Drug Causes Missed Diagnosis of Protein S Deficiency

Rivaroxaban is a direct, antithrombin-independent factor Xa inhibitor, which inhibits not only free factor Xa, but also clot-bound factor Xa and the prothrombinase complex. It is used for treatment and prevention of venous thromboembolism, as well as for prophylaxis of stroke in patients with atrial fibrillation.

Many patients taking rivaroxaban undergo hypercoagulation testing to rule out common inherited or acquired causes of hypercoagulability, including assays for activated protein C resistance (APCR) to detect factor V Leiden (FVL), and tests for protein S deficiency. However, it has been reported that spiking normal plasma with rivaroxaban caused an artefactual increase in the APCR ratio.


Scientists at Massachusetts General Hospital (Boston, MA, USA) compared of 60 patients in four different groups: FVL heterozygous (FVL-HET)/taking rivaroxaban, wild-type/taking rivaroxaban, FVL-HET/no rivaroxaban, and normal APCR/no rivaroxaban, and 32 patients taking rivaroxaban were tested for protein S functional activity and free antigen.

The patients were evaluated using the standard FVL testing protocol: an activated partial thromboplastin time (aPTT)-based APCR assay with dilution in factor V–deficient plasma on a Star Evolution analyzer and an FVL DNA assay. Protein S functional activity was measured using the Stago STACLOT Protein S assay on a Star Evolution analyzer, and free protein S antigen was measured using the Stago Asserachrom Free Protein S.

The team found that the FVL-HET patients taking rivaroxaban had lower APCR ratios than wild-type patients. For FVL-HET patients taking rivaroxaban, mean APCR was 1.75 ± 0.12, versus 1.64 ± 0.3 in FVL-HET patients not taking rivaroxaban. Activated protein C resistance in FVL-HET patients fell well below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite rivaroxaban, but in contrast, rivaroxaban falsely elevated functional protein S activity, regardless of the presence or absence of FVL. A total of 4/32 patients (12.5%) had low free protein S antigen (range, 58%–67%), whereas their functional protein S activity appeared normal (range 75%–130%).

The authors concluded that 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. The study was published in January 2018 in the journal Archives of Pathology & Laboratory Medicine.

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