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Coagulation & its Disorders
New insight into antiphospholipid syndrome: antibodies to β glycoprotein I-domain 5 fail
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):819-826
2
to induce thrombi in rats
Paolo Durigutto,1 Claudia Grossi,2 Maria Orietta Borghi,2,3 Paolo Macor,1 Francesca Pregnolato,2 Elena Raschi,2 Michael P. Myers,4 Philip G. de Groot,5 Pier Luigi Meroni2 and Francesco Tedesco2
1Department of Life Sciences, University of Trieste, Italy; 2Istituto Auxologico Italiano, IRCCS, Laboratory of Immuno-Rheumatology, Milan, Italy; 3Department of Clinical Sciences and Community Health, University of Milan, Italy; 4International Centre for Genetic Engineering and Biotechnology, Trieste, Italy and 5Department of Clinical Chemistry and Haematology, University of Utrecht, University Medical Center Utrecht, the Netherlands
PD and CG contributed equally to this work. PLM and FT contributed equally to this work.
ABSTRACT
Clinical studies have reported different diagnostic/predictive values
of antibodies to domain 1 or 4/5 of β2glycoproteinI in terms of
risk of thrombosis and pregnancy complications in patients with
antiphospholipid syndrome. To obtain direct evidence for the pathogen-
ic role of anti-domain 1 or anti-domain 4/5 antibodies, we analyzed the
in vivo pro-coagulant effect of two groups of 5 sera IgG each reacting
selectively with domain 1 or domain 5 in lipopolysaccharide (LPS)-treat-
ed rats. Antibody-induced thrombus formation in mesenteric vessels
was followed by intravital microscopy, and vascular deposition of
β glycoproteinI, human IgG and C3 was analyzed by immunofluores- 2
cence. Five serum IgG with undetectable anti-β glycoproteinI antibodies 2
served as controls. All the anti-domain 1-positive IgG exhibited potent
pro-coagulant activity while the anti-domain 5-positive and the negative
control IgG failed to promote blood clot and vessel occlusion. A stronger
granular deposit of IgG/C3 was found on the mesenteric endothelium of
rats treated with anti-domain 1 antibodies, as opposed to a mild linear
IgG staining and absence of C3 observed in rats receiving anti-domain 5
antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not
recognize cardiolipin-bound β glycoproteinI while being able to interact 2
with fluid-phase β glycoproteinI. These findings may explain the failure 2
of anti-domain 5 antibodies to exhibit a thrombogenic effect in vivo, and the interaction of these antibodies with circulating β2glycoproteinI sug- gests their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining “really at risk” patients for more appropriate treatments to avoid recurrences and disability.
Introduction
Antiphospholipid syndrome (APS) is a chronic autoimmune disorder character- ized by recurrent episodes of vascular thrombosis and adverse pregnancy out- comes in the presence of antibodies to phospholipid-binding proteins (aPL). It occurs either as a primary disease or concomitantly to other connective tissue dis- eases, particularly systemic lupus erythematosus (SLE).1 Although thrombotic occlusion may affect the vessels of all organs and tissues, common presentations of the syndrome are: a) deep vein thrombosis in the legs often complicated by pul- monary embolism; and b) thrombotic occlusion of cerebral and coronary arteries leading to stroke and myocardial infarction.2 This clinical condition is also associ- ated with pregnancy morbidity, including fetal loss, pre-eclampsia, pre-term deliv- ery, and ‘small for gestational age’ babies.3 These are serious complications that
Correspondence:
FRANCESCO TEDESCO
tedesco@units.it
Received: May 22, 2018.
Accepted: November 14, 2018. Pre-published: November 15, 2018.
doi:10.3324/haematol.2018.198119
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/819
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haematologica | 2019; 104(4)
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