Browsing by Author "Fulkerson, Daniel"

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    Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation
    (Springer Nature, 2019-01-31) Shim, Joon W.; Territo, Paul R.; Simpson, Stefanie; Watson, John C.; Jiang, Lei; Riley, Amanda A.; McCarthy, Brian; Persohn, Scott; Fulkerson, Daniel; Blazer-Yost, Bonnie L.; Biology, School of Science
    Transmembrane protein 67 (TMEM67) is mutated in Meckel Gruber Syndrome type 3 (MKS3) resulting in a pleiotropic phenotype with hydrocephalus and renal cystic disease in both humans and rodent models. The precise pathogenic mechanisms remain undetermined. Herein it is reported for the first time that a point mutation of TMEM67 leads to a gene dose-dependent hydrocephalic phenotype in the Wistar polycystic kidney (Wpk) rat. Animals with TMEM67 heterozygous mutations manifest slowly progressing hydrocephalus, observed during the postnatal period and continuing into adulthood. These animals have no overt renal phenotype. The TMEM67 homozygous mutant rats have severe ventriculomegaly as well as severe polycystic kidney disease and die during the neonatal period. Protein localization in choroid plexus epithelial cells indicates that aquaporin 1 and claudin-1 both remain normally polarized in all genotypes. The choroid plexus epithelial cells may have selectively enhanced permeability as evidenced by increased Na+, K+ and Cl- in the cerebrospinal fluid of the severely hydrocephalic animals. Collectively, these results suggest that TMEM67 is required for the regulation of choroid plexus epithelial cell fluid and electrolyte homeostasis. The Wpk rat model, orthologous to human MKS3, provides a unique platform to study the development of both severe and mild hydrocephalus.
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    Immuno-Thrombotic Complications of COVID-19: Implications for Timing of Surgery and Anticoagulation
    (Frontiers Media, 2022-05-04) Bunch, Connor M.; Moore, Ernest E.; Moore, Hunter B.; Neal, Matthew D.; Thomas, Anthony V.; Zackariya, Nuha; Zhao, Jonathan; Zackariya, Sufyan; Brenner, Toby J.; Berquist, Margaret; Buckner, Hallie; Wiarda, Grant; Fulkerson, Daniel; Huff, Wei; Kwaan, Hau C.; Lankowicz, Genevieve; Laubscher, Gert J.; Lourens, Petrus J.; Pretorius, Etheresia; Kotze, Maritha J.; Moolla, Muhammad S.; Sithole, Sithembiso; Maponga, Tongai G.; Kell, Douglas B.; Fox, Mark D.; Gillespie, Laura; Khan, Rashid Z.; Mamczak, Christiaan N.; March, Robert; Macias, Rachel; Bull, Brian S.; Walsh, Mark M.; Surgery, School of Medicine
    Early in the coronavirus disease 2019 (COVID-19) pandemic, global governing bodies prioritized transmissibility-based precautions and hospital capacity as the foundation for delay of elective procedures. As elective surgical volumes increased, convalescent COVID-19 patients faced increased postoperative morbidity and mortality and clinicians had limited evidence for stratifying individual risk in this population. Clear evidence now demonstrates that those recovering from COVID-19 have increased postoperative morbidity and mortality. These data-in conjunction with the recent American Society of Anesthesiologists guidelines-offer the evidence necessary to expand the early pandemic guidelines and guide the surgeon's preoperative risk assessment. Here, we argue elective surgeries should still be delayed on a personalized basis to maximize postoperative outcomes. We outline a framework for stratifying the individual COVID-19 patient's fitness for surgery based on the symptoms and severity of acute or convalescent COVID-19 illness, coagulopathy assessment, and acuity of the surgical procedure. Although the most common manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19 pneumonitis, every system in the body is potentially afflicted by an endotheliitis. This endothelial derangement most often manifests as a hypercoagulable state on admission with associated occult and symptomatic venous and arterial thromboembolisms. The delicate balance between hyper and hypocoagulable states is defined by the local immune-thrombotic crosstalk that results commonly in a hemostatic derangement known as fibrinolytic shutdown. In tandem, the hemostatic derangements that occur during acute COVID-19 infection affect not only the timing of surgical procedures, but also the incidence of postoperative hemostatic complications related to COVID-19-associated coagulopathy (CAC). Traditional methods of thromboprophylaxis and treatment of thromboses after surgery require a tailored approach guided by an understanding of the pathophysiologic underpinnings of the COVID-19 patient. Likewise, a prolonged period of risk for developing hemostatic complications following hospitalization due to COVID-19 has resulted in guidelines from differing societies that recommend varying periods of delay following SARS-CoV-2 infection. In conclusion, we propose the perioperative, personalized assessment of COVID-19 patients' CAC using viscoelastic hemostatic assays and fluorescent microclot analysis.
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    SHock-INduced Endotheliopathy (SHINE): A mechanistic justification for viscoelastography-guided resuscitation of traumatic and non-traumatic shock
    (Frontiers Media, 2023-02-27) Bunch, Connor M.; Chang, Eric; Moore, Ernest E.; Moore, Hunter B.; Kwaan, Hau C.; Miller, Joseph B.; Al-Fadhl, Mahmoud D.; Thomas, Anthony V.; Zackariya, Nuha; Patel, Shivani S.; Zackariya, Sufyan; Haidar, Saadeddine; Patel, Bhavesh; McCurdy, Michael T.; Thomas, Scott G.; Zimmer, Donald; Fulkerson, Daniel; Kim, Paul Y.; Walsh, Matthew R.; Hake, Daniel; Kedar, Archana; Aboukhaled, Michael; Walsh, Mark M.; Graduate Medical Education, School of Medicine
    Irrespective of the reason for hypoperfusion, hypocoagulable and/or hyperfibrinolytic hemostatic aberrancies afflict up to one-quarter of critically ill patients in shock. Intensivists and traumatologists have embraced the concept of SHock-INduced Endotheliopathy (SHINE) as a foundational derangement in progressive shock wherein sympatho-adrenal activation may cause systemic endothelial injury. The pro-thrombotic endothelium lends to micro-thrombosis, enacting a cycle of worsening perfusion and increasing catecholamines, endothelial injury, de-endothelialization, and multiple organ failure. The hypocoagulable/hyperfibrinolytic hemostatic phenotype is thought to be driven by endothelial release of anti-thrombogenic mediators to the bloodstream and perivascular sympathetic nerve release of tissue plasminogen activator directly into the microvasculature. In the shock state, this hemostatic phenotype may be a counterbalancing, yet maladaptive, attempt to restore blood flow against a systemically pro-thrombotic endothelium and increased blood viscosity. We therefore review endothelial physiology with emphasis on glycocalyx function, unique biomarkers, and coagulofibrinolytic mediators, setting the stage for understanding the pathophysiology and hemostatic phenotypes of SHINE in various etiologies of shock. We propose that the hyperfibrinolytic phenotype is exemplified in progressive shock whether related to trauma-induced coagulopathy, sepsis-induced coagulopathy, or post-cardiac arrest syndrome-associated coagulopathy. Regardless of the initial insult, SHINE appears to be a catecholamine-driven entity which early in the disease course may manifest as hyper- or hypocoagulopathic and hyper- or hypofibrinolytic hemostatic imbalance. Moreover, these hemostatic derangements may rapidly evolve along the thrombohemorrhagic spectrum depending on the etiology, timing, and methods of resuscitation. Given the intricate hemochemical makeup and changes during these shock states, macroscopic whole blood tests of coagulative kinetics and clot strength serve as clinically useful and simple means for hemostasis phenotyping. We suggest that viscoelastic hemostatic assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are currently the most applicable clinical tools for assaying global hemostatic function—including fibrinolysis—to enable dynamic resuscitation with blood products and hemostatic adjuncts for those patients with thrombotic and/or hemorrhagic complications in shock states.
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    TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus
    (American Society for Clinical Investigation, 2020-09-17) Hochstetler, Alexandra E.; Smith, Hillary M.; Preston, Daniel C.; Reed, Makenna M.; Territo, Paul R.; Shim, Joon W.; Fulkerson, Daniel; Blazer-Yost, Bonnie L.; Biology, School of Science
    Hydrocephalus is a serious condition that impacts patients of all ages. The standards of care are surgical options to divert, or inhibit production of, cerebrospinal fluid; to date, there are no effective pharmaceutical treatments, to our knowledge. The causes vary widely, but one commonality of this condition is aberrations in salt and fluid balance. We have used a genetic model of hydrocephalus to show that ventriculomegaly can be alleviated by inhibition of the transient receptor potential vanilloid 4, a channel that is activated by changes in osmotic balance, temperature, pressure and inflammatory mediators. The TRPV4 antagonists do not appear to have adverse effects on the overall health of the WT or hydrocephalic animals.
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    Whole Blood, Fixed Ratio, or Goal-Directed Blood Component Therapy for the Initial Resuscitation of Severely Hemorrhaging Trauma Patients: A Narrative Review
    (MDPI, 2021-01-17) Walsh, Mark; Moore, Ernest E.; Moore, Hunter B.; Thomas, Scott; Kwaan, Hau C.; Speybroeck, Jacob; Marsee, Mathew; Bunch, Connor M.; Stillson, John; Thomas, Anthony V.; Grisoli, Annie; Aversa, John; Fulkerson, Daniel; Vande Lune, Stefani; Sjeklocha, Lucas; Tran, Quincy K.; Medicine, School of Medicine
    This narrative review explores the pathophysiology, geographic variation, and historical developments underlying the selection of fixed ratio versus whole blood resuscitation for hemorrhaging trauma patients. We also detail a physiologically driven and goal-directed alternative to fixed ratio and whole blood, whereby viscoelastic testing guides the administration of blood components and factor concentrates to the severely bleeding trauma patient. The major studies of each resuscitation method are highlighted, and upcoming comparative trials are detailed.