Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific ^99mTc Probe

Abstract

Treatment of advanced heart failure with implantable LVADs is increasing, driven by profound unmet patient need despite potential serious complications: bleeding, infection, and thrombus. The experimental objective was to develop a sensitive imaging approach to assess early thrombus accumulation in LVADs under operational high flow and high shear rates.Methods: A monomeric bifunctional ligand with a fibrin-specific peptide, a short spacer, and 99mTc chelating amino acid sequence (F1A) was developed and compared to its tetrameric PEG analogue (F4A).Results: 99mTc attenuation by LVAD titanium (1 mm) was 23%. 99mTc-F1A affinity to fibrin was Kd ~10 µM, whereas, the bound 99mTc-F4A probe was not displaced by F1A (120,000:1). Human plasma interfered with 99mTc-F1A binding to fibrin clot (p<0.05) in vitro, whereas, 99mTc-F4A targeting was unaffected. The pharmacokinetic half-life of 99mTc-F4A was 28% faster (124±41 min) than 99mTc-F1A (176±26 min) with both being bioeliminated through the urinary system with negligible liver or spleen biodistribution. In mice with carotid thrombus, 99mTc-F4A binding to the injured carotid was much greater (16.3±3.3 %ID/g, p=0.01) than that measured with an irrelevant negative control, 99mTc-I4A (3.4±1.6 %ID/g). In an LVAD mock flow-loop (1:1, PBS:human plasma:heparin) operating at maximal flow rate, 99mTc-F4A bound well to phantom clots in 2 min (p<0.05), whereas 99mTc-F1A had negligible targeting. Excised LVADs from patients undergoing pump exchange or heart transplant were rewired, studied in the mock flow loop, and found to have spatially variable fibrin accumulations in the inlet and outlet cannulas and bearings.Conclusions: 99mTc-F4A is a high-avidity prototype probe for characterizing thrombus in LVADs that is anticipated to help optimize anticoagulation, reduce thromboembolic events, and minimize pump exchange.

Platelet adhesion emulation: A novel method for estimating the device thrombosis potential of a ventricular assist device

“…The diameter of the magnesium arsenate fluorescent particles was 3-5 µm to match the platelet diameter. The density of the fluorescent particles was 1.34 g/cm 3 . The test axial blood pump was performed at a 3-L/min flow rate and a rotational speed of 9000 ± 50 r/min.…”

“…In recent years, continuous-flow left ventricular assist devices (LVADs) have been successfully used to rescue severe heart failure patients in many countries. [1][2][3][4][5][6] The most widely implanted LVADs are the HeartMate II, HeartWare HVAD, and HeartMate III. However, adverse events, such as gastrointestinal bleeding, stroke, right heart failure, and thrombosis, have occurred after these VADs were implanted into heart failure patients.…”

On the Optimization of a Centrifugal Maglev Blood Pump Through Design Variations

“…In recent years, ventricular assist devices (VAD, also called blood pumps) have gradually replaced heart transplantation as an effective treatment for heart failure (Bellumkonda and Bonde, 2012;Molina and Boyce, 2013;Magruder et al, 2016;Cui et al, 2018;Gaffey et al, 2018;Kawabori et al, 2018;Shahreyar et al, 2018). However, after the implantation of these VADs, adverse effects related to blood mechanical damage, such as bleeding and stroke and thromboembolic events, were often reported (Birschmann et al, 2014;Maltais et al, 2016;Netuka et al, 2016;Mehra et al, 2017;Shah et al, 2017).…”

A two-phase flow approach for modeling blood stasis and estimating the thrombosis potential of a ventricular assist device

“…In recent years, ventricular assist devices (VAD) have gradually replaced heart transplantation as an effective treatment for heart failure. [1][2][3][4][5][6][7] However, after the implantation of these VADs, adverse effects related to thrombosis, such as bleeding and stroke and thromboembolic events, were often reported. [8][9][10][11][12] INTERMACS database of 2019 provided the statistics of 25,145 patients who received the VAD therapy, and found that bleeding and stroke occurred in 40% of patients on centrifugal flow support and 38% of patients on axial flow support.…”