Authors:	Döhrmann, Mareike Makhoul, Stephanie Gross, Kathrin Krause, Manuela Pillitteri, Daniele Auer, Charis von Walter, Ulrich Lutz, Jens Volf, Ivo Kehrel, Beate E. Kerstin, Jurk
Title:	CD36-fibrin interaction propagates FXI-dependent thrombin generation of human platelets
Online publication date:	16-Aug-2021
Year of first publication:	2020
Language:	english
Abstract:	Thrombin converts fibrinogen to fibrin and activates blood and vascular cells in thrombo-inflammatory diseases. Platelets are amplifiers of thrombin formation when activated by leukocyte- and vascular cell-derived thrombin. CD36 on platelets acts as sensitizer for molecules with damage-associated molecular patterns, thereby increasing platelet reactivity. Here, we investigated the role of CD36 in thrombin-generation on human platelets, including selected patients with advanced chronic kidney disease (CKD). Platelets deficient in CD36 or blocked by anti-CD36 antibody FA6.152 showed impaired thrombin generation triggered by thrombin in calibrated automated thrombography. Using platelets with congenital function defects, blocking antibodies, pharmacological inhibitors, and factor-depleted plasma, CD36-sensitive thrombin generation was dependent on FXI, fibrin, and platelet signaling via GPIbα and SFKs. CD36-deficiency or blocking suppressed thrombin-induced platelet αIIbβ3 activation, granule exocytosis, binding of adhesion proteins and FV, FVIII, FIX, FX, but not anionic phospholipid exposure determined by flow cytometry. CD36 ligated specifically soluble fibrin, which recruited distinct coagulation factors via thiols. Selected patients with CKD showed elevated soluble fibrin plasma levels and enhanced thrombin-induced thrombin generation, which was normalized by CD36 blocking. Thus, CD36 is an important amplifier of platelet-dependent thrombin generation when exposure of anionic phospholipids is limited. This pathway might contribute to hypercoagulability in CKD.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6280
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY-NC
Information on rights of use:	https://creativecommons.org/licenses/by-nc/4.0/
Journal:	The FASEB journal 34 7
Pages or article number:	9337 9357
Publisher:	Wiley
Publisher place:	Hoboken, NJ
Issue date:	2020
ISSN:	1530-6860
Publisher URL:	https://doi.org/10.1096/fj.201903189R
Publisher DOI:	10.1096/fj.201903189R
Appears in collections:	JGU-Publikationen