Human complement factor H is a reductase for large soluble von Willebrand factor multimers--brief report

Area of Science:

• Biochemistry
• Hematology
• Immunology

Background:

• Ultralarge von Willebrand factor (vWF) strings are secreted by endothelial cells and are crucial in hemostasis.
• A disintegrin and metalloprotease with thrombospondin domains-type 13 (ADAMTS13) cleaves ultralarge vWF strings into large soluble vWF multimers.
• Normal plasma possesses a nonproteolytic reducing activity that further reduces the size of these large vWF multimers.

Purpose of the Study:

• To identify the nonproteolytic reducing activity responsible for diminishing large soluble vWF multimer size.
• To elucidate the role of this activity in regulating vWF multimer size.

Main Methods:

• Isolation and purification of vWF reductase activity from human plasma using chromatography.
• Identification of the purified protein using mass spectroscopy, SDS-PAGE, and antibody-based methods.
• Assay of recombinant human factor H (FH) activity on large soluble vWF multimers in a thiol-dependent reaction.

Main Results:

• The vWF reductase activity was isolated and identified as the complement regulatory protein, factor H (FH).
• Immunoabsorption of FH from partially purified vWF reductase abolished the reducing activity, which was recovered in the eluates.
• Recombinant human FH demonstrated the ability to reduce large soluble vWF multimers through a free thiol-dependent mechanism, unaffected by protease inhibitors.

Conclusions:

• Factor H (FH) is identified as the protein responsible for the nonproteolytic reduction of large soluble von Willebrand factor (vWF) multimers.
• FH plays a significant role in regulating vWF multimer size, independent of proteolytic cleavage.