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Thromb Res. 2019 Jul;179:140-146. doi: 10.1016/j.thromres.2019.05.005. Epub 2019 May 9.

The role of variant alleles of the mannose-binding lectin in the inhibitor development in severe hemophilia A.

Author information

1
Medical Clinic III, University Hospital Bonn, Centre for Internal Medicine, Sigmund-Freud Street 25, D-53127 Bonn, Germany. Electronic address: gudrun.ulrich-merzenich@ukbonn.de.
2
Medical Clinic I, University Hospital Bonn, Centre for Internal Medicine, Sigmund-Freud Street 25, D-53127 Bonn, Germany. Electronic address: annekristin.hausen@ukbonn.de.
3
Medical Clinic I, University Hospital Bonn, Centre for Internal Medicine, Sigmund-Freud Street 25, D-53127 Bonn, Germany. Electronic address: heike.zeitler@ukbonn.de.
4
Institute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, Sigmund-Freud Street 25, D-53127 Bonn, Germany. Electronic address: georg.goldmann@ukbonn.de.
5
Institute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, Sigmund-Freud Street 25, D-53127 Bonn, Germany. Electronic address: johannes.oldenburg@ukbonn.de.
6
Institute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, Sigmund-Freud Street 25, D-53127 Bonn, Germany. Electronic address: anna.pavlova@ukbonn.de.

Abstract

INTRODUCTION:

The administration of FVIII leads to inhibitors in up to 30% of patients with hemophilia A (HA), the most severe treatment complication. FVIII-mannosylation fosters the presentation of FVIII to CD4+-T-lymphocytes. Mannose as primary ligand for the mannose-binding lectin (MBL) activates the lectin pathway of complement. MBL2 single nucleotide polymorphisms (SNPs) lead to low peripheral MBL concentrations that may hamper the removal of mannosylated FVIII.

OBJECTIVE:

Investigation of the association between the inhibitor development in hemophilia A and MBL2-SNPs.

METHODS:

In a case-control study the MBL2-SNPs in exon 1 at codons 52, 54 and 57 (C, B, D-Alleles respectively) were determined in 237 patients with severe hemophilia A with and without inhibitors to FVIII (119 vs 118). The association of MBL2-SNPs and the -308 G>A TNF-α-polymorphism with the presence of inhibitors were determined.

RESULTS:

In the inhibitor group higher frequencies of the B allele (codon 54) (OR: 1.77, P < 0.05) were present. Summarising the MBL2 SNPs (alleles B, C and D) as 0, the 0/0 type occurred only in the inhibitor group (frequencies: 0.08 vs 0, P = 0.003). Based on the genetic background a functional immune response phenotype was determined. 11.8% of patients with inhibitors were of the low MBL/high TNF-α phenotype vs 0.03% of the non-inhibitor patients (OR: 3.71).

CONCLUSION:

Data suggest an association of MBL2-SNPs alone or combined with the 308-TNF-α polymorphism in the inhibitor development. Investigations of components of all three complement pathways are required to comprehend their individual and overall contribution to the inhibitor development in HA.

KEYWORDS:

Coagulation; FVIII-inhibitor; Hemophilia A; Innate immune system; MBL; Mannosylation

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