Abstract Number: PB1182
Meeting: ISTH 2020 Congress
Background: Variants in the collagen-related genes COL1A1, COL3A1, COL5A1 and COL5A2 are associated with Ehlers-Danlos syndrome (EDS), a group of heterogeneous connective tissue disorders known to be associated with increased bleeding. Following genetic screening, a relatively high proportion of patients suspected of inherited bleeding disorders were found to harbor at least one heterozygous variant of unknown significance in one of the above-mentioned collagen-related genes. For the synthesis of functional collagen molecules, ascorbic acid (AA) is required.
Aims: To investigate the functional consequences of variants in COL1A1, COL3A1, COL5A1 and COL5A2, as well as plasma levels of AA in patients with incompletely explained bleeding tendencies.
Methods: In total, 31 patients harboring at least one heterozygous variant in COL1A1, COL3A1, COL5A1 or COL5A2 and 20 healthy controls were included. The turnover of collagen type I, III and V was assessed in patients and controls using validated ELISAs based on monoclonal antibodies targeting neo-epitopes specific for collagen formation and degradation. In addition, plasma levels of AA were analyzed in patients using high-performance liquid chromatography. Written informed consent was obtained from patients and controls. The study was approved by regional ethical committees.
Results: On a group basis, no significant differences were found between patients and controls regarding collagen turnover, with the exception of lower levels of C5M (degradation of collage type V) in the patients (p = 0.033) (Table 1). A negative correlation between bleeding, assessed by the ISTH-BAT score, and plasma AA levels was shown in the patients (r = -0.42; r2 = 0.17; p = 0.020) (Figure 1).
Conclusions: Functional investigations of the turnover of collagen type I, III and V were not able to confirm the variants in COL1A1, COL3A1, COL5A1 and COL5A2 as causative of increased bleeding. However, the correlation between bleeding and plasma AA levels warrants further investigations.
|Patients (n = 31)||Controls (n = 20)||p|
|PRO-C1 (ng/mL)||63.5 (41.1 – 104)||77.5 (48.8 – 114)||0.48|
|C1M (ng/mL)||28.7 (21.0 – 36.9)||29.0 (22.5 – 35.9)||0.81|
|PRO-C1/C1M||2.30 (1.34 – 3.64)||2.43 (1.36 – 4.93)||0.71|
|PRO-C3 (ng/mL)||9.49 (8.24 – 10.6)||10.5 (8.75 – 12.1)||0.23|
|C3M (ng/mL)||10.4 (8.95 – 11.6)||10.8 (9.88 – 12.1)||0.29|
|PRO-C3/C3M||0.91 (0.80 – 1.10)||1.00 (0.83 – 1.07)||0.58|
|PRO-C5 (ng/mL)||415 (346 – 464)||413 (352 – 472)||0.93|
|C5M (ng/mL)||3.45 (3.02 – 4.49)||4.44 (3.83 – 5.21)||0.033*|
|PRO-C5/C5M||114 (67.7 – 155)||89.3 (69.6 – 113)||0.081|
[Table 1. Turnover of collagen type I, III and V. Data are presented as medians (Q1 – Q3). Mann-Whitney tests were used. *, p-value < 0.05.]
To cite this abstract in AMA style:Fager Ferrari M, Zetterberg E, Rossing M, Manon-Jensen T, Pehrsson M, Karsdal M, Lykkesfeldt J, Leinoe E. Collagen Turnover and Plasma Ascorbic Acid Levels in Patients Suspected of Inherited Bleeding Disorders Harboring Variants in Collagen-related Genes [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/collagen-turnover-and-plasma-ascorbic-acid-levels-in-patients-suspected-of-inherited-bleeding-disorders-harboring-variants-in-collagen-related-genes/. Accessed October 1, 2023.
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