Rivaroxaban Causes Missed Diagnosis of Protein S Deficiency but Not of Activated Protein C Resistance (Factor V Leiden)

Maryamchik, Elena; Rosenbaum, Michael; Cott, Elizabeth M. Van

doi:10.5858/arpa.2016-0616-oa

Cited by 10 publications

(17 citation statements)

References 17 publications

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“…Marked differences have been seen in PS activity results between different kits complicating the interpretation of quality assurance assessment for these assays 137 . Some DOAC have been reported to impact on the results of these assays 138 but not others 139 …”

Section: Fibrinogenmentioning

confidence: 99%

Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis

et al. 2020

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Section: Fibrinogenmentioning

confidence: 99%

Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis

et al. 2020

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“…12,26 DOAC may or may not falsely elevate PS activity. 26,31,32 Known conditions that interfere with PS activity and antigen tests results are listed in Table 1.…”

Section: Pre Analy Tic Al and P Os Tanaly Tic Al Variab Le S 41 | mentioning

confidence: 99%

Recommendations for clinical laboratory testing for protein S deficiency: Communication from the SSC committee plasma coagulation inhibitors of the ISTH

Marlar

Gausman

Tsuda

et al. 2021

Journal of Thrombosis and Haemostasis

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Hereditary deficiencies of protein S (PS) increase the risk of venous thrombosis; however, assessing the plasma levels of PS can be difficult because of its complex physiological interactions in plasma, sample‐related preanalytical variables, and numerous acquired disease processes. Reliable laboratory assays are essential for accurate evaluation of PS when diagnosing a congenital deficiency based on the plasma phenotype alone. This report presents the current evidence‐based recommendations for clinical PS assays as well as when to test for PS abnormalities.

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“…Most assays are designed to reduce or eliminate the effects of vitamin K antagonist and heparin anticoagulation, whereas interference by direct‐acting anticoagulants is reagent‐dependent and drug level–dependent . Direct activated FX (FXa) inhibitors and direct thrombin inhibitors (DTIs) can falsely elevate APC‐R ratios, resulting in the potential for samples with APC‐R to be misclassified as normal, although a recent study showed that APTT‐based testing with predilution distinguished FVL heterozygotes from normal patients despite rivaroxaban treatment, even at high drug levels …”

Section: Preanalytic Issuesmentioning

confidence: 99%

“…The modified APC‐R (MAPC‐R) assay is performed identically to the CAPC‐R assay, except that plasma is diluted 1:5 in FV‐deficient plasma (FVDP) to reduce or eliminate interferences and make the assay more specific for abnormalities in FV . The FVDP eliminates interference from reduced or elevated coagulation factor levels, vitamin K antagonist therapy, low protein S levels, pregnancy, and oral contraceptives .…”

Section: Analytic Issuesmentioning

confidence: 99%

Recommendations for clinical laboratory testing of activated protein C resistance; communication from the SSC of the ISTH

Moore

Cott

Cutler

et al. 2019

Journal of Thrombosis and Haemostasis

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| INTRODUC TI ONRegulation of fibrin formation through activated protein C (APC) degradation of activated factor V (FVa) and activated FVIII is a major anticoagulant process of hemostasis. In 1993, Dahlbäck et al 1 identified thrombophilic individuals whose plasma showed a poor response to APC in a coagulation assay based on activated partial thromboplastin time (APTT). This was found to be related to an arginine 506 to glutamine substitution in F5 rendering FV resistant to APC inactivation, and called FV Leiden (FVL). 2 Mutations in F5 other than FVL that confer APC resistance (APC-R) with various degrees of clinical severity have been described, although they appear to be very rare. 3 As the original assay was based on APTTs performed on undiluted plasma, it was prone to numerous interferences, so a modification was subsequently proposed that improved sensitivity and specificity by diluting test plasma in FV-deficient plasma, and remains in widespread use. 4-6 Acquired APC-R may occur in the absence of F5 mutations, and represents an independent risk factor for venous thrombosis. 7 APC-R detection has evolved since the original assay and its modification, and this is the first guideline to address clinical laboratory testing recommendations for the wider set of commonly available phenotypic assays. | PRE ANALY TIC ISSUE S | Patient selectionIndiscriminate testing for APC-R is not recommended in unselected patients with venous thromboembolism (VTE). Targeted testing is recommended for those situations in which the results may give an indication of risk of recurrence and influence treatment, as is the case for any patient undergoing evaluation for thrombophilia involving VTE. More detail is available in recent clinical guidelines. 8-10 | Sample handlingVenous blood should be collected into a one-tenth volume of 3.2% (0.105-0.109 mol/L) trisodium citrate, and double-centrifuged to ensure a residual platelet count of <10.0 × 10 9 /L. 4,11,12 As some other thrombophilia assays also require similarly effective platelet removal, this permits running of multiple assays with the same, suitably prepared, plasma sample. The white cells remaining after plasma removal can be stored for DNA extraction should molecular analysis be required, or cells from an EDTA-anticoagulated sample can be used.Plasma for APC-R assays should be tested within 4 hours of collection or frozen (at -20°C if stored for ≤2 weeks, and at −70°C or below if stored for >2 weeks) if testing is postponed. Frozen samples should be rapidly thawed in a waterbath at 37°C, and thoroughly mixed by multiple, gentle inversions prior to testing. Icterus, hemolysis and lipemia can interfere, especially in assays performed on undiluted plasma. Plasma predilution assays are less affected by platelet contamination. 3 Preliminary coagulation screening is useful to detect previously unknown factor deficiencies and anticoagulation, and, if a suitably sensitive APTT reagent is employed, lupus anticoagulants (LAs) may also be detected. | InterferencesAssay design and reag...

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Rivaroxaban Causes Missed Diagnosis of Protein S Deficiency but Not of Activated Protein C Resistance (Factor V Leiden)

Abstract: - Despite rivaroxaban treatment, APCR testing can distinguish FVL-HET from normal patients, rendering indiscriminate FVL DNA testing of all patients on rivaroxaban unnecessary. Free protein S should be tested in patients taking rivaroxaban to exclude hereditary protein S deficiency.

Cited by 10 publications

References 17 publications

Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis

Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis

Recommendations for clinical laboratory testing for protein S deficiency: Communication from the SSC committee plasma coagulation inhibitors of the ISTH

Recommendations for clinical laboratory testing of activated protein C resistance; communication from the SSC of the ISTH

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