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      Activated Protein C Resistance Does Not Increase Risk for Recurrent Stroke or Death in Stroke Patients

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          Abstract

          Background

          Activated protein C (APC) resistance is the most common inherited prothrombotic disorder. The role of APC resistance in ischemic stroke is controversially discussed.

          Objectives

          The aim of this single center follow up study was to investigate the effect of APC resistance on stroke recurrence and survival in stroke patients.

          Patients/Methods

          We retrospectively identified 966 patients who had had an ischemic stroke or transitory ischemic attack (TIA) and in whom laboratory tests for APC resistance had been conducted. These patients were contacted to determine the primary outcomes of recurrent ischemic stroke or death.

          Results

          A total of 858 patients with an average follow up time of 8.48 years were included. APC resistance did not influence cumulative incidence functions for stroke free and total survival. In multivariate analyses, crude and adjusted hazard ratios for recurrent stroke as well as for death where not significantly increased in patients with APC resistance. This also applies to the subgroups of young patients, patients with cryptogenic stroke and patients with atrial fibrillation.

          Conclusion

          APC-resistance is not a risk factor for subsequent stroke or death in patients with a first ischemic stroke or TIA. Testing for APC-resistance in stroke patients therefore cannot be routinely recommended.

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          Most cited references44

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          The mstate package for estimation and prediction in non- and semi-parametric multi-state and competing risks models.

          Marta Fiocco, Hein Putter, Corneliu Luca (2010)
          In recent years, multi-state models have been studied widely in survival analysis. Despite their clear advantages, their use in biomedical and other applications has been rather limited so far. An important reason for this is the lack of flexible and user-friendly software for multi-state models. This paper introduces a package in R, called 'mstate', for each of the steps of the analysis of multi-state models. It can be applied to non- and semi-parametric models. The package contains functions to facilitate data preparation and flexible estimation of different types of covariate effects in the context of Cox regression models, functions to estimate patient-specific transition intensities, dynamic prediction probabilities and their associated standard errors (both Greenwood and Aalen-type). Competing risks models can also be analyzed by means of mstate, as they are a special type of multi-state models. The package is available from the R homepage http://cran.r-project.org. We give a self-contained account of the underlying mathematical theory, including a new asymptotic result for the cumulative hazard function and new recursive formulas for the calculation of the estimated standard errors of the estimated transition probabilities, and we illustrate the use of the key functions of the mstate package by the analysis of a reversible multi-state model describing survival of liver cirrhosis patients. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
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            Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.

            M Stampfer, R Eisenberg, C Hennekens … (1995)
            A specific point mutation in the gene coding for coagulation factor V is associated with resistance to degradation by activated protein C, a recently described abnormality of coagulation that may be associated with an increased risk of venous thrombosis. Whether this mutation also predisposes patients to arterial thrombosis is unknown, as is the value of screening for the mutation in order to define the risk of venous thrombosis among unselected healthy people. Among 14,916 apparently healthy men in the Physicians' Health Study who provided base-line blood samples, 374 had myocardial infarctions, 209 had strokes, and 121 had deep venous thrombosis, pulmonary embolism, or both, during a mean follow-up of 8.6 years. We determined whether a mutation at nucleotide position 1691 of the factor V gene was present or absent in these 704 men and in an equal number of matched participants who remained free of vascular disease. The prevalence of heterozygosity for the mutation among men who had myocardial infarctions (6.1 percent, P = 0.9) or strokes (4.3 percent, P = 0.4) was similar to that among men who remained free of vascular disease (6.0 percent). However, the prevalence of the mutation was significantly higher among men who had venous thrombosis, pulmonary embolism, or both (11.6 percent, P = 0.02). In adjusted analyses, the relative risk of venous thrombosis among men with the mutation was 2.7 (95 percent confidence interval, 1.3 to 5.6; P = 0.008). This increased risk was seen with primary venous thrombosis (relative risk, 3.5; 95 percent confidence interval, 1.5 to 8.4; P = 0.004) but not with secondary venous thrombosis (relative risk, 1.7; 95 percent confidence interval, 0.6 to 5.3; P = 0.3), and it was most apparent among older men. Specifically, the prevalence of the mutation among men over the age of 60 in whom primary venous thrombosis developed was 25.8 percent (relative risk, 7.0; 95 percent confidence interval, 2.6 to 19.1; P < 0.001). In a large cohort of apparently healthy men, the presence of a specific point mutation in the factor V gene was associated with an increased risk of venous thrombosis, particularly primary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. This mutation appears to be the most common inherited factor thus far recognized that predisposes patients to venous thrombosis.
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              High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance)

              P Reitsma, Jan P. Vandenbroucke, F Rosendaal … (1995)
              Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.
              Article 0 comments Cited 53 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Giuseppe Pignataro: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 10 August 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 8
                Electronic Location Identifier: e0160382
                Affiliations
                [1 ]Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar der Technischen Universität München, München, Germany
                [2 ]Neurologische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, München, Germany
                [3 ]Institut für Medizinische Statistik und Epidemiologie, Klinikum rechts der Isar der Technischen Universität München, München, Germany
                Universita degli Studi di Napoli Federico II, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: CT RF HP.

                • Performed the experiments: CT NS MS.

                • Analyzed the data: MT RF IR.

                • Contributed reagents/materials/analysis tools: HP.

                • Wrote the paper: MT RF IR HP.

                Article
                Publisher ID: PONE-D-16-13066
                DOI: 10.1371/journal.pone.0160382
                PMC ID: 4980060
                PubMed ID: 27508300
                SO-VID: 18d5a9b2-208a-4969-8017-e45d07c8ef0d
                Copyright © © 2016 Thaler et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 31 March 2016
                Date accepted : 13 June 2016
                Page count
                Figures: 1, Tables: 7, Pages: 13
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: Antigen-Presenting Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antigen-Presenting Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antigen-Presenting Cells
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Cerebrovascular Diseases
                Subject: Stroke
                Subject: Ischemic Stroke
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Stroke
                Subject: Ischemic Stroke
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Cerebrovascular Diseases
                Subject: Stroke
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Stroke
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Arrhythmia
                Subject: Atrial Fibrillation
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Multivariate Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Multivariate Analysis
                Subject: Medicine and Health Sciences
                Subject: Endocrinology
                Subject: Endocrine Disorders
                Subject: Diabetes Mellitus
                Subject: Medicine and Health Sciences
                Subject: Metabolic Disorders
                Subject: Diabetes Mellitus
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Myocardial Infarction
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Blood Pressure
                Subject: Hypertension
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

                ScienceOpen disciplines: Uncategorized
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