Activated Protein C Resistance Assay Detects Thrombotic Risk Factors Other Than Factor V Leiden

Graf, Laurie L.; Welsh, Carolyn H.; Qamar, Zainab; Marlar, Richard A.

doi:10.1309/qcuunrmvjy8mwppl

Cited by 39 publications

(37 citation statements)

References 34 publications

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“…Previous reports have shown that 5-10 % of APC resistance does not involve FV Leiden [21] whereas in our study this percentage was 38.4 %, increasing the possibility of other inherited or acquired factors contributing towards APC resistance in Indian population like elevated factor VIII levels [22]. Hong Kong and Cambridge gene mutations were absent in all the patients and controls.…”

Section: Discussioncontrasting

confidence: 61%

Polymorphisms in factor V and antithrombin III gene in recurrent pregnancy loss: a case–control study in Indian population

Sharma

Bhakuni

Ranjan

et al. 2015

J Thromb Thrombolysis

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Recurrent pregnancy loss (RPL) can be caused due to diverse factors with thrombophilia being one of them. The association of various thrombophilic risk factors with RPL is inconsistent in different studies and the frequency of these risk factors in Indian population is obscure. Five hundred and eighty patients with either recurrent early miscarriage or a history of at least one late miscarriage were screened for deficiency of protein C (PC), protein S (PS), antithrombin III (AT), APC resistance and prothrombin 20210G > A mutation. APC resistance positive patients were typed for the factor V Leiden, factor V Hong Kong/Cambridge mutations, and HR2 haplotype. PstI and rs2227589 AT mutations were detected by direct sequencing. APC resistance (13.4 %) was detected to be most common in Indian RPL patients followed by PS (10.6 %), PC (9.8 %) and AT deficiency (4.31 %.). FV Leiden was shown to be associated with APC resistance while HR2 haplotype was not associated with APC resistance (p values: 0.0001 and 0.327 respectively) and the increased risk of RPL. PstI and rs2227589 polymorphisms were similar in patients and controls and not associated with AT deficiency in RPL. Our study emphasizes the presence of other contributory factors towards APC resistance rather than FV Leiden alone. This is the first Indian study where HR2 haplotype and rs2227589 are observed to be present in RPL population. Although not significant, occurrence of rs2227589 and FV HR2 in homozygous condition necessitates the study of these polymorphisms in a larger sample size.

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Section: Discussioncontrasting

confidence: 61%

Polymorphisms in factor V and antithrombin III gene in recurrent pregnancy loss: a case–control study in Indian population

Sharma

Bhakuni

Ranjan

et al. 2015

J Thromb Thrombolysis

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“…[15][16][17][18] Nevertheless, it is probable that use of the aPTT-based assay is still warranted, given that acquired conditions or mutations other than FVL (to which the RVVT assays are quite sensitive) are likely to be important contributors to APCR. 15,19,20 For LA, error rates were also generally < 5%. The error rates in part were dependent on the strength of the LA (higher rates for weaker LA).…”

Section: Discussionmentioning

confidence: 96%

Multilaboratory Testing of Thrombophilia: Current and Past Practice in Australasia as Assessed through the Royal College of Pathologists of Australasia Quality Assurance Program for Hematology

Favaloro

Bonar²,

Sioufi³

et al. 2005

Semin Thromb Hemost

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We have conducted a series of multilaboratory surveys during the last 6 years to evaluate testing proficiency in the detection of congenital and acquired thrombophilia. For lupus anticoagulant (LA) testing, participant laboratories used a panel of tests, including activated partial thromboplastin time (aPTT; 100% of laboratories), kaolin clotting time (26 to 70%), and Russell's viper venom time (RVVT; 75 to 100%). Coefficients of variation (CVs) for assays ranged from 5 to 40%. RVVT assays appeared to be most sensitive and specific for detection of LA (fewer false-negatives or -positives), although laboratories performed best when they used a panel of tests. For congenital thrombophilia, tests evaluated comprised protein C (PC), protein S (PS), antithrombin (AT), and activated protein C resistance (APCR). Most participant laboratories performed PC using chromogenic (approximately 75%), or clot based (approximately 15%) assays, with few (< 10%) performing antigenic assessments. PS was most often assessed (approximately 60%) by immunological or antigenic assays, usually of free PS, or by functional or clot-based assays (approximately 40%). AT is usually assessed by functional chromogenic assays (approximately 95%). APCR was assessed using aPTT (approximately 50%) or RVVT (approximately 50%) clot-based assays, with the aPTT APCR typically performed using factor V-deficient plasma predilution, but the RVVT APCR typically performed without. Laboratories using the RVVT APCR generally performed better in detection of factor V Leiden-associated APCR, with the aPTT method group yielding higher false-negative and/or false-positive findings (approximately 5% of occasions). Some clot-based PC and PS assays appeared to be influenced by APCR status, and yielded lower apparent PC and PS levels with positive APC resistance. The overall error rate for PC, PS, and AT was approximately 2 to 8% (i.e., false-normal interpretations for deficient plasma or false-abnormal interpretations for normal plasma). The CVs for these assays ranged from 5 to 40%, with highest CVs typically obtained with PS assays.

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“…A limited repertoire of functional and genetic laboratory assays are currently available for risk assessment. These include FV Leiden [20,21], prothrombin G20210 [22,23], the FXIIIVal34Leu polymorphism [24], FVIII measurements [25], activated protein C resistance assays [26,27] and fibrinogen [28]. These assays, while informative, provide no integrated evaluation of potential stimulus–response coupling.…”

Section: Introductionmentioning

confidence: 99%

Thrombin generation: phenotypic quantitation

Brummel‐Ziedins

Pouliot

Mann

2004

Journal of Thrombosis and Haemostasis

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An individual's ability to generate thrombin following tissue factor stimulus was evaluated in 13 healthy male donors in a 6-month study. Thrombin generation in whole blood collected by phlebotomy, contact pathway suppressed by the presence of 100 micro g mL-1 corn trypsin inhibitor, was initiated by the addition of 5 pm tissue factor/10 nm phospholipid. Reactions were quenched at 20 min by the addition of an ethylenediaminetetraacetic acid (EDTA), benzamidine, FPRck cocktail. Thrombin generation was determined by an ELISA for thrombin-antithrombin III (TAT) complex formation. Results showed that the levels of TAT observed varied from 245 to 775 nm. Thrombin production was consistent within each individual, CVi = 11.6%, but varied significantly within the group, CVg = 25.2%, and correlated inversely with an individual's clotting time (r = - 0.54, P = 0.07). No correlations were individually observed between TAT and C-reactive protein, antithrombin III, factors II, V, VII, VIII, IX and X, fibrinogen and prothrombin time. However, computer simulations, which integrated each individual's coagulation factor levels using the Speed Rx method (Hockin et al., J Biol Chem 2002; 277: 18322), predicted maximum active thrombin levels (ranging from calculated values of 220-500 nm) consistent with the empirically determined values. Overall, these data suggest that thrombin generated in whole blood exclusively by tissue factor stimulation can be used as an integrative phenotypic marker to determine an individual's response to a tissue factor challenge.

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Activated Protein C Resistance Assay Detects Thrombotic Risk Factors Other Than Factor V Leiden

Cited by 39 publications

References 34 publications

Polymorphisms in factor V and antithrombin III gene in recurrent pregnancy loss: a case–control study in Indian population

Polymorphisms in factor V and antithrombin III gene in recurrent pregnancy loss: a case–control study in Indian population

Multilaboratory Testing of Thrombophilia: Current and Past Practice in Australasia as Assessed through the Royal College of Pathologists of Australasia Quality Assurance Program for Hematology

Thrombin generation: phenotypic quantitation

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