Frederik Denorme

University of Utah | UOU · Department of Molecular Medicine

Introduction Neutrophil extracellular traps (NETs) clear pathogens but may contribute Q8 pathogenically to host inflammatory tissue damage during sepsis. Innovative therapeutic agents targeting NET formation and their potentially harmful collateral effects remain understudied. Methods We investigated a novel therapeutic agent, neonatal NET-Inhibit...

Non-acute subdural hematomas (NASHs) are a cause of significant morbidity and mortality, particularly with recurrences. Although recurrence is believed to involve a disordered neuroinflammatory cascade involving vascular endothelial growth factor (VEGF), this pathway has yet to be completely elucidated. Neutrophil extracellular traps (NETs) are key...

Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We examined if non-viral sepsis induces differential platelet gene expression and reactivity. Non-viral sepsis upregulated IFITM3, an inter...

Platelets play a key role in maintaining hemostasis. However, dysregulated platelet activation can lead to pathological thrombosis or bleeding. Once a platelet gets activated, it will either become an aggregatory platelet or eventually a procoagulant platelet with both types playing distinct roles in thrombosis and hemostasis. While aggregatory pla...

The MAPK-interacting kinase (Mnk) family includes Mnk1 and Mnk2, which are phosphorylated and activated in response to extracellular stimuli. Mnk1 contributes to cellular responses by regulating mRNA translation and mRNA translation influences platelet production and function. However, the role of Mnk1 in megakaryocytes and platelets has not previo...

Background: Treatment of neonatal peritonitis and sepsis is challenging. Following infection, neutrophils elaborate neutrophil extracellular traps (NETs)-extracellular lattices of decondensed chromatin decorated with antimicrobial proteins. NETs, however, can augment pathogenic inflammation causing collateral damage. We hypothesized that NET inhib...

Large-vessel occlusion is rare in children, but its results can be devastating and may lead to recurrent strokes, persistent neurological deficits, and decreased quality of life. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has yielded extrapulmonary effects and multiorgan diseases, many of which are neurological manifestations. The...

Ischemic stroke prompts a strong inflammatory response which is associated with exacerbated outcomes. In this study, we investigated mechanistic regulators of neutrophil extracellular trap (NET) formation in stroke and if they contribute to stroke outcomes. NET forming neutrophils were found throughout brain tissue of ischemic stroke patients and e...

Rationale: Ischemic stroke prompts an inflammatory response which is associated with worse outcomes. Classic anti-inflammatory strategies were unsuccessful in clinical trials, implying other mechanisms contribute to injurious inflammation in stroke. In response to stimuli, neutrophils can release DNA web-like structures called neutrophil extracellu...

Coagulopathy and platelet hyperactivity are hallmarks of coronavirus disease 2019 (COVID-19) and contribute to an increased thrombotic burden observed in many COVID-19 patients. Anticoagulation and/or anti-platelet drugs are actively pursued in clinical trials aimed at improving outcomes in COVID-19 patients. However, while a consensus exists on th...

Platelet-neutrophil interactions regulate ischemic vascular injury. Platelets are activated by serine proteases that cleave protease activated receptor (PAR) amino-termini, resulting in an activating tethered ligand. Neutrophils release cathepsin G (CatG) at sites of injury and inflammation, which activates PAR4 but not PAR1, although the molecular...

Background: Cerebral malaria is a highly prevalent infectious disease in Sub-Saharan Africa caused by the Plasmodium parasite. The pathogenesis of cerebral malaria results from damaged vascular endothelium induced by parasite sequestration, inflammatory cytokine production and vascular leakage, which results in increased brain permeability and deat...

Genome wide association studies (GWAS) have associated mitochondria related loci with platelet numbers, function, and CVD. However, causality has not been established for many of these variants, and their mechanism and functional consequences are unknown. One such variant, MFN2 eQTL rs1474868 (T/T), has been associated with reduced platelet counts...

Background: Ischemic stroke provokes a strong inflammatory response which has been shown to exacerbate ischemic stroke brain injury in mice and is associated with worse outcomes in ischemic stroke patients. Classic anti-inflammatory strategies have been unsuccessful in clinical trials for ischemic stroke, implying other mechanisms contribute to inj...

The purpose of this research was to assess the effects of a microRNA (miRNA) cluster on platelet production. Human chromosome 19q13.41 harbors an evolutionarily conserved cluster of three miRNA genes (MIR99B, MIRLET7E, MIR125A) within 727 base-pairs. We now report that levels of miR-99b-5p, miR-let7e-5p and miR-125a-5p are strongly correlated in hu...

Chronic subdural hematomas (CSDH) are an increasingly common pathology encountered in a neurosurgical trauma practice. Although the operative and nonoperative management of CSDH has been studied extensively, the recurrence rate of CSDH remains high, with no significant decrease in recent years. We undertook a detailed assessment of the known pathop...

Ischemic stroke prompts a strong inflammatory response which is associated with exacerbated stroke outcomes. However, classic anti-inflammatory strategies have been unsuccessful in stroke patients implying other unknown mechanisms contribute to injurious inflammation in stroke. Increasing evidence suggests immunothrombosis, a process involving coag...

Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness as in the case of seps...

Purpose of review: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2. Over the past year, COVID-19 has posed a significant threat to global health. Although the infection is associated with mild symptoms in many patients, a significant proportion of patients develop a prothrombot...

Neutrophil extracellular traps (NETs) are important components of innate immunity. Neonatal neutrophils (PMNs) fail to form NETs due to circulating NET-Inhibitory Peptides (NIPs) -cleavage fragments of alpha-1-antitrypsin (A1AT). However, how fetal and neonatal blood NIPs are generated remains unknown. The placenta expresses High-Temperature Requir...

Purpose of review: In this review, we will describe how the combined ability of platelets and neutrophils to interact with each other drives ischemic stroke brain injury. Recent findings: Neutrophils are one of the first cells to respond during ischemic stroke. Although animals stroke models have indicated targeting neutrophils improves outcomes...

Background Coronavirus disease 2019 (COVID-19) is associated with activation of coagulation that mainly presents as thrombosis. Sepsis is also associated with activation of coagulation that mainly presents as disseminated intravascular coagulation. Many studies have reported increased levels of plasma D-dimer in patients with COVID-19 that is assoc...

Circulating platelets interact with leukocytes to modulate host immune and thrombotic responses. In sepsis, platelet-leukocyte interactions are increased, and have been associated with adverse clinical events, including increased platelet-T cell interactions. Sepsis is associated with reduced CD8+ T cell numbers and functional responses, but whethe...

As a result of the coronavirus disease 2019 pandemic, the International Society on Thrombosis and Haemostasis (ISTH), like many societies around the world, canceled their in‐person hematology congress planned for Milan, Italy, in July 2020. As a result, the first virtual ISTH congress in the organisation’s 51‐year history was delivered, inviting fr...

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with derangement in biomarkers of coagulation and endothelial function and has been likened to the coagulopathy of sepsis. However, clinical laboratory metrics suggest key differences in these pathologies. We sought to determine whether plasma coagulation and fibrinolytic potential in pat...

Human platelets express two thrombin-activated G-protein coupled receptors, PAR1 and PAR4, that activate upon protease cleavage of the amino-terminus of the receptor. Thrombin induces rapid and transient platelet activation through PAR1, while PAR4 mediates slower and sustained activation, as well as greater phosphatidylserine (PS) exposure and thr...

Objective Hyperglycemia is a common comorbidity for ischemic stroke and is associated with worsened neurological outcomes. Platelets are central mediators of ischemic stroke and hyperglycemia mediates platelet hyperactivity. In this study, we investigated the contribution of platelet glucose metabolism to ischemic stroke. Methods Mice lacking both...

Background: Emerging evidence implicates dysfunctional platelet responses in thrombotic complications in COVID-19 patients. Platelets are important players in inflammation-induced thrombosis. In particular, procoagulant platelets support thrombin generation and mediate thromboinflammation. Objectives: To examine if procoagulant platelets formati...

COVID-19 affects millions of patients worldwide with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens and can trigger immunothrombosis. We studied the connectio...

There is an urgent need to understand the pathogenesis of coronavirus disease 2019 (COVID-19). In particular, thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated w...

von Willebrand factor (VWF) plays an important role in ischemic stroke. However, the exact mechanism by which VWF mediates progression of ischemic stroke brain damage is not completely understood. Using flow cytometric analysis of single cell suspensions prepared from brain tissue and immunohistochemistry, we investigated the potential inflammatory...

Rationale: Besides their role in thrombosis, platelets also mediate inflammation through platelet-neutrophil aggregates (PNA). Recently, cyclophilin D (CypD)-mediated platelet necrosis emerged as a potential mediator of detrimental PNA during thrombosis. However, the role of platelet CypD in ischemic stroke has never been examined. Objective: Here,...

Platelets play critical roles in maintaining hemostasis. Dysregulated platelet functions contribute to both the development and progression of ischemic stroke. Utilizing mice with a platelet-specific deletion of cyclophilin D (CypD), a mediator of necrosis, we found that platelet necrosis regulates tissue damage and outcomes during ischemic stroke...

von Willebrand factor (VWF) and platelets are key mediators of normal hemostasis. At sites of vascular injury, VWF recruits platelets via binding to the platelet receptor glycoprotein Ibα (GPIbα). Over the past decades, it has become clear that many hemostatic factors, including VWF and platelets, are also involved in inflammatory processes, formin...

Background: Anti-platelet agents are used clinically to prevent ischemic stroke but are incompletely effective. Emerging evidence highlights that platelets contribute to ischemic stroke through mechanisms and pathways that are not targeted by classic anti-platelet agents. Besides their role in thrombosis, platelets also mediate inflammation through...

The recent advent of endovascular procedures has created the unique opportunity to collect and analyze thrombi removed from cerebral arteries, instigating a novel subfield in stroke research. Insights into thrombus characteristics and composition could play an important role in ongoing efforts to improve acute ischemic stroke therapy. An increasing...

Ischemic stroke is caused by a thromboembolic occlusion of cerebral arteries. Treatment is focused on fast and efficient removal of the occluding thrombus, either via intravenous thrombolysis or via endovascular thrombectomy. Recanalization, however, is not always successful and factors contributing to failure are not completely understood. Althoug...

Rationale: Acute increases the risk for stroke and adverse outcomes following stroke, such as disability and death. Aging is characterized by increased circulating inflammatory agonists, including interferons (IFNs), and hyperactive platelets. However, whether IFNs generated during aging enhance platelet activation to promote ischemic stroke remain...

Rationale: Platelets are critical cellular effectors in the development of ischemic stroke. Translational control pathways, such as the mammalian target of rapamycin (mTOR), are active in platelets, and can be targeted therapeutically, but have not been examined in stroke. Objective: To determine if activation of the mTOR pathway regulates platelet...

Background: ADAMTS13 circulates in a closed conformation, only achieving full proteolytic activity against von Willebrand Factor (VWF) following a substrate-induced conformational change. A gain of function (GoF) ADAMTS13 variant (R568K/F592Y/R660K/Y661F/Y665F) is conformationally pre-activated. Objectives: To establish how the hyperactivity of...

Objective: Neutrophil extracellular traps (NETs) have been shown to promote thrombus formation. Little is known about the exact composition of thrombi that cause ischemic stroke. In particular no information is yet available on the presence of NETs in cerebral occlusions. Such information is however essential to improve current thrombolytic therap...

Von Willebrand Factor (VWF) plays a major role in thrombosis and hemostasis and its thrombogenicity is controlled by ADAMTS13. Whereas increasing evidence shows a clear association between VWF levels and acute ischemic stroke, little is known about a correlation with ADAMTS13. Therefore, the aim of this study was to compare plasma levels of ADAMTS1...

Raw de-identified dataset. For sex: 1 indicates male, 2 indicates female; for modality: 1 indicates TIA, 2 indicates stroke. (XLSX)

Correlation analysis between ADAMTS13 and VWF levels. A spearman correlation analysis was performed for the healthy volunteers (A), the chronic cerebrovascular disease patients (B) and on day 0 in the acute stroke patients (C). No correlation was found between plasma ADAMTS13 and VWF antigen levels. (TIFF)

Time point of blood withdrawal did not influence ADAMTS13 levels or VWF:ADAMTS13 ratio in acute stroke patients. Levels of ADAMTS13 were plotted as a percentage of the level in a normal human plasma pool (NHP), consisting of pooled plasma from 20 healthy donors. VWF levels were measured previously and were used to calculate the VWF:ADAMTS13 ratios....

Full GARP knockout mice are not viable. Mice with the Cmv promotor driven Cre recombinase were crossed with Garpfl/fl mice in the first generation. Garpfl/-Cre+/- mice were backcrossed with Garpfl/fl mice to generate full Garp knockout mice. (A) Genotypic analysis of genomic DNA from neonates from the second generation, Floxed allele is 670 bp (fl/...

Background Glycoprotein-A Repetitions Predominant protein (GARP or LRRC32) is present on among others human platelets and endothelial cells. Evidence for its involvement in thrombus formation was suggested by full knockout of GARP in zebrafish. Objectives To evaluate the role of GARP in platelet physiology and in thrombus formation using platelet a...

Background and purpose: Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of isc...

Stroke is a leading cause of death and long-term disability worldwide. Ischaemic stroke is caused by a blood clot that obstructs cerebral blood flow. Current treatment mainly consists of achieving fast reperfusion, either via pharmacological thrombolysis using tissue plasminogen activator or via endovascular thrombectomy. Unfortunately, reperfusion...

Rapid vascular recanalization forms the basis for successful treatment of cerebral ischemia. Currently, tissue plasminogen activator (t-PA) is the only approved thrombolytic drug for ischemic stroke. However, t-PA does not always result in efficient thrombus dissolution and subsequent blood vessel recanalization. To better understand thrombus compo...

The main goal of ischemic stroke treatment is rapid recanalization of the occluded blood vessel to limit brain injury and to salvage threatened cerebral tissue. To achieve early vessel recanalization, thrombolysis using recombinant tissue-type plasminogen activator is currently the only approved pharmacological intervention. Only recently, endovasc...

Von Willebrand factor (VWF) is a key hemostatic protein synthesized in both endothelial cells and megakaryocytes. Megakaryocyte-derived VWF is stored in α-granules of platelets and is enriched in hyperactive 'ultra-large' VWF multimers. To elucidate the specific contribution of platelet VWF in hemostasis and thrombosis we performed crossed bone mar...

Background: Currently, thrombolysis using tissue-plasminogen activa- tor is the only treatment option in acute ischemic stroke, but it has serious limitations. By cleaving von Willebrand factor, the metalloprotease ADAMTS13 has both antithrombotic and anti-inflammatory properties. Aims: In this study, we analyzed whether ADAMTS13 can pro- mote t...

Background: Cerebral ischemia/reperfusion injury is associated with activation of the blood coagulation cascade and fibrin deposition in cerebral microvessels. Endogenous tissue plasminogen activator (tPA)-mediated fibrinolysis is attenuated by thrombin activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1). Activat...

Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic a...