TY  - JOUR
U1  - Wissenschaftlicher Artikel
A1  - Nguyen, Thi‐Huong
A1  - Xu, Yongmei
A1  - Brandt, Sven
A1  - Mandelkow, Martin
A1  - Raschke, Ricarda
A1  - Strobel, Ulrike
A1  - Delcea, Mihaela
A1  - Zhou, Wen
A1  - Liu, Jian
A1  - Greinacher, Andreas
T1  - Characterization of the interaction between platelet factor 4 and homogeneous synthetic low molecular weight heparins
JF  - Journal of Thrombosis and Haemostasis
N2  - Abstract

Background
Heparins are usually produced from animal tissues. It is now possible to synthesize heparins. This provides the abilities to overcome shortages of heparin, to optimize biological effects, and to reduce adverse drug effects. Heparins interact with platelet factor 4 (PF4), which can induce an immune response causing thrombocytopenia. This side effect is called heparin‐induced thrombocytopenia (HIT). We characterized the interaction of PF4 and HIT antibodies with oligosaccharides of 6‐, 8‐, 10‐, and 12‐mer size and a hypersulfated 12‐mer (S12‐mer).


Methods
We utilized multiple methodologies including isothermal calorimetry, circular dichroism spectroscopy, single molecule force spectroscopy (SMFS), enzyme immunosorbent assay (EIA), and platelet aggregation test to characterize the interaction of synthetic heparin analogs with PF4 and anti‐PF4/heparin antibodies.


Results
The synthetic heparin‐like compounds display stronger binding characteristics to PF4 than animal‐derived heparins of corresponding lengths. Upon complexation with PF4, 6‐mer and S12‐mer heparins showed much lower enthalpy, induced less conformational changes in PF4, and interacted with weaker forces than 8‐, 10‐, and 12‐mer heparins. Anti‐PF4/heparin antibodies bind more weakly to complexes formed between PF4 and heparins ≤ 8‐mer than with complexes formed between PF4 and heparins ≥ 10‐mer. Addition of one sulfate group to the 12‐mer resulted in a S12‐mer, which showed substantial changes in its binding characteristics to PF4.


Conclusions
We provide a template for characterizing interactions of newly developed heparin‐based anticoagulant drugs with proteins, especially PF4 and the resulting potential antigenicity.
KW  - -
KW  - anti‐PF4/heparin antibodies
KW  - interaction
KW  - length
KW  - platelet factor 4
KW  - synthetic heparins
Y1  - 2020
UN  - https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-40536
SN  - 1538-7836
SS  - 1538-7836
U6  - https://doi.org/10.1111/jth.14657
DO  - https://doi.org/10.1111/jth.14657
VL  - 18
IS  - 2
SP  - 390
EP  - 398
PB  - Wiley
CY  - Hoboken, New Jersey
ER  -