Mobile and Web-Based Partnered Intervention to Improve Remote Access to Pain and Posttraumatic Stress Disorder Symptom Management: Recruitment and Attrition in a Randomized Controlled Trial.

BACKGROUND: Increasing access to nonpharmacological interventions to manage pain and posttraumatic stress disorder (PTSD) is essential for veterans. Complementary and integrative health (CIH) interventions can help individuals manage symptom burden with enhanced accessibility via remotely delivered health care. Mission Reconnect (MR) is a partnered, self-directed intervention that remotely teaches CIH skills. OBJECTIVE: The purpose of this paper is to describe the recruitment, onboarding phase, and attrition of a fully remote randomized controlled trial (RCT) assessing the efficacy of a self-directed mobile and web-based intervention for veterans with comorbid chronic pain and PTSD and their partners. METHODS: A total of 364 veteran-partner dyads were recruited to participate in a mixed methods multisite waitlist control RCT. Qualitative attrition interviews were conducted with 10 veterans with chronic pain and PTSD, and their self-elected partners (eg, spouse) who consented but did not begin the program. RESULTS: At the point of completing onboarding and being randomized to the 2 treatment arms, of the 364 recruited dyads, 97 (26.6%) failed to complete onboarding activities. Reported reasons for failure to complete onboarding include loss of self-elected partner buy-in (n=8, 8%), difficulties with using remote data collection methods and interventions (n=30, 31%), and adverse health experiences unrelated to study activities (n=23, 24%). Enrolled veterans presented at baseline with significant PTSD symptom burden and moderate-to-severe pain severity, and represented a geographically and demographically diverse population. Attrition interviews (n=10) indicated that misunderstanding MR including the intent of the intervention or mistaking the surveys as the actual intervention was a reason for not completing the MR registration process. Another barrier to MR registration was that interviewees described the mailed study information and registration packets as too confusing and excessive. Competing personal circumstances including health concerns that required attention interfered with MR registration. Common reasons for attrition following successful MR registration included partner withdrawal, adverse health issues, and technological challenges relating to the MR and electronic data collection platform (Qualtrics). Participant recommendations for reducing attrition included switching to digital forms to reduce participant burden and increasing human interaction throughout the registration and baseline data collection processes. CONCLUSIONS: Challenges, solutions, and lessons learned for study recruitment and intervention delivery inform best practices of delivering remote self-directed CIH interventions when addressing the unique needs of this medically complex population. Successful recruitment and enrollment of veterans with chronic pain and PTSD, and their partners, to remote CIH programs and research studies requires future examination of demographic and symptom-associated access barriers. Accommodating the unique needs of this medically complex population is essential for improving the effectiveness of CIH programs. Disseminating lessons learned and improving access to remotely delivered research studies and CIH programs is paramount in the post-COVID-19 climate. TRIAL REGISTRATION: ClinicalTrials.gov NCT03593772; https://clinicaltrials.gov/ct2/show/NCT03593772.

Empower Veterans Program (EVP): a chronic pain management program demonstrates positive outcomes among veterans.

BACKGROUND: Chronic pain is a highly prevalent health condition among veterans. Traditional pharmacological interventions present unique challenges for chronic pain management including prescription opioid addiction and overdose. In alignment with the 2016 Comprehensive Addiction and Recovery Act and VA's Stepped Care Model to meet veterans' pain management needs, the Offices of Rural Health and Pain Management, Opioid Safety, and Prescription Drug Monitoring Program (PMOP) funded an enterprise-wide initiative to implement a Step 3 integrated tele-pain program: Empower Veterans Program (EVP). EVP provides veterans with chronic pain self-care skills using a whole health driven approach to pain management. OBJECTIVES: The Comprehensive Addiction and Recovery Act prompted the strategic approach to offer non-pharmacological options to meet veterans' pain management needs. EVP, a 10-week interdisciplinary group medical appointment, leverages Acceptance and Commitment Therapy, Mindful Movement, and Whole Health to provide veterans with chronic pain self-care skills. This evaluation was conducted to describe participant characteristics, graduation, and satisfaction rates; and assess pre-post patient-reported outcomes (PRO) associated with EVP participation. METHODS: A sample of 639 veterans enrolled in EVP between May, 2015 and December, 2017 provided data to conduct descriptive analyses to assess participant demographics, graduation, and satisfaction rates. PRO data were analyzed using a within-participants pre-post design, and linear mixed-effects models were used to examine pre-post changes in PRO. RESULTS: Of 639 participants, 444 (69.48%) graduated EVP. Participant median program satisfaction rating was 8.41 (Interquartile Range: 8.20-9.20). Results indicate pre-post EVP improvements (Bonferroni-adjusted p < .003) in the three primary pain outcomes (intensity, interference, catastrophizing), and 12 of 17 secondary outcomes, including physical, psychological, health-related quality of life (HRQoL), acceptance, and mindfulness measures. DISCUSSION: Data suggest that EVP has significant positive outcomes in pain, psychological, physical, HRQoL, acceptance, and mindfulness measures for veterans with chronic pain through non-pharmacological means. Future evaluations of intervention dosing effect and long-term effectiveness of the program is needed.

Functional Outcome of Internal Fixation (INFIX) in Anterior Pelvic Ring Fractures.

Introduction Pelvic injuries account for 2% of all orthopedic admissions and are associated with high mortality rates. They need a stable fixation and not an anatomical fixation. Hence, the role of internal fixation (INFIX) comes into play, which provides a stable internal fixation without the complication of open reduction and external fixation with plates and screws. Materials and methodology Thirty-one patients with unstable pelvic ring injuries coming to a tertiary care hospital in the state of Maharashtra, India, were selected retrospectively. They were operated on with INFIX. Patients were followed up for a period of six months and evaluated according to the Majeed score. Results There was a significant functional outcome in patients operated on with INFIX in pelvic ring injuries in terms of the ability to sit, stand, rejoin work, take part in sexual intercourse, and bear pain. An average Majeed score of 78 with signs of a stable bony union by six months and a full range of motion was noticed in most patients with no problems in day-to-day work. Conclusion INFIX provides stable internal fixation of pelvic fractures with good functional outcome without the disadvantages of external fixation or open reduction with plates.

Comparing Outcomes of the Veterans Health Administration's Traumatic Brain Injury and Mental Health Screening Programs: Types and Frequency of Specialty Services Used.

The Veterans Health Administration (VHA) screens veterans who deployed in support of the wars in Afghanistan and Iraq for traumatic brain injury (TBI) and mental health (MH) disorders. Chronic symptoms after mild TBI overlap with MH symptoms, for which there are already established screens within the VHA. It is unclear whether the TBI screen facilitates treatment for appropriate specialty care over and beyond the MH screens. Our primary objective was to determine whether TBI screening is associated with different types (MH, Physical Medicine & Rehabilitation [PM&R], and Neurology) and frequency of specialty services compared with the MH screens. A retrospective cohort design examined veterans receiving VHA care who were screened for both TBI and MH disorders between Fiscal Year (FY) 2007 and FY 2018 (N = 241,136). We calculated service utilization counts in MH, PM&R, and Neurology in the six months after the screens. Zero-inflated negative binomial regression models of encounters (counts) were fit separately by specialty care type and for a total count of specialty services. We found that screening positive for TBI resulted in 2.38 times more specialty service encounters than screening negative for TBI. Compared with screening positive for MH only, screening positive for both MH and TBI resulted in 1.78 times more specialty service encounters and 1.33 times more MH encounters. The TBI screen appears to increase use of MH, PM&R, and Neurology services for veterans with post-deployment health concerns, even in those also identified as having a possible MH disorder.

Provider reported value and use of virtual resources in extended primary care prior to and during COVID-19.

BACKGROUND: A proactive approach to delivering care using virtual resources, while reducing in-person contact, is needed during the COVID-19 pandemic. OBJECTIVE: In the current study we describe pre- to post- COVID-19 pandemic onset related changes in electronic delivery of primary care. METHODS: A longitudinal, pre-post within-subjects design was used. Patient-aligned care team providers from one VA medical center, a primary care annex, and four affiliated community-based outpatient clinics completed both a baseline and follow up survey (N = 62) or the follow-up survey only (N = 85). The follow-up survey contained questions about COVID-19. RESULTS: The majority of providers (88%) reported they would continue virtual care once pandemic restrictions were lifted. Most (83%) felt prepared to transition to virtual care when pandemic restrictions began. Use of My HealtheVet, Telehealth, and mobile apps showed a significant increase (22.7%; 31.1%; 48.5%). Barriers to virtual care included (1) internet connectivity; (2) patients' lack of technology comfort and skills; and (3) technical issues. Main supports to provide virtual care to patients were (1) peers/ colleagues; (2) technology support through help desk; (3) equipment such as laptops and dual screens; (4) being able to use doximety and virtual care manager, and (5) training. CONCLUSIONS: Overall, provider-use and perceptions related to using virtual care improved over time. Providers adapted quickly to providing virtual care during COVID-19 and planned to provide virtual care long-term.

Primary care virtual resource use prior and post COVID-19 pandemic onset.

BACKGROUND: The COVID-19 pandemic has been a catalyst for rapid uptake of virtual care through the use of virtual health resources (VHR). In the Department of Veterans Affairs (VA) Healthcare System, virtual care has been critical to maintaining healthcare access for patients during COVID-19. In the current study we describe primary care patient aligned care team (PACT) VHR use patterns within one VA medical center (i.e., hospital facility and five community-based outpatient clinics) pre- and post-COVID-19 onset. METHODS: VHR provider and patient use data from 106 individual PACTs were extracted monthly between September 2019 to September 2020. Data were extracted from VHA web-based project application and tracking databases. Using longitudinal data, mixed effect models were used to compare pre- and post-COVID onset slopes. RESULTS: Findings highlight an increase in patient users of secure messaging (SM) and telehealth. The rate of utilization among these patients increased for SM but not for telehealth visits or online prescription refill (RxRefill) use. Finally, VetLink Kiosk check ins that are done at in person visits, diminished abruptly after COVID-19 onset. CONCLUSIONS: These data provide a baseline of VHR use at the PACT level after the initial impact of the COVID-19 pandemic and can inform healthcare delivery changes within the VA systems over time. Moreover, this project produced a data extraction blueprint, that is the first of its kind to track VA VHR use leveraging secondary data sources.

Platelet reactivity and platelet count in women with iron deficiency treated with intravenous iron.

Background: Iron deficiency anemia (IDA) and heavy menstrual bleeding are prevalent, interrelated issues impacting over 300 million premenopausal women worldwide. IDA is generally associated with increased platelet counts; however, the effects of IDA and its correction on platelet function in premenopausal women remain unknown. Objectives: We sought to determine how IDA and intravenous iron affect platelet count and platelet function in premenopausal women. Methods: Hematologic indices were assessed in a multicenter, retrospective cohort of 231 women repleted with intravenous iron. Pre- and postinfusion blood samples were then obtained from a prospective cohort of 13 women to analyze the effect of intravenous iron on hematologic parameters as well as platelet function with flow cytometry and platelet aggregation assays under physiologic shear. Results: Following iron replacement, anemia improved, and mean platelet counts decreased by 26.5 and 16.0 K/mm3 in the retrospective and prospective cohorts, respectively. Replacement reduced baseline platelet surface P-selectin levels while enhancing platelet secretory responses to agonists, including collagen-related peptide and ADP. Platelet adhesion and aggregation on collagen under physiologic shear also significantly increased following repletion. Conclusion: We find that intravenous iron improves anemia while restoring platelet counts and platelet secretory responses in premenopausal women with iron deficiency. Our results suggest that iron deficiency as well as iron replacement can have a range of effects on platelet production and function. Consequently, platelet reactivity profiles should be further examined in women and other groups with IDA where replacement offers a promising means to improve anemia as well as quality of life.

Preliminary Evidence on the Association of Complementary and Integrative Health Care Program Participation and Medical Cost in Veterans.

INTRODUCTION: Transforming Health and Resilience through Integration of Values-based Experiences (THRIVE) is a complimentary and integrative health program. THRIVE is delivered through shared medical appointments where participants engage in provider-led education and group discussion on wellness-related topics. THRIVE has been associated with improved patient-reported outcomes in a female veteran cohort. This quality improvement study evaluated the association between THRIVE participation and Veterans Health Administration (VHA) healthcare costs across a 1 year period. MATERIALS AND METHODS: A cohort study design (n = 184) used VHA administrative data to estimate the cost difference between 1 year pre- and post-THRIVE participation. The 1 year post-cost of the THRIVE cohort was then compared to the 1 year cost of a quasi-experimental waitlist control group (n = 156). Data sources included VHA administrative and electronic health records. RESULTS: Patients were roughly 51 years old, were typically White/Caucasian, and had a service priority level representing catastrophic disability. The adjusted post-THRIVE cost was $26,291 [95% confidence interval (CI): $23,014-29,015]; $1,720 higher than the previous year's cost but was not statistically significant (P = 0.289). However, a comparison between the THRIVE cohort and a group of waitlist THRIVE patients (n = 156) the intervention group on average was $8,108 more than the waitlist group (95% CI: $3,194-14,005; P < 0.01). CONCLUSIONS: In summary, data analysis of veterans' annual healthcare cost trajectories were inconclusive. This preliminary study produced mixed results requiring more research with larger samples and randomized control trial methodology. Evidence of whether the THRIVE intervention can maintain cost effectiveness while maintaining its supported evidence of healthcare quality is needed.

Microstimulation in Different Parts of the Periaqueductal Gray Generates Different Types of Vocalizations in the Cat.

In the cat four different types of vocalization, mews, howls, cries, and hisses were generated by microstimulation in different parts of the periaqueductal gray (PAG). While mews imply positive vocal expressions, howls, hisses, and cries represent negative vocal expressions. In the intermediate PAG, mews were generated in the lateral column, howls, and hisses in the ventrolateral column. Cries were generated in two other regions, the lateral column of the rostral PAG and the ventrolateral column of the caudal PAG. In order to define the specific motor patterns of the mews, howls, and cries, the following muscles were recorded during these vocalizations; larynx (cricothyroid, thyroarytenoid, and posterior cricoarytenoid), tongue (genioglossus), jaw (digastric), and respiration muscles (diaphragm, internal intercostal, external, and internal abdominal oblique). During these mews, howls, and cries we analyzed the frequency, intensity, activation cascades power density, turns, and amplitude analysis of the electromyograms (EMGs). It appeared that each type of vocalization consists of a specific circumscribed motor coordination. The nucleus retroambiguus (NRA) in the caudal medulla is known to serve as the final premotor interneuronal output system for vocalization. Although neurochemical microstimulation in the NRA itself also generated vocalizations, they only consisted of guttural sounds, the EMGs of which involved only small parts of the EMGs of the mews, howls, and cries generated by neurochemical stimulation in the PAG. These results demonstrate that positive and negative vocalizations are generated in different parts of the PAG. These parts have access to different groups of premotoneurons in the NRA, that, in turn, have access to different groups of motoneurons in the brainstem and spinal cord, resulting in different vocalizations. The findings would serve a valuable model for diagnostic assessment of voice disorders in humans.

Antibody inhibition of contact factor XII reduces platelet deposition in a model of extracorporeal membrane oxygenator perfusion in nonhuman primates.

BACKGROUND: The contact factor XII (FXII) activates upon contact with a variety of charged surfaces. Activated FXII (FXIIa) activates factor XI, which activates factor IX, resulting in thrombin generation, platelet activation, and fibrin formation. In both in vitro and in vivo rabbit models, components of medical devices, including extracorporeal oxygenators, are known to incite fibrin formation in a FXII-dependent manner. Since FXII has no known role in hemostasis and its inhibition is therefore likely a safe antithrombotic approach, we investigated whether FXII inhibition also reduces accumulation of platelets in extracorporeal oxygenators. OBJECTIVES: We aimed to determine the effect of FXII inhibition on platelet deposition in perfused extracorporeal membrane oxygenators in nonhuman primates. METHODS: A potent FXII neutralizing monoclonal antibody, 5C12, was administered intravenously to block contact activation in baboons. Extracorporeal membrane oxygenators were temporarily deployed into chronic arteriovenous access shunts. Radiolabeled platelet deposition in oxygenators was quantified in real time using gamma camera imaging. Biochemical assays were performed to characterize the method of action of 5C12. RESULTS: The anti-FXII monoclonal antibody 5C12 recognized both the alpha and beta forms of human and baboon FXII by binding to the protease-containing domain, and inhibited FXIIa activity. Administration of 5C12 to baboons reduced platelet deposition and fibrin formation in the extracorporeal membrane oxygenators, in both the presence and absence of systemic low-dose unfractionated heparin. The antiplatelet dose of 5C12 did not cause measurable increases in template bleeding times in baboons. CONCLUSIONS: FXII represents a possible therapeutic and safe target for reducing platelet deposition and fibrin formation during medical interventions including extracorporeal membrane oxygenation.

Comparative evaluation of intraoperative use of normal saline, Ringer's lactate, and combination of normal saline and Ringer's lactate in neurosurgical patients - A preliminary randomized clinical trial.

BACKGROUND: Fluid management during intracranial surgery is an important concern. The type of fluid used can have biochemical and metabolic effects during intraoperative management. However, it is yet to be known whether biochemical and metabolic effects have an influence on the clinical outcome of a patient. OBJECTIVE: A prospective evaluation of the effects of normal saline (NS), Ringer's lactate (RL), and a combination of NS and RL on the biochemical, metabolic, and clinical outcomes in patients undergoing intracranial tumor surgery was carried out. MATERIALS AND METHODS: Ninety patients undergoing elective intracranial tumor surgery were randomized to receive NS, RL, or a combination of NS and RL. The biochemical and metabolic parameters were studied at different time points in the intraoperative and postoperative period. The hemodynamic parameters, brain relaxation score at the time of bone flap elevation, postoperative complications, and the duration of hospital stay were the clinical outcome variables of our study. RESULTS: The use of NS was associated with hyperchloremic metabolic acidosis and ionic hypocalcemia. RL caused significant hyponatremia and increase in serum lactate levels. The combination of NS and RL has least influence on biochemical and metabolic parameters. The effects of three fluids were similar on the hemodynamics, brain relaxation score, as well as on postoperative complications and the duration of postoperative hospital stay. CONCLUSION: There are variable effects of NS, RL, or its combination on the biochemical and metabolic parameters in patients undergoing intracranial tumor surgery. However, the clinical outcome of the patients remains similar.

The midbrain periaqueductal gray as an integrative and interoceptive neural structure for breathing.

The periaqueductal gray (PAG) plays a critical role in autonomic function and behavioural responses to threatening stimuli. Recent evidence has revealed the PAG's potential involvement in the perception of breathlessness, a highly threatening respiratory symptom. In this review, we outline the current evidence in animals and humans on the role of the PAG in respiratory control and in the perception of breathlessness. While recent work has unveiled dissociable brain activity within the lateral PAG during perception of breathlessness and ventrolateral PAG during conditioned anticipation in healthy humans, this is yet to be translated into diseases dominated by breathlessness symptomology, such as chronic obstructive pulmonary disease. Understanding how the sub-structures of the PAG differentially interact with interoceptive brain networks involved in the perception of breathlessness will help towards understanding discordant symptomology, and may reveal treatment targets for those debilitated by chronic and pervasive breathlessness.

Preparative enrichment of human tissue cells capable to change a site of growth in vitro or in vivo - Recent developments.

Human cells are heterogeneous in regard to their biochemical features and functions. Detailed knowledge about each single cell type is important to understand the whole organism. In order to get a deeper insight in the concert of life, it has to be considered that cell populations such as thyroid cells, epithelial breast cells, endothelial cells, or chondrocytes are heterogeneous in regard to function, RNA expression patterns and protein content. This is true for normal cells and even more relevant for cancer cells. A number of sophisticated methods were developed to enrich cohorts of cells generally belonging to a defined type but outstanding by distinct characteristics, which can be detected by microscopic, proteomic or genomic methods. There is a great interest to investigate human cells, which are able to change their site of growth within the human body leaving an original site, migrating through vessels and reentering another site. In this review experiments are summarized showing that the application of microgravity-exposure of human cells and cell electrophoresis enable a characterization of cells, which leave a site of growth to enter another one. Biochemical features of separated subpopulations are described and their usefulness for deeper investigation is highlighted.

The physiological motor patterns produced by neurons in the nucleus retroambiguus in the rat and their modulation by vagal, peripheral chemosensory, and nociceptive stimulation.

The nucleus retroambiguus (NRA) is a neuronal cell group in the medullary ventrolateral tegmentum, rostrocaudally between the obex and the first cervical spinal segment. NRA neurons are premotor interneurons with direct projections to the motoneurons of soft palate, pharynx, and larynx in the nucleus ambiguus in the lateral medulla as well as to the motoneurons in the spinal cord innervating diaphragm, abdominal, and pelvic floor muscles and the lumbosacral motoneurons generating sexual posture. These NRA premotor interneurons receive very strong projections from the periaqueductal gray (PAG) in the context of basic survival mechanisms as fight, flight, freezing, sound production, and sexual behavior. In the present study in rat we investigated the physiological motor patterns generated by NRA neurons, as the result of vagal, peripheral chemosensory, and nociceptive stimulation. The results show that the NRA contains phasic respiratory modulated neurons, as well as nonphasic tonically modulated neurons. Stimulation in the various rostrocaudal levels of the NRA generates site-specific laryngeal, respiratory, abdominal, and pelvic floor motor activities. Vagal and peripheral chemosensory stimulation induces both excitatory and inhibitory modulation of phasic NRA-neurons, while peripheral chemosensory and nociceptive stimulation causes excitation and inhibition of nonphasic NRA-neurons. These results are in agreement with the concept that the NRA represents a multifunctional group of neurons involved in the output of the emotional motor system, such as vomiting, vocalization, mating, and changes in respiration.

Design and Utility of a Point-of-Care Microfluidic Platform to Assess Hematocrit and Blood Coagulation.

PURPOSE­: To develop a small volume whole blood analyzer capable of measuring the hematocrit and coagulation kinetics of whole blood. METHODS AND RESULTS­: A co-planar microfluidic chamber designed to facilitate self-driven capillary action across an internal electrical chip was developed and used to measure the electric parameters of whole human blood that had been anticoagulated or allowed to clot. To promote blood clotting, select chip surfaces were coated with a prothrombin time (PT) reagent containing lipidated tissue factor (TF), which activates the extrinsic pathway of coagulation to promote thrombin generation and fibrin formation. Whole human blood was added to the microfluidic device, and voltage changes within the platform were measured and interpreted using basic resistor-capacitor (RC) circuit and fluid dynamics theory. Upon wetting of the sensing zone, a circuit between two co-planar electrodes within the sensing zone was closed to generate a rapid voltage drop from baseline. The voltage then rose due to sedimentation of red blood cells (RBC) in the sensing zone. For anticoagulated blood samples, the time for the voltage to return to baseline was dependent on hematocrit. In the presence of coagulation, the initiation of fibrin formation in the presence of the PT reagent prevented the return of voltage to baseline due to the reduced packing of RBCs in the sensing zone. CONCLUSIONS­: The technology presented in this study has potential for monitoring the hematocrit and coagulation parameters of patient samples using a small volume of whole blood, suggesting it may hold clinical utility as a point-of-care test.

Dynamics of blood flow and thrombus formation in a multi-bypass microfluidic ladder network.

The reaction dynamics of a complex mixture of cells and proteins, such as blood, in branched circulatory networks within the human microvasculature or extravascular therapeutic devices such as extracorporeal oxygenation machine (ECMO) remains ill-defined. In this report we utilize a multi-bypass microfluidics ladder network design with dimensions mimicking venules to study patterns of blood platelet aggregation and fibrin formation under complex shear. Complex blood fluid dynamics within multi-bypass networks under flow were modeled using COMSOL. Red blood cells and platelets were assumed to be non-interacting spherical particles transported by the bulk fluid flow, and convection of the activated coagulation factor II, thrombin, was assumed to be governed by mass transfer. This model served as the basis for predicting formation of local shear rate gradients, stagnation points and recirculation zones as dictated by the bypass geometry. Based on the insights from these models, we were able to predict the patterns of blood clot formation at specific locations in the device. Our experimental data was then used to adjust the model to account for the dynamical presence of thrombus formation in the biorheology of blood flow. The model predictions were then compared to results from experiments using recalcified whole human blood. Microfluidic devices were coated with the extracellular matrix protein, fibrillar collagen, and the initiator of the extrinsic pathway of coagulation, tissue factor. Blood was perfused through the devices at a flow rate of 2 µL/min, translating to physiologically relevant initial shear rates of 300 and 700 s-1 for main channels and bypasses, respectively. Using fluorescent and light microscopy, we observed distinct flow and thrombus formation patterns near channel intersections at bypass points, within recirculation zones and at stagnation points. Findings from this proof-of-principle ladder network model suggest a specific correlation between microvascular geometry and thrombus formation dynamics under shear. This model holds potential for use as an integrative approach to identify regions susceptible to intravascular thrombus formation within the microvasculature as well as extravascular devices such as ECMO.