-
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 -
The Lancet. Respiratory Medicine Nov 2023In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular... (Observational Study)
Observational Study
BACKGROUND
In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials.
METHODS
We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect.
FINDINGS
A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72).
INTERPRETATION
Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis.
FUNDING
US National Institutes of Health.
Topics: Adult; Humans; Shock, Septic; Protein C; Retrospective Studies; Prospective Studies; Sepsis; Phenotype; Biomarkers; Vasoconstrictor Agents; Respiratory Distress Syndrome; Randomized Controlled Trials as Topic
PubMed: 37633303
DOI: 10.1016/S2213-2600(23)00237-0 -
Current Opinion in Hematology Sep 2022To provide an overview of the state-of-the-art in protein C (PC) pathway research. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of the state-of-the-art in protein C (PC) pathway research.
RECENT FINDINGS
The PC pathway is crucial for maintaining hemostasis to prevent venous thromboembolism. This is evident from genetic mutations that result in impaired PC pathway activity and contribute to increased venous thromboembolism risk in affected individuals. In addition to its anticoagulant role, activated PC (APC) also mediates a complex, pleiotropic role in the maintenance of vascular cell health, which it achieves via anti-inflammatory and antiapoptotic cell signaling on endothelial cells. Emerging data have demonstrated that cell signaling by APC, mediated by multiple receptor interactions on different cell types, also confers cytoprotective and anti-inflammatory benefits. Defects in both arms of the PC pathway are associated with increased susceptibility to thrombo-inflammatory disease in various preclinical thrombotic, proinflammatory and neurological disease models. Moreover, recent studies have identified attenuation of anticoagulant PC pathway activity as an exciting therapeutic opportunity to promote hemostasis in patients with inherited or acquired bleeding disorders.
SUMMARY
In this review, we provide an overview of some recent developments in our understanding of the PC pathways.
Topics: Anticoagulants; Endothelial Cells; Humans; Protein C; Signal Transduction; Venous Thromboembolism
PubMed: 35852855
DOI: 10.1097/MOH.0000000000000726 -
Blood May 2022
Topics: Animals; Anticoagulants; Arthritis; Hemarthrosis; Hematologic Diseases; Hemophilia A; Mice; Protein C
PubMed: 35511191
DOI: 10.1182/blood.2022015776 -
Expert Review of Hematology Sep 2020Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of...
INTRODUCTION
Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important.
AREAS COVERED
The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e., factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed.
EXPERT OPINION
Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.
Topics: Activated Protein C Resistance; Alleles; Animals; Contraceptives, Oral; Disease Models, Animal; Disease Susceptibility; Epistasis, Genetic; Gene Expression; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; High-Throughput Nucleotide Sequencing; Humans; Mutation; Protein C Deficiency; Protein S Deficiency; Risk Factors; Thrombophilia; Venous Thromboembolism
PubMed: 32731838
DOI: 10.1080/17474086.2020.1804354 -
Arteriosclerosis, Thrombosis, and... Jul 2023
Topics: Protein C; Protein S; Prothrombin; Blood Coagulation
PubMed: 37199157
DOI: 10.1161/ATVBAHA.123.319442