@article{sheridan_nellenbach_pandit_byrnes_hardy_lutz_moiseiwitsch_scull_mihalko_levy_et al._2024, title={Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications}, volume={6}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.4c00162}, abstractNote={Disseminated intravascular coagulation (DIC) is a pathologic state that follows systemic injury and other diseases. Often a complication of sepsis or trauma, DIC causes coagulopathy associated with paradoxical thrombosis and hemorrhage. DIC upregulates the thrombotic pathways while simultaneously downregulating the fibrinolytic pathways that cause excessive fibrin deposition, microcirculatory thrombosis, multiorgan dysfunction, and consumptive coagulopathy with excessive bleeding. Given these opposing disease phenotypes, DIC management is challenging and includes treating the underlying disease and managing the coagulopathy. Currently, no therapies are approved for DIC. We have developed clot-targeted therapeutics that inhibit clot polymerization and activate clot fibrinolysis to manage DIC. We hypothesize that delivering both an anticoagulant and a fibrinolytic agent directly to clots will inhibit active clot polymerization while also breaking up pre-existing clots; therefore, reversing consumptive coagulopathy and restoring hemostatic balance. To test this hypothesis, we single- and dual-loaded fibrin-specific nanogels (FSNs) with antithrombinIII (ATIII) and/or tissue plasminogen activator (tPA) and evaluated their clot preventing and clot lysing abilities in vitro and in a rodent model of DIC. In vivo, single-loaded ATIII-FSNs decreased fibrin deposits in DIC organs and reduced blood loss when DIC rodents were injured. We also observed that the addition of tPA in dual-loaded ATIII-tPA-FSNs intensified the antithrombotic and fibrinolytic mechanisms, which proved advantageous for clot lysis and restoring platelet counts. However, the addition of tPA may have hindered wound healing capabilities when an injury was introduced. Our data supports the benefits of delivering both anticoagulants and fibrinolytic agents directly to clots to reduce the fibrin load and restore hemostatic balance in DIC.}, journal={ACS NANO}, author={Sheridan, Anastasia and Nellenbach, Kimberly and Pandit, Sanika and Byrnes, Elizabeth and Hardy, Grace and Lutz, Halle and Moiseiwitsch, Nina and Scull, Grant and Mihalko, Emily and Levy, Jerrold and et al.}, year={2024}, month={Jun} }
 @article{nellenbach_mihalko_nandi_koch_shetty_moretti_sollinger_moiseiwitsch_sheridan_pandit_et al._2024, title={Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma}, volume={16}, ISSN={["1946-6242"]}, DOI={10.1126/scitranslmed.adi4490}, abstractNote={Uncontrolled bleeding after trauma represents a substantial clinical problem. The current standard of care to treat bleeding after trauma is transfusion of blood products including platelets; however, donated platelets have a short shelf life, are in limited supply, and carry immunogenicity and contamination risks. Consequently, there is a critical need to develop hemostatic platelet alternatives. To this end, we developed synthetic platelet-like particles (PLPs), formulated by functionalizing highly deformable microgel particles composed of ultralow cross-linked poly (N-isopropylacrylamide) with fibrin-binding ligands. The fibrin-binding ligand was designed to target to wound sites, and the cross-linking of fibrin polymers was designed to enhance clot formation. The ultralow cross-linking of the microgels allows the particles to undergo large shape changes that mimic platelet shape change after activation; when coupled to fibrin-binding ligands, this shape change facilitates clot retraction, which in turn can enhance clot stability and contribute to healing. Given these features, we hypothesized that synthetic PLPs could enhance clotting in trauma models and promote healing after clotting. We first assessed PLP activity in vitro and found that PLPs selectively bound fibrin and enhanced clot formation. In murine and porcine models of traumatic injury, PLPs reduced bleeding and facilitated healing of injured tissue in both prophylactic and immediate treatment settings. We determined through biodistribution experiments that PLPs were renally cleared, possibly enabled by ultrasoft particle properties. The performance of synthetic PLPs in the preclinical studies shown here supports future translational investigation of these hemostatic therapeutics in a trauma setting.}, number={742}, journal={SCIENCE TRANSLATIONAL MEDICINE}, author={Nellenbach, Kimberly and Mihalko, Emily and Nandi, Seema and Koch, Drew W. and Shetty, Jagathpala and Moretti, Leandro and Sollinger, Jennifer and Moiseiwitsch, Nina and Sheridan, Ana and Pandit, Sanika and et al.}, year={2024}, month={Apr} }
 @article{moiseiwitsch_nellenbach_downey_boorman_brown_guzzetta_2023, title={Influence of Fibrinogen Concentrate on Neonatal Clot Structure When Administered Ex Vivo After Cardiopulmonary Bypass}, volume={137}, ISSN={0003-2999}, url={http://dx.doi.org/10.1213/ANE.0000000000006357}, DOI={10.1213/ANE.0000000000006357}, abstractNote={
            BACKGROUND:
            Bleeding is a serious complication of cardiopulmonary bypass (CPB) in neonates. Blood product transfusions are often needed to adequately restore hemostasis, but are associated with significant risks. Thus, neonates would benefit from other effective, and safe, hemostatic therapies. The use of fibrinogen concentrate (FC; RiaSTAP, CSL Behring, Marburg, Germany) is growing in popularity, but has not been adequately studied in neonates. Here, we characterize structural and degradation effects on the neonatal fibrin network when FC is added ex vivo to plasma obtained after CPB.
          }, number={3}, journal={Anesthesia & Analgesia}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Moiseiwitsch, Nina and Nellenbach, Kimberly A. and Downey, Laura A. and Boorman, David and Brown, Ashley C. and Guzzetta, Nina A.}, year={2023}, month={Jan}, pages={682–690} }
 @article{moiseiwitsch_zwennes_szlam_sniecinski_brown_2022, title={COVID‐19 patient fibrinogen produces dense clots with altered polymerization kinetics, partially explained by increased sialic acid}, volume={20}, ISSN={1538-7836}, url={http://dx.doi.org/10.1111/jth.15882}, DOI={10.1111/jth.15882}, abstractNote={Thrombogenicity is a known complication of COVID‐19, resulting from SARS‐CoV‐2 infection, with significant effects on morbidity and mortality.}, number={12}, journal={Journal of Thrombosis and Haemostasis}, publisher={Elsevier BV}, author={Moiseiwitsch, Nina and Zwennes, Nicole and Szlam, Fania and Sniecinski, Roman and Brown, Ashley}, year={2022}, month={Dec}, pages={2909–2920} }
 @article{moiseiwitsch_nellenbach_guzzetta_brown_downey_2021, title={Ex Vivo and In Vivo Evaluation of Fibrinogen Concentrate to Mitigate Post-Surgical Bleeding in Neonates}, volume={138}, ISSN={["1528-0020"]}, DOI={10.1182/blood-2021-153823}, abstractNote={Abstract}, journal={BLOOD}, author={Moiseiwitsch, Nina and Nellenbach, Kimberly A. and Guzzetta, Nina A. and Brown, Ashley C. and Downey, Laura}, year={2021}, month={Nov} }
 @article{mihalko_nellenbach_krishnakumar_moiseiwitsch_sollinger_cooley_brown_2021, title={Fibrin‐specific <scp>poly(N‐isopropylacrylamide)</scp> nanogels for targeted delivery of tissue‐type plasminogen activator to treat thrombotic complications are well tolerated in vivo}, volume={7}, ISSN={2380-6761 2380-6761}, url={http://dx.doi.org/10.1002/btm2.10277}, DOI={10.1002/btm2.10277}, abstractNote={Abstract}, number={2}, journal={Bioengineering & Translational Medicine}, publisher={Wiley}, author={Mihalko, Emily P. and Nellenbach, Kimberly and Krishnakumar, Manasi and Moiseiwitsch, Nina and Sollinger, Jennifer and Cooley, Brian C. and Brown, Ashley C.}, year={2021}, month={Dec} }
 @article{moiseiwitsch_brown_2021, title={Neonatal coagulopathies: A review of established and emerging treatments}, volume={246}, ISSN={1535-3702 1535-3699}, url={http://dx.doi.org/10.1177/15353702211006046}, DOI={10.1177/15353702211006046}, abstractNote={ Despite the relative frequency of both bleeding and clotting disorders among patients treated in the neonatal intensive care unit, few clear guidelines exist for treatment of neonatal coagulopathies. The study and treatment of neonatal coagulopathies are complicated by the distinct hemostatic balance and clotting components present during this developmental stage as well as the relative scarcity of studies specific to this age group. This mini-review examines the current understanding of neonatal hemostatic balance and treatment of neonatal coagulopathies, with particular emphasis on emerging treatment methods and areas in need of further investigative efforts. }, number={12}, journal={Experimental Biology and Medicine}, publisher={Frontiers Media SA}, author={Moiseiwitsch, Nina and Brown, Ashley C}, year={2021}, month={Apr}, pages={1447–1457} }