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Tissue Factor Pathway Inhibitor Is Increased in Plasma of Patients with a mild to Moderate Bleeding Tendency Independent of Known Genetic Variations in the factor V Encoding Gene

D. Mehic1, A. Tolios2, S. Hofer1, H. Haslacher3, J. Rejtö1, C. Ay1, M. Haimel4, I. Pabinger1, W. Ouwehand5, K. Downes5, J. Gebhart1

1Medical University of Vienna, Department of Medicine I, Clinical Division of Haematology and Haemostaseology, Vienna, Austria, 2Medical University of Vienna, Department of Blood Group Serology and Transfusion Medicine, Vienna, Austria, 3Medical University of Vienna, Department of Laboratory Medicine, Vienna, Austria, 4CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria, 5University of Cambridge, Department of Haematology, Cambridge, United Kingdom

Abstract Number: PB0417

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Tissue Factor Pathway

Background: Increased levels of free tissue factor pathway inhibitor(TFPI) based on 2 mutations in the factor V(FV) gene (Transcript-NCBI ID:NM_000130.4) were reported as cause of bleeding tendencies (Vincent et al., 2013; Cunha et al., 2015). Recently, the intronic single-nucleotide variant(SNV) rs10800453 in the FV gene was related to elevated TFPI levels in a genome wide association study (Sun et al., 2018).

Aims: To investigate TFPI levels in a large cohort of adult patients with a mild-to-moderate bleeding tendency(MBD) and healthy controls and to identify possible underlying genetic alterations in the FV encoding gene.

Methods: Patients from the Vienna Bleeding Biobank study and 122 healthy controls were investigated after written informed consent. Free TFPI levels were measured using an ELISA (Stago, Asniéres France). Genetic data were generated by the ThromboGenomics assay (Downes et al., 2019) and using Affymetrix Axiom genotyping arrays. The genotypes for rs10800453 were imputed using the Sanger Imputation Service

Results: 620 patients (81.5% females) and 122 controls were investigated (Table 1). Median [IQR] free TFPI levels were higher in patients than in healthy controls (8.3 [5.7-11.8] vs. 7.8 [4.9-11.2] ng/mL; p=0.016). TFPI levels were higher in male patients (10.0 [7.8-13.2] vs. 7.7 [5.4-11.4] ng/mL; p=0.006) and associated with higher age (rs=0.401). The statistically significant difference between TFPI levels in patients and healthy controls prevailed after adjusting for sex and age in multivariable linear regression analysis. We could not identify the reported mutations c. 2588 C>G or c.2440 A>G in our patients. The SNV rs10800453 did not affect TFPI levels in our patients (Figure 1).

Conclusions: Free TFPI levels were increased and might contribute to the bleeding tendency in our patients. We did not identify known genetic alterations for increased TFPI levels in our cohort. Further investigations are needed to understand the underlying mechanisms of increased TFPI levels in patients with MBDs.

  All Patients (n=620) Healthy Controls (n=122)
Female, n (%) 505 (81.5%) 82 (67.2%)
  median [25-75 percentile] median [25-75 percentile]
Age, years 40 [28-52.75] 38.5 [28.75-52]
Vicenza bleeding score 5 [4-8] 0 [0-0]
ISTH BAT bleeding score (available from 359 patients) 6 [4-9] –
Platelets, x10^9/L 244.5 [209-283.75] 257 [221.8-292]
APTT, seconds 35.9 [33.7-38.9] 35.1 [33.2-36.4]
PT, % 95 [88-104] 100 [91-109]
TFPI, ng/mL (available from 607 patients) 8.3 [5.7-11.8] 7.8 [4.9-11.2]

[Table1 Patient characteristics including clinical data and parameters]


[Figure 1 Genetic Analysis: Comparison of TFPI levels in patients with 0, 1 or 2 alleles of evaluated SNV rs10800453]

To cite this abstract in AMA style:

Mehic D, Tolios A, Hofer S, Haslacher H, Rejtö J, Ay C, Haimel M, Pabinger I, Ouwehand W, Downes K, Gebhart J. Tissue Factor Pathway Inhibitor Is Increased in Plasma of Patients with a mild to Moderate Bleeding Tendency Independent of Known Genetic Variations in the factor V Encoding Gene [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/tissue-factor-pathway-inhibitor-is-increased-in-plasma-of-patients-with-a-mild-to-moderate-bleeding-tendency-independent-of-known-genetic-variations-in-the-factor-v-encoding-gene/. Accessed September 21, 2023.

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