Whoops Discusses the thrombotic risks of this inherited disorder, also known as Factor V Leiden. http://www.beckmancoulter.com/Coulter/Techpubs/coagulation/APC.asp
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Template For Redirect Center for Disease Control's page discussing the background of this disorder including study results, testing, and complications. http://www.cdc.gov/genetics/info/reports/research/protein_C.html
FVL: Activated Protein C Resistance FVL activated protein c resistance A However, it *is* possible tohave activated protein c resistance without having FVL. There http://www.naturalchildbirth.org/natural/resources/prebirth/prebirth31.htm
Extractions: A New Test for Patients with Thrombosis Franklin A. Bontempo, M.D., Medical Director, Coagulation Services Andrea Cortese Hassett, Ph.D., Scientific Director, Coagulation Services Description The activated protein C (APC) resistance test is a recently described clotting assay that is an important new diagnostic tool to define a cause of hypercoagulability in patients with thrombosis. Defects affecting APC appear to be the most common cause of systemic tendency for excessive clotting. This review will summarize current information as to the incidence and significance of this abnormality. Protein C, in the presence of its cofactor thrombomodulin and thrombin, is enzymatically cleaved to its active form, Activated Protein C. APC is an important natural anticoagulant which functions by inactivating the critical coagulation factors FVa and FVIIIa. The many causes of thrombosis include both hereditary and acquired conditions. Inherited predispositions to thrombosis are perhaps the most disturbing clinically, because they affect patients at a younger age. Currently, only about 5-10% of patients with thrombosis have a definable cause of their thrombotic tendency. In the past year, however, groups working independently in California and Europe have found that failure of the APTT to prolong with the addition of activated protein C occurs in 30-40% of patients with an otherwise unknown cause of thrombosis. Further studies have shown that in 80% of these patients the cause of the APC resistance is a mutant factor V molecule, recently designated factor V Leiden, which is able to clot in the classic coagulation cascade but is resistant to activation by activated protein C.
Activated Protein C Resistance activated protein c resistance (Factor V Leiden). I. Review of ProteinC and Factor V Factor V is a proenzyme that is activated to http://www.medinfo.ufl.edu/year2/coag/apc.html
Extractions: I. Review of Protein C and Factor V II. History Then in 1993 in Holland, Dahlback et al. made a significant discovery. In their experiments to determine the cause of many of these unexplained thrombotic events, they administered exogenous activated protein C (APC) to patients' plasma and then measured the aPTT . In normal healthy men, when exogenous APC was given, the aPTT was substantially prolonged. This was expected given the role of Protein C in inhibiting factors Va and VIIIa. However, when many men with history or family history of unexplained thrombosis were given APC, the aPTT was not prolonged nearly as much. With this novel finding in mind, they proposed mechanisms that could account for this APC resistance. Their hypotheses included: autoantibody against Protein C, antiphospholipid antibodies inhibiting APC function, fast-acting inhibitor of APC, and Protein S Deficiency. They excluded all of these possibilities experimentally, leaving mutation in the genes for Factors V and VIII as possible mechanisms. Through their experiments they eventually found that adding normal Factor V corrected the abnormality and actually prolonged the aPTT to expected levels. This led to studies searching for mutations in the gene for Factor V as the cause for APC resistance.
Resistance To Activated Protein C activated protein c resistance Molecular mechanisms based on studiesusing purified Gln506factor V. Blood 1995; 85 3405-3411. http://www.jr2.ox.ac.uk/bandolier/bandopubs/keeling.html
Extractions: The phenomenon of resistance to activated protein C (APC) was discovered only three years ago. Dahlback and colleagues identified a middle aged man with a personal and a family history of thrombosis whose APTT did not show the expected prolongation when exogenous APC was added to his plasma [1]. The same phenomenon was found in several of the patient's relatives. The mechanism was unknown but inheritance of a deficiency of a cofactor for APC was hypothesised. This proved not to be the case and one year later the molecular defect was identified as a point mutation in factor V (FV) [2]. The mutation was a G to A substitution at nucleotide position 1,691. This results in the arginine at position 506 (coding triplet CGA) being replaced by a glutamine (coding triplet CAA). Using the single letter amino-acid code the mutant FV can therefore be written as FV R506Q but is more often referred to as FV Leiden (Figure 1). Figure 1. The G to A point mutation results in the arginine at the protein C cleavage site being replaced by glutamine.
Whoops Features articles about blood coagulation disorders including activated protein c resistance, von Willbrand's disease, and hypercoagulability. http://www.beckmancoulter.com/Coulter/Techpubs/coagulation/
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FamilyPractice.com - References activated protein c resistance The Most Common Risk Factor for Venous Thromboembolism http://www.familypractice.com/references/referencesframe.htm?main=/journal/2000/
Extractions: Journal Publication This review was published with modifications in Am J Med Sci. 1998 Aug; 316(2): 120-128 The Role of Activated Protein C Resistance in the Pathogenesis of Venous Thrombosis by W. Craig Hooper and Bruce L. Evatt Introduction Pathophysiology APC-R and Factor V Leiden: Clinical Features FV Leiden in Women ... References Introduction Following myocardial infarction and stroke, venous thromboembolism (VTE) is the third most common cardiovascular disease in the United States. The mortality and morbidity of VTE is significant with an annual incidence of approximately 1:1000 individuals and pulmonary embolism is a leading cause of in-patient hospital deaths (1,2). It has been estimated that venous thrombosis is responsible for between 300,000-600,000 hospitalizations and up to 100,000 deaths annually (3,4). The clinical consequences of venous thrombosis such as chronic venous insufficiency with skin ulceration affects up to 500,000 individuals per year. Studies have reported that as many as 90% of patients with venous thrombosis suffer significant disabilities at 2-5 year follow-up intervals (5). The current health costs associated with VTE are significant and are expected to rise as the prevalence of VTE increases in the aging population (6,7). The purpose of this review is to briefly re-acquaint the reader with the pathobiology of the anticoagulant protein system and to review the clinical implications of APC-R.
Activated Protein C Resistance January 2001 activated protein c resistance. INTRODUCTION. The phenomenon of activatedprotein C resistance (APCr) was first reported by Dahlback (1) et al. http://www.itxm.org/TMU2001/tmu1-2001.htm
Extractions: Franklin A. Bontempo, M.D. The phenomenon of activated protein C resistance (APCr) was first reported by Dahlback (1) et al. in 1993 and refers to the ability to mount an effective anticoagulant response. Clinically this results in an increased risk of thrombosis. Most cases of APC resistance are associated with a single point mutation in the factor V gene (Leiden mutation), which results in the substitution of arginine at position 506 by glutamine. Cleavage of this site by APC is necessary for exposure of the two additional cleavage sites needed for inactivation. The rate of inactivation of factor V Leiden (FVL) is therefore slower than that of normal factor V. In vivo this manifests as an 8 fold increased risk of thrombosis in heterozygotes and a 50 to 100 fold increased risk of thrombosis in homozygotes (2,3). The presence of the FVL allele is the major cause of APCr and a well-documented risk factor for venous thrombosis. APC resistance testing is performed on citrated plasma (blue tops) preferably away from the time of the acute event, when the patient is not on treatment with anticoagulants. The first generation, original assay consists of a standard APTT test performed in the absence and presence of commercially available activated protein C.
ACTIVATED PROTEIN C RESISTANCE ASSAY activated protein c resistance Assay The Hemostasis Reference Laboratory of The Blood Center Diagnostic Laboratories has modified the method used in the activated protein c resistance Assay. http://www.clinlabs.org/activatedproteincresistanceassay.htm
Extractions: Activated Protein C Resistance Assay The Blood Center of Southeastern Wisconsin Hemostasis Reference Laboratory has implemented a new method for its Activated Protein C Resistance Assay. BACKGROUND: Resistance to activated protein C (APCR) is the most common inherited condition associated with increased risk for thrombosis. APCR is present in 3 to 5% of asymptomatic Caucasians, and is found in about 20% of unselected patients with venous thrombosis. A single point mutation (Factor V Leiden , encoding for substitution of amino acid glutamine for arginine in the factor V protein) accounts for 95 to 99% of cases of observed activated protein C resistance. APCR/Factor V Leiden have become associated with multiple disease states including: venous thromboembolic disease, stroke in children, preeclampsia and fetal wastage. REASONS FOR REFERRAL: Evaluation of patients with hypercoagulable state, patients with a history of preeclampsia or recurrent fetal loss, and for prediction of disease risk in individuals with a positive family member. METHOD dRVVT based clotting time ratio. Patient plasma is incubated with snake venom (to activate endogenous protein C) or saline, and the dRVVT is determined for each sample. Results are expressed as the ratio of dRVVT when venom is present to the dRVVT with saline only.
Extractions: Activated Protein C Resistance, screening assay (with dilution in factor V deficient plasma) Ratios above reference range cut-off: Consistent with normal response to activated protein C No evidence for activated protein C resistance or for the factor V Leiden mutation Confirmatory assay is not necessary.
Extractions: When thrombin (IIa) is generated, it has both procoagulant activities and anticoagulant activities. Excess thrombin is washed downstream where it binds to thrombomodulin (TM) on endothelial cells of the vessel wall. Protein C from plasma binds to the IIa/TM complex and is cleaved to its active form, termed "activated Protein C" (APC). APC is one of the most physiologically important anticoagulants as it selectively degrades the coagulation cofactors, Va and VIIIa to limit thrombin generation, fibrin formation and blood clotting in vivo. It has been shown that APC resistance results from a mutant Factor Va molecule, termed Factor V Leiden. This molecule has a specific point mutation (Arg -> Gln ) which cannot be degraded by APC in more than 90% of all APC resistant patients2. The defective Va is able to clot as normal and clotting continues because of this resistance to inactivation by APC. Other APC cleavage sites in the Factor Va molecule are potential mutation sites. These sites include: Arg -> Gln and Arg -> Gln . The other 10% of APC resistance includes Acquired APC Resistance and these secondary sites. Recent studies have shown the occurrence of APC resistance to vary from 2 - 16% depending on the population studied. This data suggests that screening protocols for hereditary thrombotic disorders should include testing for APC resistance as an important genetic risk factor. Hypercoagulability has been explained by hereditary deficiencies of Protein C, Protein S and Antithrombin in only 9 to 21% of thrombotic cases in patients without the usual risk factors for thrombosis (i.e., cancer, recent surgery, lupus anticoagulant)
Extractions: Alternate Tests Activated Protein C Resistance, screening assay (without dilution into factor V deficient plasma) Normalized ratio for Activated Protein C Resistance, screening assay (with or without dilution into factor V deficient plasma) Invasive Signal Amplification Reaction Activated Protein C Resistance, screening assay (without dilution into factor V deficient plasma) [CPT-85999] Performed the same as described in Recommended Tests , except sample is not diluted beforehand. First test described for activated protein C resistance [ ref Many laboratories have replaced this test with the modified screening test that includes dilution into factor V deficient plasma. The dilution step improves assessment for the factor V Leiden mutation. Sensitivity for detecting factor V Leiden mutation is only 50-86%. The specificity is 75-98% in adults [ ref ]. There is considerable overlap between normals and heterozygotes in the 2.0 to 3.0 range of assay values [ ref Inaccurate in individuals with an abnormal baseline Partial Thromboplastin Time (PTT).
Member Sign In activated protein c resistance The Most Common Risk Factor for Venous Thromboembolismfrom Journal of the American Board of Family Practice http://www.medscape.com/viewarticle/405768
Member Sign In Hypercoagulability Clinical Assessment and Treatment from Southern MedicalJournal. activated protein c resistance. The pathophysiologic http://www.medscape.com/viewarticle/415086_4
Extractions: Aviat Space Environ Med 1997; 68:606-8 Aviators are occasionally diagnosed as suffering from deep venous thrombosis (DVT). Despite the recognition of the "Economy Class Syndrome" in the 1960's, the relationship between DVT and aviation is not clear cut. A case of DVT is described in a military navigator who was also found to be a heterozygote for activated protein C resistance. This case highlights the importance of considering all components of Virchow's triad when assessing the significance and management of DVTs. Aspects of the Economy Class Syndrome and of activated protein C resistance are discussed. Information on subscribing, and on obtaining copies of an article or of an entire issue. Table of Contents for Volume 68, Number 7 of the ASEM journal. ASEM Home Page
ACTIVATED PROTEIN C (APC) RESISTANCE TEST - Plasma Interpretation activated protein c resistance is due to an inherited disorderof the (coagulation) factor V molecule, and is associated with venous http://www.rcpa.edu.au/pathman/activat3.htm
Extractions: Application: Investigation of tendency to venous thromboembolism: unexplained, recurrent, or with a positive family history. The test has high sensitivity and specificity and is an adequate initial test, except for patients receiving heparin or warfarin and those with other abnormalities of coagulation. In these circumstances, DNA testing for detection of the abnormal factor V gene is also available; see MOLECULAR GENETICS- INDIVIDUAL GENETIC DISORDERS FACTOR V LEIDEN MUTATION
Extractions: The APC is inhibited in plasma by two major inhibitors, protein C inhibitor (PCI) which is heparin dependent and a1 - proteinase inhibitor (historically called a1 - antitrypsin) which is heparin independent. a2 - macroglobulin also appears to play a role when large amounts of activated protein C are generated in pathologic conditions such as disseminated intravascular coagulation (60).
