Economic Impact of a Screening Strategy for Protein C Pathway Abnormalities Based on a New Global Chromogenic Assay (HemosIL ThromboPath) as a First Step Screening Assay In a Series of 597 Unselected Consecutive Patients.
Authors: Toulon Pierre A. , Martin-Toutain Isabelle , Ankri Annick 
Published: October 2019

Abstract
Abstract 3822
To date, screening for biological risk factors for thrombosis has been based on the measurement of individual parameters such as Protein C, PS, activated PC resistance and/or identification of the causative mutation R506Q (Factor V Leiden), and lupus anticoagulant (LA) in the case of PC pathway abnormalities. As FVL mutation can de demonstrated in around 20% of the patients of Caucasian origin with a history of thrombosis, and less than 5% of them presented with either PC or PS deficiency or LA, any of such abnormalities is found in less than one third of the tested samples. This suggests that the current screening strategy is costly and time-consuming and highlights the potential usefulness of a simple assay to screen globally for these abnormalities, as this would rationalize the use of expensive individual assays. The HemosIL ThromboPath assay (Instrumentation Laboratory) is a new chromogenic assay designed to globally evaluate the functionality of the PC pathway. It is based on the ability of endogenous APC generated after activation of PC by a snake venom extract (Protac) to reduce the thrombin generation induced by a reagent containing tissue factor. Briefly, optical density is measured after addition of a thrombin-specific chromogenic substrate in the presence (OD A) or absence (OD B) of Protac. It is recommended by the manufacturer to express test results as the Protac-Induced Coagulation Inhibition percentage (PICI%) which corresponds to the ratio [OD B-OD A]/OD B × 100 and to consider as normal, test results above the cut-off level defined as the mean minus 1 SD of the PICI% measured in the plasma of 30 healthy controls. The aim of this retrospective study was to evaluate the economic impact of a screening strategy for PC pathway abnormalities based on that new global assay as a first step screening assay, in a series of unselected consecutive patients referred to our laboratory for screening of biological risk factors for thrombosis, during a 6-month period. At the time of the study, 697 frozen plasma samples were still available, and 597 samples were further evaluated after excluding those obtained from patients on oral anticoagulant treatment (n=83) or with evidence of liver failure (n=17), both situations being associated with a decreased response to the global assay. There were 215 M and 382 F with a mean age of 45.6 years (range: 15–100). PICI% was significantly lower in patients who presented with any PC pathway abnormality than in those without [median=69.0% (range: 15.3–88.3), n=100 vs. 89.8 (range: 38.5–98.0), n=497; p<0.0001]. All patients with PC pathway abnormality i.e. FVL mutation (1 homozygous and 32 heterozygous carriers), PC deficiency (activity <70%, n=14), PS deficiency (free antigen concentration<50%, n=45) and LA (n=8) had a PICI% below the cut-off level (88.5%) and the same applied to 41.5% of the patients without PC pathway abnormality (n=206/496). As the test performed well in those patients, with an overall sensitivity to PC pathway abnormalities of 100% (95%CI=96.4-100), a specificity of 58.5% (95%CI=54.1-63.0), negative predictive value (NPV) of 100% (95%CI=98.7-100) and a PPV of 32.7% (95%CI=27.4-38.2), a screening strategy could be proposed in which the HemosIL ThromboPath assay would be used as a first-step screening test for all these PC pathway abnormalities, and the corresponding individual assays be performed only in the case of an abnormal test result. If applied to our series, such a screening strategy would have leaded to a 28.6% decrease in the total number of tests performed and to a 30.1% reduction in the screening costs (incl. reagents and labor) when compared to the routine strategy. In conclusion, the high sensitivity of the HemosIL ThromboPath assay to PC pathway abnormalities and the high NPV (100%) associated with a normal test result, suggest its potential interest as part of a screening strategy for these abnormalities. In our technical conditions and with a 16.8% frequency of PC pathway abnormalities in our population, such a strategy, in which the HemosIL ThromboPath would be performed as a first screening assay and specific assays only performed when test result was abnormal, would have been associated with a 28.6% reduction in the number of tests performed and a 30.1% reduction in the total screening costs. However, these results deserve to be confirmed in larger scale studies involving populations of different origins and/or in different technical conditions.

Disclosures:
No relevant conflicts of interest to declare.