Procoagulant in vitro effects of clinical cellular therapeutics in a severely injured trauma population

George, Mitchell J.; Prabhakara, Karthik S.; Toledano-Furman, Naama E.; Gill, Brijesh S.; Wade, Charles E.; Cotton, Bryan A.; Andrew, P.; Olson, Scott D.; Cox, Charles S.

doi:10.1002/sctm.19-0206

Cited by 19 publications

(23 citation statements)

References 26 publications

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“…delivery in COVID-19, considering that MSC products express variable levels of highly procoagulant tissue factor (TF/CD142) (58), compromising the cells' hemocompatibility and safety profile ( Figure 1B) (6)(7)(8)(59)(60)(61). Numerous clinical reports indicate (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)) that many of the critically ill COVID-19 patients with poor prognosis are in a systemic procoagulant state at high risk of disseminated intravascular coagulation (DIC), thromboembolism, and thrombotic multi-organ failure, one of the leading causes of death in these patients.…”

Section: Hypercoaguability In Covid-19 Patients With Poor Prognosis Mmentioning

confidence: 99%

“…Numerous clinical reports indicate (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)) that many of the critically ill COVID-19 patients with poor prognosis are in a systemic procoagulant state at high risk of disseminated intravascular coagulation (DIC), thromboembolism, and thrombotic multi-organ failure, one of the leading causes of death in these patients. This would make IV applications of MSCs a contraindication in COVID-19 due to the potential harm to these patients (6)(7)(8)(59)(60)(61).…”

Section: Hypercoaguability In Covid-19 Patients With Poor Prognosis Mmentioning

confidence: 99%

“…This could prove particularly problematic for those patients that suffer from a dysregulation of the hemostatic system (66). George et al reported that blood clotting in trauma patients in a state of hypercoagulability was accelerated by commonly used IV-infused cellular therapeutics in relation to the degree of TF/CD142 expression in the product (8,60,61,66). To illustrate that this is not just a hypothetical risk, peripheral microthrombosis, embolism, and even potential cases of death have already been documented in patients that received infusions of highly TF/CD142-expressing MSCs (67)(68)(69), and it is expected that similar cases may arise as a result of MSC infusion in COVID-19.…”

Section: Need For Hemocompatibility Testing Of IV Applied Cellular Thmentioning

confidence: 99%

“…In addition, standardized in vitro and in vivo hemocompatibility testing should be conducted for all new IV-applied MSC(-like) products and other cellular therapeutics prior to application in clinical trials. Cellular therapeutics differ greatly in TF/CD142 expression (7,8,(59)(60)(61), but their hemocompatibility is not yet tested even when applied to patients via IV delivery (85). Thus, the risk of (lethal) thrombotic complications is most apparent if clinicians are not fully aware of this problem, and it is imperative that they are aware of said risks to enable the use of appropriate countermeasures (e.g.…”

Section: Integrating Hemocompatibility Testing Of Cellular Therapeutimentioning

confidence: 99%

“…Needs: The clinical cell product properties and mode of celldelivery should anticipate the specific patient needs under consideration of the target indication to be treated (e.g., anticipation of anticoagulation protocols/bleeding risk and IM application as an alternative to IV infusion, shown to result in longer cell survival in vivo, associated with prolonged secretory activities, and a lack of coagulation issues, which may be important in the treatment of COVID-19) (7,8,60,73).…”

Section: Updated Cell Therapy Routines Reflecting the Specific Patientmentioning

confidence: 99%

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MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy

et al. 2020

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Numerous clinical trials of mesenchymal stromal/stem cells (MSCs) as a new treatment for coronavirus-induced disease (COVID-19) have been registered recently, most of them based on intravenous (IV) infusion. There is no approved effective therapy for COVID-19, but MSC therapies have shown first promise in the treatment of acute respiratory distress syndrome (ARDS) pneumonia, inflammation, and sepsis, which are among the leading causes of mortality in COVID-19 patients. Many of the critically ill COVID-19 patients are in a hypercoagulable procoagulant state and at high risk for disseminated intravascular coagulation, thromboembolism, and thrombotic multiorgan failure, another cause of high fatality. It is not yet clear whether IV infusion is a safe and effective route of MSC delivery in COVID-19, since MSC-based products express variable levels of highly procoagulant tissue factor (TF/CD142), compromising the cells' hemocompatibility and safety profile. Of concern, IV infusions of poorly characterized MSC products with unchecked (high) TF/CD142 expression could trigger blood clotting in COVID-19 and other vulnerable patient populations and further promote the risk for thromboembolism. In contrast, well-characterized products with robust manufacturing procedures and optimized modes of clinical delivery hold great promise for ameliorating COVID-19 by exerting their beneficial immunomodulatory effects, inducing tissue repair and organ protection. While the need for MSC therapy in COVID-19 is apparent, integrating both innate and adaptive immune compatibility testing into the current guidelines for cell, tissue, and organ transplantation is critical for safe and effective therapies. It is paramount to only use wellcharacterized, safe MSCs even in the most urgent and experimental treatments. We here propose three steps to mitigate the risk for these vulnerable patients: (1) updated Moll et al. MSC Therapies for COVID-19 clinical guidelines for cell and tissue transplantation, (2) updated minimal criteria for characterization of cellular therapeutics, and (3) updated cell therapy routines reflecting specific patient needs.

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Section: Hypercoaguability In Covid-19 Patients With Poor Prognosis Mmentioning

confidence: 99%

Section: Hypercoaguability In Covid-19 Patients With Poor Prognosis Mmentioning

confidence: 99%

Section: Need For Hemocompatibility Testing Of IV Applied Cellular Thmentioning

confidence: 99%

Section: Integrating Hemocompatibility Testing Of Cellular Therapeutimentioning

confidence: 99%

Section: Updated Cell Therapy Routines Reflecting the Specific Patientmentioning

confidence: 99%

See 3 more Smart Citations

MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy

et al. 2020

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Engineering the MSC Secretome: A Hydrogel Focused Approach

Wechsler

Rao

Borelli

et al. 2021

Adv Healthcare Materials

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The therapeutic benefits of exogenously delivered mesenchymal stromal/stem cells (MSCs) have been largely attributed to their secretory properties. However, clinical translation of MSC‐based therapies is hindered due to loss of MSC regenerative properties during large‐scale expansion and low survival/retention post‐delivery. These limitations might be overcome by designing hydrogel culture platforms to modulate the MSC microenvironment. Hydrogel systems could be engineered to i) promote MSC proliferation and maintain regenerative properties (i.e., stemness and secretion) during ex vivo expansion, ii) improve MSC survival, retention, and engraftment in vivo, and/or iii) direct the MSC secretory profile using tailored biochemical and biophysical cues. Herein, it is reviewed how hydrogel material properties (i.e., matrix modulus, viscoelasticity, dimensionality, cell adhesion, and porosity) influence MSC secretion, mediated through cell–matrix and cell–cell interactions. In addition, it is highlighted how biochemical cues (i.e., small molecules, peptides, and proteins) can improve and direct the MSC secretory profile. Last, the authors’ perspective is provided on future work toward the understanding of how microenvironmental cues influence the MSC secretome, and designing the next generation of biomaterials, with optimized biophysical and biochemical cues, to direct the MSC secretory profile for improved clinical translation outcomes.

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