Thrombosis in Continuous-Flow Left Ventricular Assist Devices: Pathophysiology, Prevention, and Pharmacologic Management

Jennings, Douglas L.; Weeks, Phillip

doi:10.1002/phar.1501

Cited by 37 publications

(29 citation statements)

References 52 publications

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“…Currently, ASA is the dominant and often sole agent utilized, at doses of 81 – 325 mg/day, for patients implanted with continuous flow VADs, which are comparable to those we have emulated in the present study [50]. Despite ASA management, VAD thrombosis continues to occur to varying degrees in patients and recently has been on the rise [4].…”

Section: Discussionsupporting

confidence: 67%

Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices

Dimasi

Rasponi

Consolo

et al. 2017

Medical Engineering & Physics

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Thrombus formation is a major adverse event affecting patients implanted with ventricular assist devices (VADs). Despite anti-thrombotic drug administration, thrombotic events remain frequent within the first year post-implantation. Platelet activation (PA) is an essential process underling thrombotic adverse events in VAD systems. Indeed, abnormal shear forces, correlating with specific flow trajectories of VADs, are strong agonists mediating PA. To date, the ability to determine efficacy of anti-platelet (AP) agents under shear stress conditions is limited. Here, we present a novel microfluidic platform designed to replicate shear stress patterns of a clinical VAD, and use it to compare the efficacy of two AP agents in vitro. Gel-filtered platelets were incubated with i) acetylsalicylic acid (ASA) and ii) ticagrelor, at two different concentrations (ASA: 125 and 250μM; ticagrelor: 250 and 500nM) and were circulated in the VAD-emulating microfluidic platform using a peristaltic pump. GFP were collected after 4 and 52 repetitions of exposure to the VAD shear pattern and tested for shear-mediated PA. ASA significantly inhibited PA only at 2-fold higher concentration (250 μM) than therapeutic dose (125 μM). The effect of ticagrelor was not dependent on drug concentration, and did not show significant inhibition with respect to untreated control. This study demonstrates the potential use of microfluidic platforms as means of testing platelet responsiveness and AP drug efficacy under complex and realistic VAD-like shear stress conditions.

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Section: Discussionsupporting

confidence: 67%

Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices

Dimasi

Rasponi

Consolo

et al. 2017

Medical Engineering & Physics

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“…Thrombolysis has been attempted in HVAD thrombosis with adequate success rates, but major hemorrhage occurred in ϳ1/3 of patients. 49 Similar rates of thrombus resolution have been reported using direct thrombin inhibitor treatment as with thrombolysis. Eptifibatide resolved thrombosis in only one-quarter of cases and major bleeding rates are unacceptably high with eptifibatide treatment.…”

Section: Thrombosis Of Continuous Flow Vads In Adolescents and Adultssupporting

confidence: 52%

“…Experts in hemostasis can significantly impact care of patients requiring MCS and are a necessary part of the management team. 51 9/10 (90) 1/10 (10) † Eptifibatide 49 7/27 (26) 13/27 (48) *Includes intraventricular and systemic fibrinolytics. †Minor hemorrhage only.…”

Section: Discussionmentioning

confidence: 99%

“…Eptifibatide resolved thrombosis in only one-quarter of cases and major bleeding rates are unacceptably high with eptifibatide treatment. [49][50][51] In the setting of inflow or outflow graft malposition or LDH levels Ͼ1000, surgical replacement of the LVAD is recommended because of a 50% mortality associated with medical management. 52…”

Section: Thrombosis Of Continuous Flow Vads In Adolescents and Adultsmentioning

confidence: 99%

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Mechanical circulatory support: balancing bleeding and clotting in high-risk patients

Kreuziger

Massicotte

2015

Hematology

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Mechanical circulatory support (MCS) provides a bridge to heart transplant in children and adults with life-threatening heart failure and sustains patients ineligible for transplant. Extracorporeal membrane oxygenation (ECMO) provides temporary support for patients in cardiac or pulmonary failure through external gas exchange and continuous flow of blood. Because the median time to heart transplant exceeds event-free time on ECMO, pulsatile left ventricular assist devices (LVADs) are used to support infants and children. Continuous flow LVADs are preferred in adolescents and adults due to increased pump durability and improved overall survival. The shear stress created by the mechanical pumps cause changes in the hematologic system; acquired von Willebrand syndrome occurs in almost all patients treated with MCS. Despite the improvements in survival, major bleeding occurs in one-third of patients with a LVAD and ischemic stroke and LVAD thrombosis can affect 12% of adults and 29% of children. An antithrombotic strategy to mitigate LVAD bleeding and thrombotic complications has been tested in a randomized trial in children, but intensity of antithrombotic therapy in adults varies widely. Consensus guidelines for antithrombotic therapy during ECMO were created due to significant differences in management across centers. Because of the high risk for both bleeding and thrombotic complications, experts in hemostasis can significantly impact care of patients requiring mechanical circulatory support and are a necessary part of the management team. Learning Objectives• Understand available options for mechanical circulatory support and the impact of mechanical circulatory support on the hematologic system • Differentiate the bleeding and thrombotic risks between children and adults requiring mechanical circulatory support • Recognize possible treatment options for mechanical circulatory support thrombosis Heart failure affects Ͼ5 million adults in the United States (US) and 23 million people globally. 1 The incidence of heart failure in children is significantly less than adults with ϳ18 admissions per 100 000 children per year; however, there is significant economic impact of pediatric heart failure given the frequent need for surgical intervention and the loss of productive years in the event of a child's death. 2 The heart failure etiology also differs with age as most children have congenital heart disease and adults experience cardiomyopathy or coronary artery disease. 1

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“…Lower rotation speed is sometimes indicated to reduce the grade of AI, 14,30) but it may be associated with a higher risk of pump thrombosis, lower exercise tolerability, 31) or inadequate stimulation of sympathetic activity. 32,33) Some authors reported successful trans-catheter aortic valve replacement during LVAD support, but the procedure has a risk of migration of the replaced device owing to the strong vacuum of blood into apical VAD inflow.…”

mentioning

confidence: 99%

Preoperative Prediction of Aortic Insufficiency During Ventricular Assist Device Treatment

Imamura

Kinugawa

2016

Int. Heart J.

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SummarySurvival rate in patients with stage D heart failure has improved significantly owing to the development of continuous flow left ventricular assist devices (LVAD), but aortic insufficiency (AI) still remains one of the major unsolved complications that impairs patient quality of life. There are no established treatments for AI, and preoperative prediction and prevention of AI is needed. The opening of a native aortic valve (AV) is a sufficient condition for prevention of AI, and improvement of LV ejection fraction due to LV reverse remodeling (LVRR) is essential to open a native AV. Preoperative insufficient β-blocker treatment and pulsatile flow LVAD usage are keys for LVRR, opening of an AV, and prevention of AI. The second mechanism that leads to AI is remodeling of the aortic root and degeneration of a native AV, which results from reduced pulse pressure during LVAD support. Centrifugal or pulsatile flow LVAD usage has an advantage in terms of preserving pulsatility, and may prevent AI compared with an axial pump. There is less probability of avoiding AI with sufficient β-blocker treatment, and these patients may be good candidates for concomitant surgical intervention to a native AV at the time of LVAD implantation. (Int Heart J 2016; 57: 3-10)Key words: Pulsatility, VAD, Carvedilol, Aortic valve C urrently, the survival rate in patients with advanced heart failure (HF) has improved due to the development of continuous flow (CF) left ventricular assist device (LVAD) treatment and improvement of perioperative management procedures.1-9) However, quality of life during CF LVAD is still not satisfactory because of several unresolved postoperative complications. 4,10,11) One of the major complications is aortic insufficiency (AI), which is characterized as continuous aortic regurgitation during both systolic and diastolic phases through a degenerated and occasionally fusional native aortic valve (AV) ( Figure 1AB). 12,13) Native AV, which is apparently normal before LVAD implantation, can be associated with a considerable level of AI after LVAD implantation. Post-LVAD AI can develop even in the preoperative setting in which there is no aortic regurgitation at all. 12,14,15) In 2000, Rose, et al first documented acquired AV disease during pulsatile flow (PF) LVAD. They identified evidence of commissural fusion of native AV.16) In 2006, Frazier, et al summarized the relationship between commissural fusion of native AV and development of AI during CF LVAD treatment.17) We also showed that AI was more frequently observed in patients with CF LVAD as compared with PF pump in 2011 ( Figure 1C). 18) Since then, a number of single-center studies have documented a wide-ranging prevalence of AI during LVAD treatment. 15,[19][20][21] The development of AI during LVAD treatment is considered to be a multifactorial phenomenon and a result of altered AV and aortic root biomechanics due to chronic and continuous ventricular unloading. Unloading of LV results in ventricular decompression, and the combination of systolic ...

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Thrombosis in Continuous-Flow Left Ventricular Assist Devices: Pathophysiology, Prevention, and Pharmacologic Management

Cited by 37 publications

References 52 publications

Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices

Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices

Mechanical circulatory support: balancing bleeding and clotting in high-risk patients

Preoperative Prediction of Aortic Insufficiency During Ventricular Assist Device Treatment

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