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Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activation in vitro.

Abstract：

:No consensus has been obtained about the question whether autoantibodies, in particular antiphospholipid antibodies (aPL), may cause thrombosis by inhibiting thrombomodulin (TM) mediated protein C activation. In order to clarify the mechanism by which autoantibodies inhibit TM-mediated protein C activation, we have screened 12 patients with autoimmune diseases for the presence of circulating autoantibodies inhibiting TM function. In a cross-sectional study we found that IgG fractions from two patients (who were aPL negative) inhibited TM mediated protein C activation in an assay system using purified components. A longitudinal study of six patients with a history of thrombosis of which two were aPL positive showed that all had at some time circulating antibodies inhibiting TM function, suggesting that the presence of these antibodies is transient. Three different TMs were used to identify the epitope of the antithrombomodulin antibodies (aTM): rabbit TM, which contains the entire TM molecule; Solulin, which contains the extracellular part of TM, and rEGF-TM, which contains the six epidermal growth factor (EGF) domains of TM. We showed that the aTM inhibited protein C activation mediated by all three TMs, indicating that the aTM are directed against the region containing the EGF domains. When TM was incorporated in phospholipid vesicles, no inhibition by these aTM could be demonstrated. In addition, protein C activation mediated by cultured endothelial cells (EC) could not be inhibited by aTM. The lack of inhibition of TM in phospholipid vesicles and EC-TM by a TM suggests that aTM only inhibit soluble TM. In conclusion, we demonstrated the transient presence of circulating autoantibodies directed against the region of TM containing the EGF domains in SLE patients with a history of thrombotic complications. We postulate that the presence of antibodies to soluble TM may be, in addition to aPL, a risk factor for the occurrence of thrombosis in patients with autoimmune diseases.

journal_name

Br J Haematol

journal_title

British journal of haematology

authors

Oosting JD,Preissner KT,Derksen RH,de Groot PG

doi

10.1111/j.1365-2141.1993.tb03220.x

subject

Has Abstract

pub_date

1993-12-01 00:00:00

pages

761-8

issue

eissn

0007-1048

issn

1365-2141

journal_volume

pub_type

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Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activation in vitro.