Unraveling the Blood Biomaterial Interaction During Extracorporeal Membrane Oxygenation*

Pediatric extracorporeal membrane oxygenation (ECMO) provides lifesaving cardiopulmonary support for patients with a multitude of clinical diagnoses, resulting from cardiac and/or respiratory failure refractory to conventional supports (1). The utilization of pediatric ECMO has doubled over the last decade (1) with survival outcomes ranging from 58% to 87% across all indications for ECMO in pediatric and neonatal populations (2). With the increased utilization of pediatric ECMO, practitioners must be familiar with the risks associated with ECMO use, particularly the risks of bleeding and thrombosis (3). Thrombosis in a component of the ECMO circuit is a common complication; the highest in the neonatal population, occurring in 0.98 to 1.24 per 1000 ECMO hours and then decreasing in the pediatric population, with the lowest rate in the adult population (1). Circuit thrombosis in ECMO occurs following blood exposure to the biomaterial of the ECMO circuit resulting in activation of platelets along with the coagulation, inflammation, and compliment cascades (3). Sites of thrombosis are generally located at tubing/connector junctions, where the shear rate of blood is lowest (4). Neonatal and pediatric circuits are particularly prone to thrombosis secondary to lower flows that predispose to hemostasis, smaller cannula sizes and circuits, less predictive response to heparin, and less available antithrombin compared with adults (3,5). Clot formation on the arterial side, post-oxygenator is most worrisome, as they can lead to arterial strokes and organ ischemia (6). The Extracorporeal Life Support Organization registry collects outcome data on clot formation but relies upon visual identification by the ECMO provider, which can lead to potential underreporting of these complications. Noninvasive real-time ultrasonic sensors are a newer means of thrombus detection; however, presently are not widely used (7). The Pediatric ECMO Anticoagulation Collaborative Consensus Conference was recently published and provides recommendations on patient and circuit thrombosis management; however, the recommendations are based on expert opinion alone (8) and highlight the need for more research in this area. The article by Cai et al (9) takes a comprehensive look at characterizing the protein deposition on extracorporeal circuits used in humans. Their study characterized the proteins adsorbed to, and the fibrin fiber thickness bound to, ECMO circuits of six pediatric patients using data-independent acquisition mass spectrometry (DIA-MS) and scanning electron microscopy (SEM). Their results identified over 2000 unique proteins, with 933 common among all circuits and involved in 212 signaling pathways. Interestingly, the composition of the protein binding profile was unique to each patient and even among the common proteins; the combination of those was very heterogeneous between each patient. The top 20 abundant proteins represented different subunits of five specific proteins (hemoglobin, fibrinogen, apolipoprotein, protein S100, and complement component protein). Additionally, of these 212 signaling pathways, there were 12 separate categories represented with the top three being signal transduction, cell cycle, and protein metabolism. As for the fibrin fiber thickness, the deposition locations along the circuit were characterized with the most common site of deposition being immediately post the venous cannula connection, the first point of blood/circuit contact. This location was also the most abundant protein deposition site. It is important to note that the deposition of protein and fibrin was not homogeneous across the circuits. The second site of greatest protein deposition was post-oxygenator, which was not the case with fibrin deposition. The authors do a great job of interpreting these results, relating it to the clinical observations and known flow dynamics within the ECMO circuit. Providing a microscopic and elemental description of the circuitry used in patient care is an important advancement to help focus the development of more compatible, less thrombogenic extracorporeal circuitries. Indeed, much work in this field has focused on therapeutic strategies to address clotting factor and platelet interaction with the biomaterial surface by systemic inhibition of the clotting cascade. Surface modifications have become very common in clinical use with the majority utilizing some form of heparin bonding. Despite, these modifications, such surfaces still require a systemic agent for anticoagulation in the pediatric population. The underlying activity of protein adsorption and fibrin deposition to the circuitry, undoubtedly play an important role that has not been well studied or documented outside of the materials’ laboratory. Over the past decade, reports in science and engineering laboratories have demonstrated on the benchtop that nitric oxide (NO) has a profound impact on fibrin deposition on surface membranes and in turn, the ability of the circuit to prevent platelet deposition and activation even after the NO is depleted (10), which demonstrates proof of principle that an in situ biocompatible generated surface is possible. The challenge has been the translation from the bench to the clinical setting. Excitingly, the work in the current article by Cai et al (9) begins to dissect the interactions of the proteins on the surface of an extracorporeal circuit in a clinical setting and lays the scientific foundation for the next steps in materials development toward the ultimate goal of ECMO without the need for systemic anticoagulation. The evaluation of not only the surface proteins via mass spec but also the biochemical pathways is a more comprehensive strategy. In summary, Cai et al (9) use a unique method of DIA-MS and SEM to describe protein and fibrin deposition on ECMO circuits in six pediatric patients. Identifying the proteins that share a commonality among all ECMO circuits has the potential to target specific cellular pathways to limit the formation of these common proteins and potentially prevent clot burden on the circuit. Furthermore, the understanding of the location of protein deposition in the circuit has the potential to guide biomaterial engineering and manufacturing to develop new ECMO circuits with the goal of decreasing thrombosis formation and protein adsorption. Deepening our understanding of the complex interplay between ECMO biomaterials, platelet activation, the coagulation cascade, and the critically ill pediatric patient will lead to improved patient outcomes. The study by Cai et al (9) pioneers the field in that direction.

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