Steven Philip Grover

Steven Philip Grover
University of North Carolina at Chapel Hill | UNC · Blood Research Center

PhD

About

92
Publications
10,691
Reads
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2,956
Citations
Introduction
My research is aimed at identifying novel mechanisms responsible for pathological activation of coagulation and venous thromboembolism. I hope that a better understanding of underlying mechanism will enable identification of at risk populations and new targets for the development of safe and effective anticoagulants. The contact pathway of coagulation and its major negative regulator C1 inhibitor are a major focus of my current efforts.
Additional affiliations
July 2017 - October 2022
University of North Carolina at Chapel Hill
Position
  • Postdoctoral Fellow
March 2015 - June 2017
Beth Israel Deaconess Medical Center
Position
  • Fellow
October 2011 - February 2015
King's College London
Position
  • PhD Student
Education
October 2011 - September 2014
King's College London
Field of study
  • Cardiovascular Medical Research
October 2010 - October 2011
King's College London
Field of study
  • Cardiovascular Science
September 2006 - July 2009
The University of Manchester
Field of study
  • Biochemistry

Publications

Publications (92)
Article
Full-text available
The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa–initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further in...
Article
Full-text available
Background The intrinsic pathway factors (F) XII and FXI have been shown to contribute to thrombosis in animal models. We assessed the role of FXII and FXI in venous thrombosis in three distinct mouse models. Methods Venous thrombosis was assessed in mice genetically deficient for either FXII or FXI. Three models were used: the inferior vena cava...
Article
Full-text available
Thrombin generation (TG) assays serve as valuable tools to study the amplifying roles of intrinsic pathway factors in human coagulation and provide functional insight into the increased bleeding observed in individuals deficient in factors (F) XI, IX or VIII. Mice are used extensively in hemostasis research due to the availability of coagulation fa...
Article
C1 inhibitor (C1INH) is a multifunctional serine protease inhibitor that functions as a major negative regulator of several biological pathways, including the contact pathway of blood coagulation. In humans, congenital C1INH deficiency results in a rare episodic bradykinin-mediated swelling disorder called hereditary angioedema (HAE). Patients with...
Article
Full-text available
Background: C1-inhibitor (C1INH) is a broad acting serine protease inhibitor with anticoagulant activity. The impact of C1INH plasma levels within the normal physiological range on risk of venous thromboembolism (VTE) is unknown. We assessed the association of plasma C1INH levels and VTE risk, and evaluated the impact of C1INH on thrombin and plas...
Article
Contact pathway inhibitors are emerging as potential therapies for venous thromboembolism with favorable bleeding risk compared to conventional agents. However, the relative importance of individual coagulation zymogens to contact pathway-initiated coagulation is unknown. Prior studies have been limited to evaluating associations between contact an...
Article
Background: Hereditary angioedema (HAE) is a rare condition caused by autosomal dominant mutations in SERPING1 that result in deficiency or dysfunction of its gene product, C1 inhibitor (C1INH). C1INH is the main physiologic inhibitor of several contact pathway constituents, including factors XI, XII, and plasma kallikrein. Although accepted wisdom...
Article
Background: Inhibition of factor XII (FXII, gene: F12) represents a potentially transformative approach to antithrombotic therapy, as severe congenital deficiency in humans is not associated with bleeding while deletion or inhibition of FXII in preclinical models consistently protects against thrombosis. However, the impact of FXII deficiency on ve...
Article
C1-inhibitor deficiency–associated hereditary angioedema (C1INH-HAE) is a rare congenital swelling disorder caused by mutations in the SERPING1 gene. Despite evidence of a systemic procoagulant state in C1INH-HAE, dogma held that this disorder was not associated with thrombotic pathologies. Recent population scale epidemiological evidence has direc...
Article
Hereditary angioedema (HAE) due to C1 inhibitor protein (C1-INH) deficiency was recently shown to be associated with increased risk of venous thromboembolism (VTE). This is the first national family study of HAE with the aim to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Regis...
Article
C1 inhibitor (C1INH) functions as a key endogenous inhibitor of contact pathway coagulation factors XII, XI and plasma kallikrein (PKa). Patients with a congenital deficiency in C1INH suffer from a rare swelling disorder called hereditary angioedema (HAE) caused by excess bradykinin generation. Patients with HAE also have elevated circulating level...
Article
Full-text available
Plasma kallikrein (PKa) is an important activator of factor (F)XII of the contact pathway of coagulation. Several studies have shown that PKa also possesses procoagulant activity independent of FXII, likely through its ability to directly activate FIX. We evaluated the procoagulant activity of PKa using a mouse whole blood (WB) thrombin generation...
Article
Background: Coagulation factor XII (FXII) has drawn significant attention as a potential drug target due to the observation that severe congenital deficiency in FXII is not associated with bleeding, while deletion or inhibition of FXII in pre-clinical models consistently protects against thrombosis. However, the contribution of FXII to thrombosis i...
Article
Individuals with sickle cell trait (SCT) are heterozygous carriers of the sickle beta-globin gene. Systematic analyses of large cohort studies over the past decade have established that SCT is a risk factor for a limited number of complications, most notably chronic kidney disease (CKD) and venous thrombosis (VT). SCT red blood cells (RBCs) can und...
Article
Background: There has been considerable interest in the collagen-specific chaperone HSP47 ( SERPINH1) as a potential drug target for the treatment of cirrhosis, fibrotic disease, and more recently, thrombosis (Thienel et al., Science 380, 178-187, 2023). While homozygous or compound heterozygous loss of function in SERPINH1 is known to cause a rare...
Article
Introduction: Hereditary Angioedema (HAE) is a rare congenital disorder primarily caused by mutations in the SERPING1 gene that results in C1 inhibitor (C1INH) deficiency or dysfunction. C1INH is a multifunctional serine protease inhibitor that functions as a major endogenous negative regulator of the kallikrein-kinin, contact pathway of coagulatio...
Article
Cancer patients have increased thrombosis and bleeding compared with the general population. Cancer is associated with activation of both platelets and coagulation. Mouse models have been used to study the dysregulation of platelets and coagulation in cancer. We established a mouse model of pancreatic cancer in which tissue factor-expressing human...
Article
Full-text available
The chemotherapeutic drug doxorubicin is cardiotoxic and can cause irreversible heart failure. In addition to being cardiotoxic, doxorubicin also induces activation of coagulation. We determined the effect of thrombin-mediated activation of protease-activated receptor 1 (PAR1) on doxorubicin-induced cardiac injury. Administration of doxorubicin to...
Article
Full-text available
Appropriate activation of coagulation requires a balance between procoagulant and anticoagulant proteins in blood. Loss in this balance leads to hemorrhage and thrombosis. A number of endogenous anticoagulant proteins, such as antithrombin and heparin cofactor II, are members of the serine protease inhibitor (SERPIN) family. These SERPIN anticoagul...
Article
Background and aims The platelet inhibitor aspirin reduces inflammation and atherosclerosis in both apolipoprotein E deficient (apoE−/−) mice and low-density lipoprotein receptor deficient (Ldlr−/−) mice. Similarly, the factor Xa inhibitor rivaroxaban reduces atherosclerosis in both apoE−/− and Ldlr−/− mice. We tested the hypothesis that the combin...
Article
Introduction: Protease-activated receptor 4 (PAR4) is expressed by a wide variety of cells, including megakaryocytes/platelets, immune cells, cardiomyocytes and lung epithelial cells, and activated by multiple ligands including thrombin and cathepsin G. Importantly, PAR4 is the only functional thrombin receptor on murine platelets. A global deficie...
Article
Background Protease-activated receptor 4 (PAR4) is expressed by a wide variety of cells, including megakaryocytes/platelets, immune cells, cardiomyocytes and lung epithelial cells. It is the only functional thrombin receptor on murine platelets. A global deficiency of PAR4 is associated with impaired hemostasis and reduced thrombosis. Objective Ge...
Article
Factor (F) XII and FXI play a central role in venous thrombus formation in preclinical disease models and contributes to venous thromboembolism (VTE) in humans. Agents targeting FXIa have been developed and effectively prevent VTE in humans. C1 esterase inhibitor (C1INH) is a serine protease inhibitor that inhibits several proteases, including FXII...
Article
Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TF‐expressing cells also release TF‐positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that anal...
Article
Full-text available
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...
Article
Full-text available
Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for...
Article
Patients with cancer have an increased risk of both arterial and venous thrombotic events compared with the general population. Both the site and stage of cancer are known to contribute to the increased risk of thrombotic events. In addition, several treatment-related factors enhance the risk of thrombosis, including hospitalization, surgery, centr...
Article
Full-text available
Pancreatic cancer patients have a high risk of venous thromboembolism (VTE). Plasminogen activator inhibitor 1 (PAI-1) inhibits plasminogen activators and increases the risk of thrombosis. PAI-1 is expressed by pancreatic tumors and human pancreatic cell lines. However, to date, there are no studies analyzing the association of active PAI-1 and VTE...
Article
Significance A thrombin-fibrin pathway drives rapid and robust bacterial killing of Staphylococcus aureus following peritoneal infection. Elimination of coagulase activity results in S. aureus protection from antimicrobial activity and a corresponding reduction in host survival. These findings provide a molecular basis for the prevalence of coagula...
Article
Full-text available
Objective Patients with coronavirus disease 2019 (COVID-19) have a high rate of thrombosis. We hypothesized that severe acute respiratory syndrome coronavirus 2 leads to induction of TF (tissue factor) expression and increased levels of circulating TF-positive extracellular vesicles (EV) that may drive thrombosis. Approach and Results We measured...
Article
Full-text available
Background The cremaster arteriole laser‐induced injury model is a powerful technique with which to investigate the molecular mechanisms that drive thrombus formation. This model is capable of direct visualization and quantification of accumulation of thrombus constituents, including both platelets and fibrin. However, a large degree of variabilit...
Article
Objective Quantitative relationships between the extent of injury and thrombus formation in vivo are not well understood. Moreover, it has not been investigated how increased injury severity translates to blood-flow modulation. Here, we investigated interconnections between injury length, clot growth, and blood flow in a mouse model of laser-induce...
Article
Atherosclerosis is a chronic inflammatory disease that is characterized by the formation of lipid rich plaques in the wall of medium to large sized arteries. Atherothrombosis represents the terminal manifestation of this pathology in which atherosclerotic plaque rupture or erosion triggers the formation of occlusive thrombi. Occlusion of arteries a...
Article
Full-text available
Background: Puumala (PUUV) orthohantavirus causes hemorrhagic fever with renal syndrome (HFRS). HFRS patients have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine if circulating extracellular vesicle tissue factor (EVTF) acti...
Article
The ferric chloride models of arterial thrombosis are useful tools with which to investigate the cellular and molecular mechanisms that contribute to arterial thrombosis. Recent insights have, however, revealed the complex and multifaceted mechanism by which ferric chloride induces thrombus formation. Here, we discuss the strengths and weaknesses o...
Article
Full-text available
Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-k...
Data
Video 1. Intravital imaging of peritoneal macrophages through the intact abdominal wall. An intravital preparation for two-photon imaging through the intact abdominal is schematically depicted. Bhlhe40GFP mice were used to visualize peritoneal macrophages, as LPMs were high expressers of GFP in this mouse model, and B cells, another numerous leukoc...
Data
Figure S1. Coagulation and adhesion additively cooperate to account for the MDR in response to inflammation. (A and B) Neutrophil numbers (A) and LPM numbers (B) in the peritoneal lavage at 3 h after zymosan injection with or without neutrophil depletion using an anti-Ly6G monoclonal antibody (1A8). (C) Neutrophil numbers in the peritoneal lavage a...
Data
Video 2. Intravital imaging of a clot after removal from a mouse 3 h after injection of GFP–E. coli. Clots were removed at 3 h after E. coli was injected i.p. and placed in a chamber for two-photon microscopy to be assessed ex vivo. Video 2 shows E. coli in green; Lyz2Cre;R26LSL-Tdtomato mice were used to reveal myeloid cells in clots that appear t...
Article
Full-text available
Pancreatic cancer is associated with high incidence of venous thromboembolism. Neutrophils have been shown to contribute to thrombosis in part by releasing neutrophil extracellular traps (NETs). A recent study showed that increased plasma levels of the NET biomarker, citrullinated histone H3 (H3Cit), are associated with venous thromboembolism in pa...
Article
Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of th...
Article
Murine models are widely used valuable tools to study deep vein thrombosis (VT). Leading experts in VT research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of VT. In this work, we provide an algorithm for model selection, with discussion of the advantages...
Article
Murine models are widely used valuable tools to study deep vein thrombosis. Leading experts in venous thrombosis research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of venous thrombosis. In this work, we provide an algorithm for model selection, with dis...
Article
Full-text available
Activation of the intrinsic pathway of coagulation contributes to the pathogenesis of arterial and venous thrombosis. Critical insights into the involvement of intrinsic pathway factors have been derived from the study of gene-specific knockout animals and targeted inhibitors. Importantly, preclinical studies have indicated that targeting component...
Article
Full-text available
Activation of the blood coagulation cascade leads to fibrin deposition and platelet activation that are required for hemostasis. However, aberrant activation of coagulation can lead to thrombosis. Thrombi can cause tissue ischemia, and fibrin degradation products and activated platelets can enhance inflammation. In addition, coagulation proteases a...
Article
Full-text available
In this issue of Blood, Yago et al¹ describe the mechanism by which neutrophils adhere to activated endothelium and enhance murine venous thrombosis through formation of neutrophil extracellular traps (NETs).
Article
Full-text available
Objective The anti-cancer anthracycline drug Doxorubicin (Dox) causes cardiotoxicity. We investigated the role of protease-activated receptor 1 (PAR-1) in Dox-induced cardiotoxicity. Methods and results In vitro experiments revealed that PAR-1 enhanced Dox-induced mitochondrial dysfunction, reactive oxygen species and cell death of cardiac myocyte...
Article
Introduction: Rivaroxaban selectively inhibits factor Xa (FXa), which plays a central role in blood coagulation. In addition, FXa activates protease-activated receptor-2 (PAR-2). We have shown that PAR-2-/- mice exhibit less cardiac dysfunction after cardiac injury. Material and methods: Wild-type (WT) and PAR-2-/- mice were subjected to left an...
Article
Full-text available
Recent studies have revealed a series of novel mechanisms that either positively or negatively regulate signaling events downstream of receptor-mediated platelet activation. In several cases, it seems that disruption of these pathways can selectively inhibit thrombosis while leaving essential hemostatic processes largely intact. These pathways may...
Article
Full-text available
Tissue factor (TF) is the high-affinity receptor and cofactor for FVII/VIIa. The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis. TF is expressed on perivascular and epithelial cells at organ and body surfaces where it forms a hemostatic barrier. TF also provides additional hemostatic protect...
Article
Full-text available
Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation (“organization”) of Prox1 hi endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc...
Article
Full-text available
Thiol isomerases such as protein disulfide isomerase (PDI) direct disulfide rearrangements required for proper folding of nascent proteins synthesized in the endoplasmic reticulum. Identifying PDI substrates is challenging since PDI catalyzes conformational changes that cannot be easily monitored (e.g., compared with proteolytic cleavage or amino a...
Article
Full-text available
Phosphodiesterase (PDE) 5 inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. Cyclic guanosine monophosphate (cGMP) binding to PKG Iα attenuates oxidant-induced disulfide formation. As PDE5 inhibition elevates cGMP and protects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG...
Article
Deep vein thrombosis and common complications, including pulmonary embolism and post-thrombotic syndrome, represent a major source of morbidity and mortality worldwide. Experimental models of venous thrombosis have provided considerable insight into the cellular and molecular mechanisms that regulate thrombus formation and subsequent resolution. He...
Article
Full-text available
Introduction: The assessment of thrombus size following treatments directed at preventing thrombosis or enhancing its resolution has generally relied on physical or histological methods. This cross-sectional design imposes the need for increased numbers of animals for experiments. Micro-computed tomography (microCT) has been used to detect the pre...
Article
Surgery is associated with an increased risk of venous thromboembolic events (VTE) including deep vein thrombosis and pulmonary embolism. Although the current treatment regiments such as mechanical manipulation and administration of pharmacological prophylaxis significantly reduced the incidence of postsurgical VTE, they remain a major cause of pos...
Conference Paper
 aim Non-contrast MRI using magnetisation transfer rate (MTR), apparent diffusion coeffi- cient (ADC) and T1 mapping can characterise the organisation of a resolving venous thrombus. We now investigate whether the combination of these non-contrast agent MRI sequences can be used to identify thrombi suitable for lysis in an experimental model and e...
Article
•HIF2α is expressed in distinct spatial and temporal patterns in thrombus resolution•HIF2α in the resolving thrombus appears to be expressed by macrophages•HIF2 could play a role in venous thrombus resolution
Article
Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus' fibrin c...
Article
Venous thromboembolism is a common complication in patients with cancer, resulting in significant morbidity and mortality. Clinical studies suggest that the incidence of venous thromboembolic events increased after treatment of these patients with antiangiogenic agents. Thrombi resolve through a process of remodeling, involving the formation of mic...
Article
The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in man. In this study, we investigate possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis. Venous thrombosis was induced in the vena cava of BALB/C mice and tem...
Article
Full-text available
A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2-expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed...