Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2015 - 2023 |
| Number of pages | 9 |
| Journal | Arteriosclerosis, Thrombosis and Vascular Biology |
| Volume | 31 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2011 |
| Externally published | Yes |
Cite this
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An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia. / Topcic, Denijal; Kim, Wookhyun; Holien, Jessica K; Jia, Fu; Armstrong, Paul; Hohmann, Jan David; Straub, Andreas; Krippner, Guy Yeoman; Haller, Carolyn A; Domeij, Helena; Hagemeyer, Christoph Eugen; Parker, Michael William; Chaikof, Elliot L; Peter, Karlheinz.
In: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 31, No. 9, 2011, p. 2015 - 2023.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia
AU - Topcic, Denijal
AU - Kim, Wookhyun
AU - Holien, Jessica K
AU - Jia, Fu
AU - Armstrong, Paul
AU - Hohmann, Jan David
AU - Straub, Andreas
AU - Krippner, Guy Yeoman
AU - Haller, Carolyn A
AU - Domeij, Helena
AU - Hagemeyer, Christoph Eugen
AU - Parker, Michael William
AU - Chaikof, Elliot L
AU - Peter, Karlheinz
PY - 2011
Y1 - 2011
N2 - Therapeutic hypothermia is successfully used, for example, in cardiac surgery to protect organs from ischemia. Cardiosurgical procedures, especially in combination with extracorporeal circulation, and hypothermia itself are potentially prothrombotic. Despite the obvious need, the long half-life of antiplatelet drugs and thus the risk of postoperative bleedings have restricted their use in cardiac surgery. We describe here the design and testing of a unique recombinant hypothermia-controlled antiplatelet fusion protein with the aim of providing increased safety of hypothermia, as well as cardiac surgery. Methods and results-: An elastin-mimetic polypeptide was fused to an activation-specific glycoprotein (GP) IIb/IIIa-blocking single-chain antibody. In silico modeling illustrated the sterical hindrance of a ?-spiral conformation of elastin-mimetic polypeptide preventing the single-chain antibody from inhibiting GPIIb/IIIa at 37?C. Circular dichroism spectra demonstrated reverse temperature transition, and flow cytometry showed binding to and blocking of GPIIb/IIIa at hypothermic body temperature (=32?C) but not at normal body temperature. In vivo thrombosis in mice was selectively inhibited at hypothermia but not at 37?C. Conclusion-: This is the first description of a broadly applicable pharmacological strategy by which the activity of a potential drug can be controlled by temperature. In particular, this drug steerability may provide substantial benefits for antiplatelet therapy.
AB - Therapeutic hypothermia is successfully used, for example, in cardiac surgery to protect organs from ischemia. Cardiosurgical procedures, especially in combination with extracorporeal circulation, and hypothermia itself are potentially prothrombotic. Despite the obvious need, the long half-life of antiplatelet drugs and thus the risk of postoperative bleedings have restricted their use in cardiac surgery. We describe here the design and testing of a unique recombinant hypothermia-controlled antiplatelet fusion protein with the aim of providing increased safety of hypothermia, as well as cardiac surgery. Methods and results-: An elastin-mimetic polypeptide was fused to an activation-specific glycoprotein (GP) IIb/IIIa-blocking single-chain antibody. In silico modeling illustrated the sterical hindrance of a ?-spiral conformation of elastin-mimetic polypeptide preventing the single-chain antibody from inhibiting GPIIb/IIIa at 37?C. Circular dichroism spectra demonstrated reverse temperature transition, and flow cytometry showed binding to and blocking of GPIIb/IIIa at hypothermic body temperature (=32?C) but not at normal body temperature. In vivo thrombosis in mice was selectively inhibited at hypothermia but not at 37?C. Conclusion-: This is the first description of a broadly applicable pharmacological strategy by which the activity of a potential drug can be controlled by temperature. In particular, this drug steerability may provide substantial benefits for antiplatelet therapy.
UR - http://atvb.ahajournals.org/content/31/9/2015
U2 - 10.1161/ATVBAHA.111.226241
DO - 10.1161/ATVBAHA.111.226241
M3 - Article
VL - 31
SP - 2015
EP - 2023
JO - Arteriosclerosis, Thrombosis and Vascular Biology
JF - Arteriosclerosis, Thrombosis and Vascular Biology
SN - 1079-5642
IS - 9
ER -