Dr. Thomas is an Assistant Investigator at Vitalant Research Institute (VRI) Denver. The overall goal of her research program is to improve precision transfusion medicine by providing patients with blood products that meet their specific needs. She applies approaches learned from her molecular and cellular immunology background to answer questions plaguing the transfusion medicine field. Dr. Thomas completed her B.S. in Biochemistry and Molecular Biology at a small liberal arts college, where she had over 3 years of hands-on molecular lab experience. This was followed by her Ph.D. in Immunology/Microbiology at the University of Alabama, Birmingham where she characterized the expression and function of a unique receptor in the TREM family found on circulating leukocytes. This led her to a postdoctoral position at UCLA in the field of alloimunity, where she studied the combinatorial effects of adaptive (antibodies) and innate (complement) immunity at the endothelial surface – the barrier between the donor organ and the recipient’s immune system. These experiences in the vascular space provided the groundwork for her next step into the field of transfusion medicine, where for the past 5 years, she has been studying the hemostatic, immune, and endothelial response to blood product transfusion.
Kimberly A. Thomas, Ph.D.
Vitalant Research Institute
717 Yosemite Street
Denver, CO 80230
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Our research program focuses identifying and leveraging differences in blood product manufacturing and storage, with an emphasis on platelets, to meet the specific needs of patients receiving transfusions. As platelets play important roles in hemostasis, immune function, and vascular maintenance, their transfusion can serve varying purposes depending on the bleeding etiology of a patient. Platelet transfusions can usually be categorized as either prophylactic (e.g., to prevent bleeding by promoting vascular integrity) or therapeutic (e.g., to stop active bleeding by forming clots). Notably, alterations in the manufacturing (e.g., pathogen reduction) and storage (e.g., room temperature vs cold) of platelet products can lead to differences in platelet function. This leads to the question: do certain platelet product manufacturing and/or storage conditions promote unique functional profiles that will meet the specific needs of a given bleeding patient population?
Using both in vitro and in vivo models, we aim to (i) identify the mechanisms regulating transfused platelet function during specific pathophysiologies and (ii) determine which manufacturing/storage practices improve hemostatic, immune, and endothelial function after transfusion in each bleeding etiology. Our ultimate goal is to inform and direct the field of personalized transfusion medicine, thereby having a positive impact on the lives of patients receiving transfusions.
Cold-stored platelets (CS-PLT) exhibit phenotypes representative of multiple endogenous platelet subpopulations (activated/adherent, aged/apoptotic, or procoagulant) that may be beneficial for actively bleeding patients, yet the mechanisms regulating the development of this hybrid phenotype/hemostatic function during storage have yet to be established. As endogenous platelet phenotypes are regulated by metabolic activity and mitochondrial function, our working hypothesis is that the CS-PLT hybrid phenotype is directly related to the cold storage-induced alterations of platelet metabolism. To test this hypothesis, we have partnered with Dr. Angelo D’Alessandro and Dr. Julie Haines (CU-Anschutz) to perform comprehensive metabolic, phenotypic, and functional profiling of CS-PLT. We found that (i) cold storage preserved key metabolic pathways used by platelets during activation and aggregation, and (ii) CS-PLT adhered to collagen more readily under arterial shear than room temperature stored platelets (RT-PLT) and maintained the ability to form clot over the course of storage. Integration of our metabolic data with phenotypic and functional findings identified key metabolic pathways associated with CS-PLT clot formation. Interestingly, some of these metabolites are known to play a role in modulating mitochondrial function in nucleated cells, however, the contributions of these metabolites to both endogenous platelet and platelet product hemostatic function are relatively unknown. We are currently exploring these areas of research, with a focus on metabolic supplementation of stored platelet products and subsequent alterations in hemostatic function.
To improve platelet product safety, the FDA is requesting implementation of pathogen reduction (PR) technologies on all platelet collections by October 2021. We and others have shown PR has minimal effects on platelet hemostatic function, yet there is contradictory evidence on whether PR promotes alloimmunization. Although platelets are most well-known for their hemostatic function, they also play important roles in pathogen sensing and modulation of innate and adaptive immunity, including antigen presentation. Moreover, platelets are the most allogeneic of all transfused blood products due to the number of polymorphic molecules they express – human platelet antigens (HPA), human leukocyte antigens (HLA), and ABO blood group antigens. This project addresses the urgent need to understand the immune consequences of platelet manufacturing, a significant issue for sensitized patients receiving multiple platelet transfusions. Using PR platelet products and both in vitro and in vivo models, we aim to address how rates of alloimmunization, antigen persistence, and the functional role of platelet:leukocyte aggregates are altered in response to changes in platelet product manufacturing and storage. Long term goals of this project are to determine key molecules involved in maintaining vascular integrity in thrombocytopenic patients versus those key molecules promoting immunogenicity; this will allow for identification of targetable mechanisms to maintain hemostatic function, but limit alloimmune responses after platelet transfusion.
Dysregulation and/or injury of the vasculature, referred to as endotheliopathy, manifests in a disease-specific fashion. The two different platelet transfusion recipient populations outlined above (prophylactic vs. therapeutic) have disparate endotheliopathies which are not well defined. In actively bleeding patients (e.g., hemorrhagic shock), the vasculature is physically damaged, and there is endothelial dysfunction, dysregulated coagulation, and inflammation – collectively referred to as the endotheliopathy of trauma, or EOT. Blood product transfusion is the main source of therapeutic management of hemorrhagic shock, with recent literature suggesting that plasma transfusion is associated with improved endothelial function. Platelets are traditionally transfused to support clot formation in actively bleeding patients, but also possess additional vascular related functions, as described in non-trauma publications: release of soluble mediators to support endothelial function and growth, physical engagement with endothelial cells to restore barrier function, and recruitment and maintenance of endothelial progenitor cells. However, the molecular mechanisms by which platelet transfusions may improve EOT remain poorly understood. We couple microfluidic devices with real time fluorescence microscopy to better understand stored platelet:endothelial interactions under physiologically relevant flow conditions and in the context of the vascular milieu associated with traumatic injury. These studies are focused on identifying key molecular interactions that promote vascular integrity and reduce inflammation, key features of EOT, that may be attributable to or associated with distinct platelet manufacturing and storage conditions.