Introduction
Understanding the hemocompatibility of mechanical circulatory support (MCS) devices requires insight into two scientific disciplines: biology and physics/engineering.
Biology related to MCS is only partially understood and at times seems unpredictable. Mother Nature is responsible for unleashing a variety of random and often chaotic situations in life, many of which are not well understood. Tissue and cells are living organisms that follow rules that are often beyond conventional wisdom.
Physics and engineering, however, are predictable. Laws of motion, for example, are repeatable and allow a degree of confidence in the output for a given input. This relationship is a powerful tool for engineers to design and accomplish monumental feats, often at the behest of Mother Nature. However, when combining these two disciplines to develop MCS devices, Mother Nature has the upper hand. The diversity of a patient population creates a conundrum when attempting to develop a single MCS device to serve them. The goal posts change from patient to patient and even change with time in the same patient.
Despite these challenges, significant advancements have been made with MCS development, on the back of an increased understanding of the biological factors that influence device hemocompatibility, as well as improvements in engineering designs and techniques available to combat the deleterious effects of poor blood handling.
This chapter discusses the biological factors that influence MCS hemocompatibility and physics/engineering techniques available to design and operate devices for short and long periods of time in this complex environment created by Mother Nature.
Biological Factors
The biological factors involved in MCS hemocompatibility are generally those provoked due to the nonphysiologic interaction between the device and the blood. The blood-to-device interaction opposes the most basic premises of the mammalian inflammation and coagulation cascade, a complex innate response designed to maintain stasis. Both intrinsic and extrinsic coagulation pathways are triggered as a response to mechanical loading on the blood and dynamic vascular endothelium. Interestingly, there are many different devices, grafts, and stents that are chronically instrumented yet do not have the same dramatic complications seen with long-term MCS.
In the native cardiovascular system, blood is exposed to shear stresses within a narrowly defined range as it circulates the body. However, when an MCS device assumes the blood pumping function of the heart, shear stresses in certain locations within the device may fall outside this range. This may be due to impeller blades producing nonphysiologic velocity profiles, small clearances between moving and stationary parts, or possibly inadequate surface washing of all regions inside the device. The MCS/cardiovascular system interface can also produce alterations in natural flow patterns within the ventricle and arteries. Some of these deviations from physiological conditions may be tolerated if the exposure time is below a threshold. Additionally, if the temperature of this material is elevated due to rubbing contact or heat dissipation of the device power components, further cellular damage may also occur. If blood is exposed to elevated shear stresses or heat for a certain period, cell lysis, platelet activation, and protein destruction may occur. In contrast, if shear stresses are too low and exposure time is too long, or inadequate washing of recirculation zones or vortices is achieved, localized coagulation of blood may result.
These effects may produce or lead to adverse events in patients receiving MCS therapy such as hemolysis, thrombosis (leading to stroke), and excessive bleeding. Along with infection, the conditions are considered important barriers to the widespread use of MCS therapy, since they increase the requirement for rehospitalization and increase therapy cost.
Hemolysis
Hemolysis relates to the destruction of red blood cells and release of hemoglobin into the plasma. This causes a drop in hematocrit levels leading to complications like those experienced with anemia, such as a reduction in the efficient transport of oxygen to cells, and may lead to a hypercoagulable state or a decrease in kidney function. The reticuloendothelial system, however, works to clear damaged erythrocytes, mostly in the spleen. While blood transfusions can assist in replenishing blood cell levels, ultimately, the device is not considered acceptable for long-term use if levels of red cell destruction approach or exceed levels that the body can replenish.
The measure of hemolysis is in milligrams per deciliter of hemoglobin concentrated in plasma. Normal levels are below 2 mg/dL. Serum concentrations of hemoglobin levels exceeding 20 mg/dL are considered significantly elevated. Higher levels of 21 ± 15 mg/dL are tolerated by some patients, while levels greater than 40 mg/dL constitute a hemolytic event. Additionally, damaged red cells release lactate dehydrogenase (LDH), for which elevated levels are considered a marker for hemolysis.
However, while these levels of cell destruction may not lead to immediate clinical issues, any level of elevated hemolysis may unmask other conditions, such as increases in platelet activation and consequences from microparticle (MP) generation.
Thrombosis
A major complicating factor for MCS device use is the development of thrombosis. Clots form in areas of stagnation and on foreign bodies or rough surfaces. Thrombosis is tolerable if small and contained but can manifest in adverse events if clots grow large enough to impede blood flow or the moving structures in the device. This situation can lead to a catastrophic adverse event, requiring attempts to pharmacologically lyse the clot or ultimately pump exchange. Additionally, strokes or infarcts in end organs may result if they break free and form emboli, which lodge in the brain or end organs, impeding blood supply.
Through the extrinsic pathway, tissue factors form active complexes with Factor VIIa, triggering Factor IX and X to convert prothrombin to thrombin. Thrombin not only exacerbates platelet activation but also speeds up the conversion of fibrinogen to strands of fibrin. Additionally, the intrinsic pathway promotes further fibrin formation via contact proteins, particularly high-molecular-weight kininogen. Fibrin strands capture erythrocytes into the platelet mass, inducing thrombus formation.
The mechanism for thrombus formation is explained by Virchow’s Triad. Essentially, the competing influences of high and low shear create a delicate environment for which shear levels must be maintained within a narrow range to avoid the creation of clots. Too high shear and white clots may form. These are predominantly composed of platelets and their formation is influenced by antiplatelet therapy. Too low shear and red clots may form due to recirculation and stasis. These are predominantly fibrin and their formation can be influenced by anticoagulant therapy.
The ability to control the clotting of blood is a feature of human circulation. The endothelial cells of arteries and veins secrete a variety of chemical substances, including thrombomodulin and heparin-like proteoglycans, that inhibit blood clotting on their walls. Artificial materials used in MCS devices do not have this ability; therefore, the blood may clot when presented with a foreign surface. The HeartMate ventricular assist device (VAD) series employs a textured surface to promote the growth of a protein layer on the blood-contacting surfaces. This technique aims to reduce levels of thrombosis formation and cell damage by attempting to recreate the arterial lining.
High Shear
Shear stress encountered by blood in transit through the pump system can affect both cells and large proteins in the plasma. Thrombosis at high shear rates depends primarily on activated platelets and the adhesion protein von Willebrand factor (vWF) and fibrinogen, with hemodynamics playing an important role in each stage of thrombus formation, including vWF binding, platelet adhesion, platelet activation, and rapid thrombus growth.
Platelets have been long regarded as the prominent cells involved in physiologic hemostasis and pathologic thrombosis. The shear-induced platelet activation generally elevated with increasing shear stress magnitude and exposure time. The areas of recirculation in a pump may trap platelets, increasing their exposure time to the artificial surface while also increasing the local concentrations of the procoagulant proteins adenosine diphosphate and thromboxane A2, continuing the self-perpetuating platelet aggregation. Also, high-shear regions in a pump may become problematic as passing platelets are transiently activated by the shear and deposit on pump seams and bearings that under low-shear flow may have been free from thrombus.
When blood experiences high shear stresses in VADs, the plasma protein vWF extends from a globular form to an elongated form and can theoretically form intertwining nets to form many bonds to platelets, capturing thousands of circulating platelets. The formation of vWF nets under high-shear conditions increases the contact area between platelets and vWF, like a catcher’s mitt. The capture of circulating platelets at high shear is primarily due to the exposure of A1 binding sites on vWF nets to rapidly capture the circulating platelet glycoprotein 1b (Gp 1b). The positive feedback cycle of platelet activation, release of more vWF into vWF nets, and capture of new circulating platelets result in the explosive growth of high-shear, platelet-rich thrombus.
Other than platelets and vWF, MCS devices expose blood cells to high shear stress, potentially resulting in the production of cell-derived MPs, which promote coagulation and inflammation. MPs are small cell vesicles that can be released by a variety of cell types during cell activation and apoptosis, and they possess inflammatory and procoagulatory characteristics. Circulating levels of MPs from platelets, leukocytes, and endothelial cells are significantly higher in patients with left VADs (LVADs) than in healthy controls. Tissue factor that rises during MCS may originate from platelet MPs, which contribute to the occurrence of thromboembolic complications, as described earlier.
Coagulation/Low Shear
Exposure of blood to implanted or temporary devices is known to be associated with coagulopathies, which historically have been managed with the administration of anticoagulants. The biological response with implanted devices is biphasic in nature. An acute fibrinolytic response preoperatively produces a high risk of bleeding. Secondary response ensures a procoagulant environment, exposing the recipient to risk of thrombus formation. This can cause catastrophic complications, including device thrombosis and stroke. MCS devices activate the coagulation system through blood contact with foreign surfaces and altered rheological conditions (blood flow or stasis in native heart).
Anticoagulants provide the pivotal therapy to avoid thrombosis formation. Anticoagulation regimes differ between institutions but typically include the use of antiplatelet therapy, vitamin K antagonists with an international normalized ratio (INR) can remain deranged for target anywhere from 1.5 to 3, with or without heparin bridging postoperatively. The coagulation system can remain deranged for up to 90 days and endothelial responses up to 180 days postimplantation. Health status, including active infection, can complicate drug effectiveness. Patient compliance can influence the levels of protection. Furthermore, patient diet (such as the ingestion of leafy greens high in vitamin K) can also lower the effectiveness of anticoagulation therapies.
Gastrointestinal (GI) bleeding is a well-documented complication of MCS that can be exacerbated with anticoagulation therapy and whose etiology is complex. Another bleeding risk associated with mechanical devices is shear stress-induced acquired vWF disease. Destruction or alteration in the composition of the vWF molecule may inhibit its ability to take part in the coagulation process, leading to prolonged bleeding episodes. Emerging evidence shows that GI bleeding may in part be caused by angiogenesis induced through the neural hormone angiotensin II pathway and associated growth factors. The causative arteriovenous malformations may be reduced with antagonism of the angiotensin II pathway with angiotensin receptor blocker or angiotensin converting enzyme inhibitor therapy, which are commonly used antihypertensives.
Considerable interpatient variability in anticoagulation substrate complicates management. For example, blood type variability leads to variations in vWF factor levels, with lower levels in patients with O blood type.
The thrombogenic environment initiated by MCS also increases the risk of venous thrombosis in an already at-risk patient cohort. Comorbid conditions that promote venous stasis and thrombosis include heart failure and/or myocardial infarction, peripheral venous congestion and stasis, and decreased mobility due to poor exercise tolerance or prolonged hospital stay, increasing age, and infection. Optimal device performance can effectively reduce venous congestion in the absence of advanced right heart failure.
Hemocompatibility-Related Engineering Aspects
MCS for left side support drains blood upstream of the aortic valve and discharges the blood downstream of the aortic valve. Right side circulatory support drains blood upstream of the pulmonary valve and discharges the blood downstream of the pulmonary valve. Draining blood from a reservoir requires careful inflow cannula placement to ensure sufficient patient support, minimize thrombosis potential in the reservoir due to the new flow patterns, and minimize cellular damage in the instance of reduced flow area due to the close proximity of the inflow cannula and any surrounding biologic structure. This can be further complicated as cardiac remodeling and/or unloading the reservoir can change the inflow cannula position relative to the surrounding structures. Thrombosis in the inflow cannula can cause reduced effective flow area into the device, leading to reduced flow capacity and possible embolization. The net effect can create nonphysiologic flow patterns and fluid stresses and associated thrombosis and cellular damage potentials.
Pump Configurations
Rotary pump technology has been incorporated commercially into implanted MCS devices since the mid-2000s. The delay in successful uptake often relates to the development of technology to minimize thrombosis and cellular damage. MCS requires a pumping mechanism, an electrical motor mechanism, a drive system connecting the pump to the motor, and an impeller suspension system to minimize or eliminate contact between the rotating pump impeller and the stationary housing.
There are three main types of rotary pumps that have been utilized in implanted MCS devices: axial flow, centrifugal flow, and mixed flow pumps. The first commercially viable rotary MCS device was the axial flow Thoratec HeartMate II long-term device. First-generation axial flow devices utilized mechanical bearings with upstream and downstream support structures to hold the rotating impeller. The upstream support member is utilized as a flow straightener, and the downstream support structure, as a vanned diffuser. The diffuser efficiently converts the swirling flow, kinetic energy, downstream of the impeller into differential pressure. The first commercially viable and Food and Drug Administration–approved centrifugal long-term MCS device was the HeartWare HVAD. This device utilized passive magnetic forces and hydrodynamic bearings to support the rotating impeller in a contactless manner. This device utilizes a traditional vaneless diffuser called a volute to collect the high-velocity blood from the impeller and efficiently direct it to the outflow cannula. The first commercially viable mixed-flow MCS device was the acute, percutaneous Abiomed Impella device. This device utilizes a solid shaft and sealed bearing system, which is externally purged with saline, connecting the motor and the rotating impeller. The intended use requires that the outer diameter is minimized to facilitate percutaneous deployment, and since sufficient performance exists, an additional diffuser was not needed.
Pump Curves
The main performance curves for a rotary pump are called a Head-Flow or “H-Q” curves. The hemodynamic consequences of pump design are covered in Chapter 7 . The characteristics of pump flow that are particularly relevant to pump thrombosis are discussed here.
Every pump rotational speed curve contains a singular differential pressure that will yield zero net flow through the device, also known as shut-off condition ( Fig. 8.1 ). If the differential pressure is higher than the shut-off condition, which may occur if the rotational speed of the device is set low and the heart contractility is high, then the net flow rate becomes retrograde. Centrifugal pumps are more susceptible to retrograde flow than axial flow pumps, with the inflection in slope typically being in the retrograde region. Typically, the slope inflection for axial flow pumps is in the forward flow portion of the curve.
The average blood residence time can be calculated with the H-Q curves by dividing the pump priming volume by the flow rate through the device. An example centrifugal pump average residence time curve is shown in Fig. 8.2 . The residence time increases exponentially as the flow rate approaches zero, thereby increasing the probability for cellular damage and thrombosis. Inefficiencies in the hydraulic design may have a portion of the flow rate, with residence times significantly longer than average. This needs to be minimized as much as possible. Note that several cardiac cycles are required to clear the pump and outflow graft, indicating that careful attention to thrombosis prevention is not limited to just the pump. Avoiding shut-off differential pressure and full or partial occlusion of either the inflow or outflow is important in maintaining reasonably short residence times and minimizing the risk for thrombus generation.
