flow cytometry was used to quantify binding of fluorescently tagged FXII to the platelet surface. We also used antibody X210-C01, a specific inhibitor of mouse and human FXIIa, in a mouse cremaster laser injury model to test the effect of FXIIa inhibition in vivo.Results: We found that stimulated platelets were able to support thrombin generation through a FXII-dependent pathway (Fig 1). By contrast, blocking key components of the extrinsic pathway, such as tissue factor or activated factor VII, did not mitigate thrombin generation by activated platelets. We found that the ability of platelets to activate FXII was contained in the membrane fraction and not in the platelet releasate. Platelets bound fluorescein isothiocyanate-tagged FXII in a specific and zinc-dependent manner; other divalent cations, including Ca 2+ , Mg 2+ , and Mn 2+ , were unable to support interaction between the platelet surface and FXII-fluorescein isothiocyanate. We found that approximately 135,000 FXII binding sites were present per stimulated platelet. Using the mouse laser injury model, we also found that treatment with X210-C01 potently abolished both platelet accumulation and fibrin formation at sites of vascular injury (Fig 2). Mice treated with high doses of X210-C01 did not demonstrate increased bleeding in the tail bleeding assay relative to mice treated with nonimmune immunoglobulin G control.Conclusions: Our data demonstrate that platelets bind and activate FXII in a zinc-dependent manner and that FXIIa inhibition in vivo can block thrombus formation without causing bleeding. Greater insight into this mechanism of FXII in coagulation could aid in the much needed development of antithrombotic medications that carry minimal risk of hemorrhage.Background: We present a "How I Do It" video on thoracic outlet decompression surgery demonstrating the transaxillary first rib resection with detailed footage of the relevant preparation, patient positioning, anatomy, and dissection tools and maneuvers.