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Archives of Pathology & Laboratory... Oct 2019Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal... (Review)
Review
Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder. Hereditary PC deficiency is caused by mutation in the PC () gene located on chromosome 2q14.3. Heterozygous and acquired PC deficiencies are more common than homozygous deficiency. The recommended initial laboratory test measures PC activity using either clot-based or chromogenic methods. There are numerous potential interferences in PC activity testing that may result in either false-positive (falsely low activity) or false-negative (falsely normal or elevated activity) results. In the present review, we discuss common clinical presentations; laboratory testing, with a focus on potential assay interferences; treatment options; and prognosis in patients with PC deficiency.
Topics: Blood Coagulation Tests; Humans; Mutation; Protein C Deficiency; Purpura Fulminans; Thrombophilia; Venous Thromboembolism
PubMed: 30702334
DOI: 10.5858/arpa.2017-0403-RS -
International Journal of Molecular... Feb 2022Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and... (Review)
Review
Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and FII G20210A variants. They are associated with a high thrombosis risk and can impact the duration of anticoagulation therapy for patients with a venous thromboembolism (VTE) event. Therefore, it is important to diagnose thrombophilia and to use adapted anticoagulant therapy. The widespread use of direct anticoagulants (DOACs) for VTE has raised new issues concerning inherited thrombophilia. Concerning inherited thrombophilia diagnosis, DOACs are directed toward either FIIa or FXa and can therefore interfere with coagulation assays. This paper reports DOAC interference in several thrombophilia tests, including the assessment of antithrombin, protein S, and protein C activities. Antithrombin activity and clot-based assays used for proteins C and S can be overestimated, with a risk of missing a deficiency. The use of a device to remove DOACs should be considered to minimize the risk of false-negative results. The place of DOACs in the treatment of VTE in thrombophilia patients is also discussed. Available data are encouraging, but given the variability in thrombosis risk within natural anticoagulant deficiencies, evidence in patients with well-characterized thrombophilia would be useful.
Topics: Administration, Oral; Anticoagulants; Antithrombins; Humans; Protein C; Risk Factors; Thrombophilia; Thrombosis; Venous Thromboembolism
PubMed: 35163742
DOI: 10.3390/ijms23031821 -
Cell Mar 2020It has generally proven challenging to produce functional β cells in vitro. Here, we describe a previously unidentified protein C receptor positive (Procr) cell...
It has generally proven challenging to produce functional β cells in vitro. Here, we describe a previously unidentified protein C receptor positive (Procr) cell population in adult mouse pancreas through single-cell RNA sequencing (scRNA-seq). The cells reside in islets, do not express differentiation markers, and feature epithelial-to-mesenchymal transition characteristics. By genetic lineage tracing, Procr islet cells undergo clonal expansion and generate all four endocrine cell types during adult homeostasis. Sorted Procr cells, representing ∼1% of islet cells, can robustly form islet-like organoids when cultured at clonal density. Exponential expansion can be maintained over long periods by serial passaging, while differentiation can be induced at any time point in culture. β cells dominate in differentiated islet organoids, while α, δ, and PP cells occur at lower frequencies. The organoids are glucose-responsive and insulin-secreting. Upon transplantation in diabetic mice, these organoids reverse disease. These findings demonstrate that the adult mouse pancreatic islet contains a population of Procr endocrine progenitors.
Topics: Animals; Cell Culture Techniques; Cell Differentiation; Cell Line; Cells, Cultured; Diabetes Mellitus, Experimental; Endothelial Protein C Receptor; Epithelial-Mesenchymal Transition; Female; Glucose; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Nude; Organoids; Pancreas; Protein C; Stem Cells
PubMed: 32200801
DOI: 10.1016/j.cell.2020.02.048 -
Journal of Thrombosis and Haemostasis :... Jun 2019Trauma remains a leading cause of death worldwide, and most early preventable deaths in both the civilian and military settings are due to uncontrolled hemorrhage,... (Review)
Review
Trauma remains a leading cause of death worldwide, and most early preventable deaths in both the civilian and military settings are due to uncontrolled hemorrhage, despite paradigm advances in modern trauma care. Combined tissue injury and shock result in hemostatic failure, which has been identified as a multidimensional molecular, physiologic and clinical disorder termed trauma-induced coagulopathy (TIC). Understanding the biology of TIC is of utmost importance, as it is often responsible for uncontrolled bleeding, organ failure, thromboembolic complications, and death. Investigations have shown that TIC is characterized by multiple phenotypes of impaired hemostasis due to altered biology in clot formation and breakdown. These coagulopathies are attributable to tissue injury and shock, and encompass underlying endothelial, immune and inflammatory perturbations. Despite the recognition and identification of multiple mechanisms and mediators of TIC, and the development of targeted treatments, the mortality rates and associated morbidities due to hemorrhage after injury remain high. The purpose of this review is to examine the past and present understanding of the multiple distinct but highly integrated pathways implicated in TIC, in order to highlight the current knowledge gaps and future needs in this evolving field, with the aim of reducing morbidity and mortality after injury.
Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Endothelium; Exsanguination; Fibrinolysis; Hemorrhage; Hemostasis; Humans; Protein C; Shock, Hemorrhagic; Wounds and Injuries
PubMed: 30985957
DOI: 10.1111/jth.14450 -
Clinical and Applied... Dec 2018Disseminated intravascular coagulation (DIC) is an acquired clinicobiological syndrome characterized by widespread activation of coagulation leading to fibrin deposition...
Disseminated intravascular coagulation (DIC) is an acquired clinicobiological syndrome characterized by widespread activation of coagulation leading to fibrin deposition in the vasculature, organ dysfunction, consumption of clotting factors and platelets, and life-threatening hemorrhage. Disseminated intravascular coagulation is provoked by several underlying disorders (sepsis, cancer, trauma, and pregnancy complicated with eclampsia or other calamities). Treatment of the underlying disease and elimination of the trigger mechanism are the cornerstone therapeutic approaches. Therapeutic strategies specific for DIC aim to control activation of blood coagulation and bleeding risk. The clinical trials using DIC as entry criterion are limited. Large randomized, phase III clinical trials have investigated the efficacy of antithrombin (AT), activated protein C (APC), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) in patients with sepsis, but the diagnosis of DIC was not part of the inclusion criteria. Treatment with APC reduced 28-day mortality of patients with severe sepsis, including patients retrospectively assigned to a subgroup with sepsis-associated DIC. Treatment with APC did not have any positive effects in other patient groups. The APC treatment increased the bleeding risk in patients with sepsis, which led to the withdrawal of this drug from the market. Treatment with AT failed to reduce 28-day mortality in patients with severe sepsis, but a retrospective subgroup analysis suggested possible efficacy in patients with DIC. Clinical studies with recombinant TFPI or TM have been carried out showing promising results. The efficacy and safety of other anticoagulants (ie, unfractionated heparin, low-molecular-weight heparin) or transfusion of platelet concentrates or clotting factor concentrates have not been objectively assessed.
Topics: Anticoagulants; Antithrombins; Clinical Trials, Phase III as Topic; Disseminated Intravascular Coagulation; Heparin; Humans; Lipoproteins; Protein C; Randomized Controlled Trials as Topic; Recombinant Proteins; Sepsis; Thrombomodulin
PubMed: 30296833
DOI: 10.1177/1076029618806424 -
Blood May 2022
Topics: Animals; Anticoagulants; Arthritis; Hemarthrosis; Hematologic Diseases; Hemophilia A; Mice; Protein C
PubMed: 35511191
DOI: 10.1182/blood.2022015776 -
Annals of Neurology Jan 2019Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic... (Randomized Controlled Trial)
Randomized Controlled Trial
Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in...
OBJECTIVE
Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients.
METHODS
The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates.
RESULTS
Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066).
INTERPRETATION
RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation.
CLINICAL TRIAL REGISTRATION
Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.
Topics: Aged; Aged, 80 and over; Brain Ischemia; Combined Modality Therapy; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Protein C; Recombinant Proteins; Severity of Illness Index; Single-Blind Method; Stroke; Thrombectomy; Tissue Plasminogen Activator
PubMed: 30450637
DOI: 10.1002/ana.25383 -
Circulation Research Dec 2018
Topics: Cardiac Myosins; Cardiomyopathies; Fibrosis; Humans; Myofibroblasts; Protein C; Transforming Growth Factor beta
PubMed: 30566054
DOI: 10.1161/CIRCRESAHA.118.314185 -
Trends in Pharmacological Sciences Aug 2017Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the... (Review)
Review
Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. In this review, we critically evaluate prospects for the next generation of PAR1-targeted therapeutics.
Topics: Animals; Humans; Lactones; Molecular Targeted Therapy; Peptides; Protein C; Pyridines; Receptor, PAR-1; Recombinant Proteins
PubMed: 28558960
DOI: 10.1016/j.tips.2017.05.001