(More than) doubling down: Effective fibrinolysis at a reduced rt-PA dose for catheter-directed thrombolysis combined with histotripsy

Deep vein thrombosis is a major source of morbidity and mortality worldwide. For acute proximal deep vein thrombosis, catheter-directed thrombolytic therapy is an accepted method for vessel recanalization. Thrombolytic therapy is not without risk, including the potential for hemorrhagic bleeding that increases with lytic dose. Histotripsy is a focused ultrasound therapy that generates bubble clouds spontaneously in tissue at depth. The mechanical activity of histotripsy increases the efficacy of thrombolytic therapy at doses consistent with current pharmacomechanical treatments for venous thrombosis. The objective of this study was to determine the influence of lytic dose on histotripsy-enhanced fibrinolysis. Human whole blood clots formed in vitro were exposed to histotripsy and a thrombolytic agent (recombinant tissue plasminogen activator, rt-PA) in a venous flow model perfused with plasma. Lytic was administered into the clot via an infusion catheter at concentrations ranging from 0 (control) to 4.54 μg/mL (a common clinical dose for catheter-directed thrombolysis). Following treatment, perfusate samples were assayed for markers of fibrinolysis, hemolysis, and intact red blood cells and platelets. Fibrinolysis was equivalent between the common clinical dose of rt-PA (4.54 μg/mL) and rt-PA at a reduction to one-twentieth of the common clinical dose (0.23 μg/mL) when combined with histotripsy. Minimal changes were observed in hemolysis for treatment arms with or without histotripsy, potentially due to clot damage from insertion of the infusion catheter. Likewise, histotripsy did not increase the concentration of red blood cells or platelets in the perfusate following treatment compared to rt-PA alone. At the highest lytic dose, a refined histotripsy exposure scheme was implemented to cover larger areas of the clot. The updated exposure scheme improved clot mass loss and fibrinolysis relative to administration of lytic alone. Overall, the data collected in this study indicate the rt-PA dose can be reduced by more than a factor of ten and still promote fibrinolysis when combined with histotripsy.

452 Saline-induced coronary hyperaemia is mediated by intravascular haemolysis

Aims Absolute coronary blood flow can be measured by intracoronary continuous thermodilution of saline through the lateral side holes of a dedicated infusion catheter placed in the proximal segment of the coronary artery. A room-temperature saline infusion rate at 15–20 ml/min induces an immediate, steady-state, maximal microvascular vasodilation. The mechanism of this hyperemic response remains unclear. The aim of the present study is to test whether local haemolysis is a potential mechanism of coronary hyperaemia. Methods and results Twelve patients undergoing left and right catheterization were included. The left coronary artery and the coronary sinus were selectively cannulated. Absolute resting and hyperemic coronary flow were measured using the continuous intracoronary thermodilution of saline through a dedicated infusion catheter (RayFlow®). Arterial and venous samples were collected from the coronary artery and the coronary sinus in five phases: baseline (BL); resting flow measurement (Rest, saline infusion at 10 ml/min); hyperaemia (Hyperaemia, saline infusion at 20 ml/min); post-hyperaemia [Post-Hyperaemia, 2 min after the cessation of saline infusion; and control phase (Control, during infusion of saline through the guide catheter at 30 mL/min). Haemolysis was visually detected only in the centrifugated venous blood samples collected during the Hyperaemia phase. As compared to Rest, during Hyperaemia both LDH [131.50 ± 21.89 U/dL (Rest) and 258.33 ± 57.40 U/dl (Hyperaemia), P < 0.001] and plasma-free haemoglobin [PFHb, 4.92 ± 3.82 mg/dl (Rest) and 108.42 ± 46.58 mg/dl (Hyperaemia), P < 0.001] significantly increased in the coronary sinus. The percentage of haemolysis was significantly higher during the hyperaemia phase [0.04 ± 0.02% (Rest) vs. 0.89 ± 0.34% (Hyperaemia), P < 0.001]. Conclusions Saline-induced hyperaemia through a dedicated intracoronary infusion catheter is associated with haemolysis. Vasodilatory compounds released locally, like ATP, are likely ultimately responsible for localized microvascular vasodilation. The role of other substances released by erythrocytes in inducing hyperaemia cannot be excluded and requires further investigations.