Cap, A. | bioRxiv Science

bioRxiv2023

Syndecan-1 and thrombomodulin are early biomarkers for development of endotheliopathy in trauma and hemorrhagic shock

The causes of endotheliopathy are multifactorial and trauma dependent, and the temporal mechanistic link that it has with acute traumatic coagulopathy (ATC) has yet to be fully determined. Therefore, we sought to define early characteristics and markers of endotheliopathy in two rat models, a time-course of acute lethal hemorrhage shock and polytrauma with hemorrhagic shock, to answer the following questions: (1) how soon can elevated biomarkers of endotheliopathy be detected in non-survivable (decompensated) hemorrhagic shock; (2) does extended hemorrhage time and accumulated hemorrhage impact biomarker levels; and (3) does the addition of polytrauma contribute to the further elevation of said biomarkers? In this study, we delineated a significant, acute elevation in end plasma levels of syndecan-1, thrombomodulin, and heparan sulfate, whose shedding patterns are a function of time as well as total hemorrhage volume vs. the addition of polytrauma. Additionally, we found that correlation of syndecan-1 and thrombomodulin to lactate levels and prothrombin times at trauma end revealed a potential for these markers to acutely predict downstream consequences of these trauma indications. Our results are of great relevance to the continued effort towards the identification and characterization of vascular dysfunction for early interventions in combat casualty care.

cell biology↗

bioRxiv2020

Preclinical Mesenchymal Stromal Cell Delivery Via An Ex Vivo Bioreactor Attenuates Clot Formation For Intravascular Applications

While mesenchymal stromal cells (MSCs) are an appealing therapeutic option for a range of clinical applications, their potential to induce clotting when used systemically remains a safety concern, particularly in hypercoagulable conditions, such as in patients with severe COVID-19, trauma, or cancers. Here, we tested a novel ex vivo approach aimed at improving the safety of MSC systemic administration by use of a bioreactor. In this device, MSCs are seeded on the outside of a hollow-fiber filter, sequestering them behind a hemocompatible membrane, while still maintaining cross talk with blood cells and circulating signaling molecules. The potential for these bioreactor MSCs to induce clots in coagulable plasma was compared against "free" MSCs, as a model of systemic administration, which were directly injected into the circuit. Our results showed that physical isolation of the MSCs via a bioreactor extends the time necessary for clot formation to occur when compared to "free" MSCs. Measurement of cell surface data indicates the presence of known clot inducing factors, namely tissue factor and phosphatidylserine. Results also showed that recovering cells and flushing the bioreactor prior to use further prolonged clot formation time. Further, application of this technology in two in vivo models did not require additional heparin to maintain target ACT levels relative to the acellular device. Taken together, the use of hollow fiber filters to house MSCs, if adopted clinically, could offer a novel method to control systemic MSC exposure and prolong clot formation time.

bioengineering↗