Hemocompatibility in Mechanical Circulatory Support

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.

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