Article
Intracellular calcium is essential for stable thrombus formation – the role of STIM1
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Authors
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David Varga-Szabo
- Helios Klinikum Wuppertal, Chirurgisches Zentrum, Wuppertal
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Hubert Zirngibl
- Helios Klinikum Wuppertal, Chirurgisches Zentrum, Wuppertal
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Bernhard Nieswandt
- Rudolf Virchow Center, Experimentelle Biomedizin - Vaskuläre Medizin, Würzburg
| Published: | May 20, 2011 |
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Outline
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Introduction: Myocardial infarction and stroke are two of the leading causes of mortality and with the worldwide growing life expectations more and more patients with cardio- and cerebrovascular diseases and with the need of lifetime anticoagulation undergo surgery. All antithrombotics available at present have, however, the major side effect of increasing bleeding risk - especially important in the case of surgery. Therefore, a better understanding of platelet function and thrombus formation is required in order to develop new antithrombotics.
Intracellular calcium is known to be of pivotal importance for platelet activation. Its role in thrombus formation in vivo, however, is unclear. Stromal interaction molecule 1 (STIM1) is a calcium sensor in the major intracellular calcium store, the endoplasmic reticulum (ER). Upon calcium release from the ER, a central event in platelet activation, it opens the calcium channels in the plasma membrane, thereby further increasing the intracellular calcium concentration.
Materials and methods: Using knock-out mice intracellular calcium measurements were performed. Further using a tail bleeding time assay and a chemical injury in vivo thrombosis model of mesenteric arteries, we have investigated the role of STIM1 and calcium in thrombus formation.
Results: Platelets lacking STIM1 show ~90% reduced calcium entry following platelet activation. This results in severely defective thrombus formation in vivo (8 of 10 arteries occluded in wild-type mice vs. 9 of 10 arteries remained open in knockout mice) with only minor influence on bleeding time (28 of 30 wild-type mice vs. 20 of 31 knockout mice stop bleeding within 10 minutes).
Conclusion: In conclusion we can say that STIM1 is the main regulator of calcium influx in platelets and this process is essential for stable thrombus formation in vivo. Importantly, the residual platelet function seems to be sufficient to limit posttraumatic bleeding. Therefore, STIM1 is a potential target for the development of new antithrombotics.
