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Effects of Heparin ...
Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation : Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses
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- Lund, Mikael (author)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
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- Macwan, Ankit (author)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
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- Tunströmer, Kjersti (author)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
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- Lindahl, Tomas (author)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Region Östergötland, Klinisk kemi
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- Boknäs, Niklas (author)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US
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(creator_code:org_t)
- 2021-09-29
- 2021
- English.
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In: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 8
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Abstract
Subject headings
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- Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In this study, we investigated how these drugs affect the ability of thrombin to generate a prothrombotic platelet response via activation of the protease-activated receptors (PARs) 1 and 4. We examined the effects of heparin/antithrombin and bivalirudin on PAR1- and PAR4-mediated intracellular calcium mobilization, aggregation, alpha-granule release, and procoagulant membrane exposure in platelets exposed to thrombin concentrations likely to be encountered in the thrombus microenvironment during thrombosis. At physiological antithrombin levels, heparin treatment resulted in complete and sustained inhibition of thrombin-induced PAR4-mediated platelet activation, but transient PAR1 signaling was sufficient to elicit significant alpha-granule release and platelet aggregation. In contrast, bivalirudin treatment resulted in rapid and profound inhibition of signaling from both PAR receptors, followed by a delayed phase of PAR4-mediated platelet activation, resulting in a robust prothrombotic response. Combination treatment with bivalirudin and subtherapeutic concentrations of heparin completely inhibited the residual platelet activation observed with single drug treatment at all time-points. Our results show that heparin and bivalirudin have different and complementary inhibitory effects on the activation of PAR1 and PAR4 by thrombin.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- heparin; bivalirudin; thrombin; PAR1; PAR4
Publication and Content Type
- ref (subject category)
- art (subject category)
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