61. Factor V - Leiden Mutation 2) Heeb MJ et al. activated protein c resistance molecular mechanisms basedon studies using purified Gln506factor V. Blood 1995; 853405-3411. http://www.euroclone.net/mol_biology/factor5.htm

FACTOR V- Leiden Mutation Code and size: EMK011050 - 50 tests BACK INTRODUCTION It has recently been demonstrated [Bertina M., 1994] that the single mutation G->A at nucleotide position 1691 in the exon 10 of the gene coding for factor V, determines an aminoacid change from Arg(R) to Gln(Q) at position 506 of the protein sequence (FV R506->FVQ506).This mutation is defined as the Leiden mutation and a study performed on different European populations, demonstrates that it is present at a frequence of 3-5% in normal populations [Dahlback B., 1995]. It has been proved that the inactivation of Factor V by the activated protein C (APC), is 10 times faster in FVArg 606 (wild-type) compared to the FVGln506 (mutant) [Heeb M.J., 1995]. Due to the presence of this mutation at a high frequency in normal population and since this mutation confers a predisposition to thrombotic events, recent reports suggest to perform a screening of people with recurrent thrombotic episodes or with subjects exposed to risk factors such as the use of oral contraceptives. The traditional laboratory assay to test this alteration, is the APC resistance test. This test evaluates the function of the factor V but it is not able to determine neither the nucleotide sequence nor the differences between the homozygous and the heterozygous mutant carriers. The traditional molecular screening for this mutation, is based on a PCR amplification followed by digestion with an appropriate restriction enzyme.

62. OBGYN.net - Risk Factors For Recurrent Early Pregnancy Loss Furthermore, activated protein c resistance is studied and if present, it is followedby screening for its main cause, the factor V Leiden mutation (1691G®A). http://www.obgyn.net/displayarticle.asp?page=/english/pubs/features/dissertation

63. HAEMOSTASIS PROTEIN C DEFICIENCY most commonly due to factor V Leiden mutation; Point mutationaffecting factor Va giving rise to activated protein c resistance (APCR). http://www.uct.ac.za/depts/doogie/mfunit/haemost.htm

HAEMOSTASIS GUIDE TO TUTORIAL ENDOTHELIUM PLATELETS CLOTTING FACTORS ANTICLOTTING MECHANISM ... QUESTIONNAIRE ROSIE BURTON Classic triad Endothelium and exposed basement membrane Platelets – qualitative and quantitative disorders Blood coagulation factors – clotting factors / fibrinolysis / anti- coagulants Major aim of haemostasis is formation of platelet plug followed by the laying down and cross-linking of fibrin – and ensuring that the haemostatic response is appropriately limited in time and space ENDOTHELIUM In response to injury: Vasoconstriction – reduced blood flow facilitates contact activation of platelets and coagulation factors Exposure of sub-endothelial basement membrane and collagen Release of tissue thromboplastins Synthesises basement membrane components, tissue factor, vWF, plasminogen activator, antithrombin III, thrombomodulin Vascular bleeding disorders: Hereditary haemorrhagic telangiectasia Scurvy – defective collagen Henoch-Schonlein purpura / infection related– immune complex deposition Connective tissue disorders – Ehlers-Danlos syndrome – defective collagen synthesis Steroid purpura – defective vascular supportive tissue PLATELETS Adhesion Adhere to exposed basement membrane and subendothelial connective tissue Fibronectin, high molecular weight vWF facilitate binding of platelets

64. Additional (Reflex) Testing Policy DSPC assay. activated protein c resistance (screen), positive, PCRfor Factor V Leiden mutation/activated protein c resistance. Anti http://labmed.bwh.harvard.edu/general/reflex.html

Additional (Reflex) Testing Policy To diagnose certain disease states additional testing is necessary; therefore, to avoid delay in the turnaround time of such testing, and the necessity of collecting new specimens, certain protocols and procedures will be followed. If the test has a result of perform additional test: Serum Protein Electrophoresis (SPEP) monoclonal spike Immunofixation (IFX) to look for IgG, IgA and IgM monoclonal gammopathies SPEP (Hematology patients only) monoclonal spike Immunofixation for IgG, IgA and IgM ANA positive Precipitin Panel, anti-dsDNA Urine Protein Electrophoresis (UPEP) monoclonal spike Immune electrophoresis less than 150 u/mL , Factor B for BWH and NE Deaconess patients Lyme Antibodies (ELISA screen) positive Confirmation by western blot CBC with automated differential 2+ left shift, IG or positive flag for blasts Manual Differential Urinalysis positive for protein, blood or leukocyte esterase urine sediment analysis (microscopic urine exam) Paroxysmal Nocturnal Hemoglobinuria (PNH; Sucrose Lysis positive acid serum Osmotic Fragility and Coombs Test positive and negative, respectively

65. Margareta Wramsby: Doktorsavhandling Från Karolinska Institutet Repetitive measurement of activated protein c resistance during menstrual cycleWramsby ML, Bremme K, Blombäck M Thromb Haemost, 2001; 85 In Print. http://diss.kib.ki.se/2001/91-628-4636-1/

sök sök personal översikt OM KAROLINSKA INSTITUTET ... Info Doktorsavhandling vid Karolinska Institutet Wramsby, Margareta Reproductive aspects of the protein C system in women Fredagen den 30 mars 2001, kl. 9.00. Nanna Svartz Auditorium, Karolinska Sjukhuset. ISBN: 91-628-4636-1 Diss: 01:167 Abstract: Of great importance to the reproductive system in women are the activating and inhibiting factors which maintain haemostatic balance. These play a prominent role in the prevention of abnormal bleeding, at ovulation as well as during menstruation, pregnancy and delivery. The coagulation cascade is primarily down regulated by the protein C system. Objective : The aim was to study the possible impact of estradiol and progesterone on the protein C system in women during menstrual cycle, controlled ovarian hyperstimulation (COH), pregnancy as well as to determine a possible association between hypercoagulation and recurrent abortions. Methods : Blood samples were drawn during; menstrual cycle days 1-3, 6-8, 13-14 and 20-24; during COH, when down regulated, at time for the peak value of estradiol, and at time for ovum pick up (OPU); during pregnancy weeks 12, 20, 28, 32, 36 and postpartum. In women with recurrent abortions and in controls, samples were collected at cycle day 5-8.

66. Third Wave Technologies - Browse References Rosendaal, FR, Koster, T., Vandenbroucke, JP Reitsma, PH High risk of thrombosisin patients homozygous for factor V Leiden (activated protein c resistance). http://www.twt.com/Browse.cfm?fldID=2837

67. Protein C (resistance To Activated Protein C) - General Practice Notebook protein C (resistance to activated protein C). Mutation in blood coaulation factorV associated with resistance to activated protein C. Nature, 369, 647. http://www.gpnotebook.co.uk/cache/1711669304.htm

protein C (resistance to activated protein C) Resistance to the anticoagulant effects of activated protein C (APC) (Factor V Leiden heterozygous*) is common (1): 5% of the general population 25-50% of patients with venous thromboembolism 50% of patients with thrombosis who have a family or personal history of thrombosis APC resistance is usually due to a single point mutation in one or both of the protein C genes. The mutation reduces the susceptibility of factor V to cleavage by APC. There is increasing evidence that individuals with two or more laboratory characterisable thrombophilic abnormalities (or who are homozygous for either factor V Leiden or prothrombin G20210A) are at a greater risk of thrombosis than those in whom there is a single gene abnormality (1). * Factor V Leiden homozygous individuals have an 80x risk of venous thromboembolism Reference: (1) British Heart Foundation (Factfile 2/2002). Thrombophilia (2) Rogier, MB. et al. (1994). Mutation in blood coaulation factor V associated with resistance to activated protein C. Nature, 369, 64-7. (3) Drugs and Therapeutics Bulletin (1995), 33 (1), 6-8.

68. Resistance To Activated Protein C - General Practice Notebook resistance to activated protein C. et al. (1994). Mutation in blood coaulation factorV associated with resistance to activated protein C. Nature, 369, 647. http://www.gpnotebook.co.uk/cache/1731526712.htm

resistance to activated protein C Resistance to the anticoagulant effects of activated protein C (APC) (Factor V Leiden heterozygous*) is common (1): 5% of the general population 25-50% of patients with venous thromboembolism 50% of patients with thrombosis who have a family or personal history of thrombosis APC resistance is usually due to a single point mutation in one or both of the protein C genes. The mutation reduces the susceptibility of factor V to cleavage by APC. There is increasing evidence that individuals with two or more laboratory characterisable thrombophilic abnormalities (or who are homozygous for either factor V Leiden or prothrombin G20210A) are at a greater risk of thrombosis than those in whom there is a single gene abnormality (1). * Factor V Leiden homozygous individuals have an 80x risk of venous thromboembolism Reference: (1) British Heart Foundation (Factfile 2/2002). Thrombophilia (2) Rogier, MB. et al. (1994). Mutation in blood coaulation factor V associated with resistance to activated protein C. Nature, 369, 64-7. (3) Drugs and Therapeutics Bulletin (1995), 33 (1), 6-8.

69. Pro- And Anticoagulant Mechanisms In Coronary Artery Disease. S. resistance to activated protein C (APC resistance) is a common risk factor forvenous thrombosis caused by a mutation in the gene for factor V (FV Q506). http://eprints.lub.lu.se/archive/00009854/

70. Main Thrombophilia Support Page Factor V Leiden Prothrombin 20210 mutation activated proteinC resistance protein C S Deficiency Antithrombin Deficiency and other http://www.fvleiden.org/main.htm

71. APC Resistance In Cancer Thrombosis APC resistance in Cancer Thrombosis. Assessment of activated protein Cresistance and factor V Leiden in patients with thrombosis and cancer. http://labhem.cjp.com/stories/storyReader$107

Menu Home Purpose and Scope Masthead Author Instructions ... Search CJP Online Journals BloodLine Heart Surgery Forum Journal Center APC Resistance in Cancer Thrombosis Assessment of activated protein C resistance and factor V Leiden in patients with thrombosis and cancer M.J. KOVACS, M. KEENEY, K. MACKINNON, L. WONG, M.K. CRUICKSHANK, E. BOYLE, P. AINSWORTH 5.2.Kovacs Carden Jennings Publishing Co., Ltd. Current Edition Biology of Blood and Marrow Transplantation Laboratory Hematology Blood and Marrow Transplantation Reviews Heart Surgery Forum

72. Hereditary Resistanace To APC In 1993 a new defect in the response to activated protein C (activated proteinC resistance) was reported as a cause of recurrent thrombosis. http://www.coagcenter.com/coag_ed_apcresistance.htm

Introduction Tests / CPT Codes / Samples Special Collection / Processing Guidelines ... Home E D U C A T I O N A L N O T E B O O K Hereditary Resistance to Activated Protein C / APC Resistance Individuals with a suspected inherited predisposition to thrombosis usually have recurrent juvenile or familial thrombotic events in usual sites (i.e. axillary vein, mesenteric vein, sagittal vein). Arterial thromboses are less common but do occur. Until now, approximately 30% of these disorders have been diagnosed as a deficiency of Antithrombin III, Protein C or Protein S. In 1993 a new defect in the response to activated Protein C (activated Protein C resistance) was reported as a cause of recurrent thrombosis. This Resistance to APC is seen in 21-64% of patients with a history of thrombotic events and appears, in part, to be due to an abnormal Factor V (Leiden) mutation. The most common test for this defect is an APTT-based assay that incorporates activated Protein C into the reagent. At this time, the test is still considered investigational and should not be used as the sole basis for diagnosis. However, this risk factor should be considered when evaluating a patient with a history of thrombosis. SPECIAL NOTE: Because the patient's APTT must be within normal range for valid results to be obtained, a screening APTT will be run by the Coagulation Center. If an abnormal APTT result is obtained, the report will state "abnormal APTT result obtained; test could not be performed."

73. Procedure ACTIVATED PROTEIN C RESISTANT FV also known as APC RESISTANT FACTOR V , protein C resistance ASSAY , FACTOR V LEIDEN, APCFV , activated protein C RESISTANT FVA, Blood. SPECIAL COAGULATION LAB, http://health.ucsd.edu/labref/P321.html

UNIVERSITY OF CALIFORNIA, SAN DIEGO CLINICAL LABORATORIES ACTIVATED PROTEIN C RESISTANT FV Specimen Type: also known as APC RESISTANT FACTOR V , PROTEIN C RESISTANCE ASSAY , FACTOR V LEIDEN , APCFV , ACTIVATED PROTEIN C RESISTANT FVA Blood SPECIAL COAGULATION LAB specimen requirements: BLUE TOP normal or reference ranges: Category LOW HIGH UNITS NORMAL unit of measure: NORMAL/ABNORMAL ideal sample: 4.5 ML WHOLE BLOOD, ADULT SIZE, 5ML TUBE absolute minimum amount: 2.7 ML WHOLE BLOOD, FILL TO THE LINE ON THE TUBE The following substances can adversely affect the results: CLOTS IN SPECIMEN , IMPROPER LINE DRAW request test on form: HEMATOLOGY TEST REQUEST ( 151-204 ) MISCELLANEOUS ( 151-858 ) order/entry screen(s): HEMATOLOGY/COAGULATION ( 08 ) method: MECHANICAL CLOT DETECTION stat frequency : NOT PERFORMED STAT routine frequency: M-F routine turn around time: 1 WEEK For Hillcrest deliver to: SPEC. PROCESS/PHLEBOTOMY : CENTRAL PROCESSING

74. Antibiotic Time Kill Synergy Clinical Significance resistance to activated protein C (APC) is a common inheritedthrombophilia that accounts for up to onehalf of inherited thromboses. http://www.aruplab.com/guides/clt/tests/clt_al66.htm

ARUP's Guide to Clinical Laboratory Testing (CLT) A B C D ... Search Note: Test code links throughout this Guide refer to the corresponding test in the User's Guide. Antibiotic Time Kill Synergy Test Number: Methodology: Time Kill Studies Synergy testing is performed by time-kill method. The initial antibiotic concentration is set to reflect achievable peak serum concentration and standard dosing for bacterial endocarditis. This test is performed for isolates from a significant site only (CSF, blood, bone, etc.). This test is not performed for respiratory isolates or isolates from a non-significant body site. Clinical Significance: Assessment of antimicrobial combinations may be of use in the following clinical situations: To provide a broader spectrum of antimicrobial activity during empirical therapy of severely ill patients when polymicrobial infection is recognized or suspected, To attempt to prevent or minimize the likelihood of the emergence of drug-resistant bacterial subpopulations, To allow the use of a lower concentration of drugs in combination and thus diminish the incidence of drug-related antibiotic toxicity. Synergy testing challenges the patient's infective organism against a combination of two or more antimicrobial agents in order to determine synergism, antagonism, or indifference.

75. Resistance To Activated Protein C (APC) In Childhood Hydrocephalus Julkaisu. Reference. Riikonen R, Kekomäki R. resistance to activated proteinC (APC) in childhood hydrocephalus. Thromb Haemost 19987910591060. http://www.uku.fi/wwwdata/julkaisutoiminta/julkaisut/1998/9801472.html

Julkaisu Reference Riikonen R, Kekomäki R. Resistance to activated protein C (APC) in childhood hydrocephalus. Thromb Haemost Julkaisutiedot Julkaisutyyppi: Kirje tiet.lehdessä. Kansainvälinen. Kieli: Englanti. Publication data Publication type: Letter/comment/tech. Note/book review. International. In English. Tekijät Contributors Kuopion yliopisto Lastenklinikka Raili Riikonen University of Kuopio Department of Paediatrics Raili Riikonen Kuopion yliopistollinen sairaala Lastenklinikka Raili Riikonen Kuopio University Hospital Children's Hospital Raili Riikonen Julkaisutietokanta Publications Data Base

76. APC (Activated Protein C) Resistance APC (activated protein C) resistance ?. Waikato. Taumarunui. TeKuiti.Thames. Tokoroa. Specimen Required 4.5 mL Citrate tube. Minimum http://www.waikatodhb.govt.nz/laboratory/tests/haematology_tests/apc.htm

APC (Activated Protein C) Resistance Waikato Taumarunui TeKuiti Thames Tokoroa Specimen Required: 4.5 mL Citrate tube Minimum Referred Volume: 0.5 mL double spun, frozen plasma Reference Interval: 0.88 - 1.15 (normalised ratio) Imprecision: Turnaround Time: Batched weekly Department Haematology Price Resistance to the anticoagulant effects of activated protein C (APC) was initially reported by Dahlback et al (1993) in a family with venous thrombosis. Protein C is an anticoagulant protein synthesised in the liver. Once activated on the endothelial cell surface APC selectively degrades the activated clotting factors Va and VIIIa. APC resistance (APCR) has been shown to be associated, in 90% or more of cases, with a mutation in the factor V gene (Arg506Gln) which gives rise to a variant form of factor V, factor V Leiden (FV Leiden). FV Leiden has normal procoagulant activity, but is partially resistant to cleavage and inactivation by APC. This gives rise to a hypercoagulable state. FV Leiden is recognised to be the commonest of the inherited risk factors for VTE with a high prevalence in populations of European origin. The prevalence of the mutation ranges from 2-5% among European studies.

77. PAPER 1 - DELTAS and VIII. resistance to activated protein C is considered the mostprevalent inherited cause of venous thrombosis. The most common http://www.cing.ac.cy/MolGen/deltas/thrombo.htm

Katerina Angelopoulou, Ph.D., Andrew Nicolaides, FRCS, C. Constantinou Deltas, Pharm.R., Ph.D. E-mail: deltasco@cing.ac.cy Thrombosis is a serious condition, killing hundreds of thousands and debilitating millions each year by myocardial infraction, pulmonary embolism, or stroke. Inherited thrombophilia is a genetically determined tendency to venous thromboembolism. The term reflects the presence of an inherited factor that, per se, predisposes towards thrombosis, but which, because of the episodic nature of thrombosis, requires interaction with other factors (inherited or acquired) before onset of the clinical disorder. Mutations in genes encoding proteins that activate coagulation pathways or inactivate anticoagulation mechanisms play an important role in the predisposition to venous thrombosis. Blood coagulation is downregulated by the protein C anticoagulant system. Protein C is activated on endothelial cells by thrombin bound to thrombomodulin. Together with its cofactor, protein S, activated protein C degrades the activated forms of factor V and VIII. Resistance to activated protein C is considered the most prevalent inherited cause of venous thrombosis. The most common cause of this resistance is a point mutation in the factor V gene (Factor V Leiden) that replaces an arginine residue at position 506 with a glutamine, R506Q (G to A transition at position 1691). This change causes the mutant factor Va to resist proteolysis by activated protein C. The frequency of the Leiden genetic variation is relatively high in Caucasian populations (up to 6%) but it is much lower in African and Asian populations (down to 0%).

78. Coagulation Reagents - Activated Protein C activated protein C is prepared from purified protein C by activation prolong theaPTT of normal human plasma, as required for the APC resistance assay (10 http://www.haemtech.com/catalog/Enzymes/e1.htm

TODAY IS document.write(monthname + " " + datenumber + ", " + year); ACTIVATED PROTEIN C Inactivation of Factor Va by Activated Protein C (APC) Proteolytic inactivation of factor Va by APC is represented, where: PS=protein S, PCPS=phospholipid vesicles (or cellular surface) and Ca Activated protein C (APC) is an anticoagulant serine protease derived from the two chain, vitamin K-dependent zymogen, protein C (3-7). A complex between a -thrombin and thrombomodulin catalyzes a single cleavage at Arg-12 (Arg-14 in bovine) in the heavy chain of protein C, to generate APC. Several non-physiologically relevant proteases such as RVV-X activator, trypsin, and PROTAC are also capable of activating protein C. APC functions as an anticoagulant which catalyzes the proteolytic inactivation of the cofactors, factors Va and VIIIa, leading to inhibition of the prothrombinase and factor Xase complexes. The inactivation of factors Va and VIIIa is both Ca and phospholipid dependent. The vitamin K dependent cofactor, protein S, moderately increases this rate of inactivation by forming a 1:1 complex with APC (K

79. Protein C Deficiency It is synthesized in the liver as an inactive form. activated protein C isa serine protease which functions to inactivate Factors Va and VIIIa. http://www.medinfo.ufl.edu/year2/coag/cdef.html

Protein C Deficiency I. Review - Protein C: It is a Vitamin K-dependent protein synthesized in the liver and is an inhibitor of the procoagulant system. It is synthesized in the liver as an inactive form. Activated Protein C is a serine protease which functions to inactivate Factors Va and VIIIa. Protein C is activated to Protein Ca when thrombin binds to thrombomodulin. This binding alters the conformation of thrombin to a form that readily activates Protein C. The activity of Protein C is markedly enhanced by its cofactor Protein S. II. Mechanisms of Inhibition A. Congenital deficiency of Protein C 1. Inherited as an autosomal dominant disorder and may account for up to 5-10% of patients with early clotting problems. 2. Heterozygous individuals have Protein C levels of 30 to 60% of normal, while homozygotes have little to no Protein C. 3. There are two types of congenital deficiencies: Type I - Decreased levels of Protein C Type II - rare - There is normal level of Protein C, but decreased functional activity. 4. Clinical features:

80. Newspath Abstracts Arch Pediatr Adolesc Med. 2001;1556065. Acquired activated proteinC resistance in cancer patients with venous thromboembolism. http://www.cap.org/newspath/archives/spring_2002/abstracts.html

Spring 2002 NEWSPATH Reliability of pediatric urinalysis in young febrile children Arch Pediatr Adolesc Med Acquired activated protein C resistance in cancer patients with venous thromboembolism Activated protein C resistance is associated with the Factor V Leiden genotype, while acquired activated protein C resistance occurs in the absence of this mutation. The authors performed a prospective, controlled study to evaluate the prevalence of inherited and acquired activated protein C resistance in cancer patients with and without venous thromboembolism. The mean values of the activated protein C sensitivity ratio (the ratio between the activated partial thromboplastin times with and without activated protein C) were significantly lower in the groups with cancer and the control group with thromboembolism as compared to the healthy controls. Cancer patients with venous thromboembolism had lower activated protein C sensitivity ratios than did cancer patients without thromboembolism ( P =0.03 after excluding those patients with the Factor V Leiden mutation). The authors concluded that acquired activated protein C resistance is a common finding in cancer patients with venous thromboembolism and that the presence of the Factor V Leiden mutation in these patients is unusual. Am J Med Prevalence of iron deficiency and cognitive impairment in school-aged children Iron deficiency is the most common hematologic disorder in childhood, but the cognitive effects of iron deficiency, particularly without anemia, are not well studied. The authors examined data from The National Health and Nutrition Examination Survey (NHANES) III, in which children between the ages of 6 and 16 years were studied. The authors found that the prevalence of iron deficiency was greater than five percent among children living below the poverty level. Average math scores were lower for the iron-deficient children without anemia compared with children with normal iron status (87.4 versus 93.7;

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