Hamostaseologie 2024; 44(S 01): S76-S77
DOI: 10.1055/s-0044-1779176
Abstracts
Topics
T-11. Platelet dysfunction and associated bleeding disorders

Mitochondrial calcium uniporter as a Key Regulator in the Generation of Procoagulant COAT Platelets

D. Shehwar
1   Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Division of Hematology and Central Hematology Laboratory, Lausanne, Switzerland
2   Quaid-i-Azam University, Department of Biochemistry, Islamabad, Pakistan
,
A. Aliotta
1   Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Division of Hematology and Central Hematology Laboratory, Lausanne, Switzerland
,
S. Barki
2   Quaid-i-Azam University, Department of Biochemistry, Islamabad, Pakistan
,
D. Bertaggia Calderara
1   Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Division of Hematology and Central Hematology Laboratory, Lausanne, Switzerland
,
L. Veuthey
1   Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Division of Hematology and Central Hematology Laboratory, Lausanne, Switzerland
,
C. Pereira Portela
1   Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Division of Hematology and Central Hematology Laboratory, Lausanne, Switzerland
,
M. Rizwam Alam
2   Quaid-i-Azam University, Department of Biochemistry, Islamabad, Pakistan
,
L. Alberio
1   Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Division of Hematology and Central Hematology Laboratory, Lausanne, Switzerland
› Author Affiliations
› Further Information
Also available at
 

Introduction Procoagulant platelets represent a subpopulation of platelets that are phenotypically and functionally different from aggregating platelets. The combined activation of platelets with collagen-plus-thrombin induces the formation of procoagulant COAT platelets, which expose phosphatidylserine (PS) and down-regulate integrin alphaIIb/beta3. This dual agonist stimulation mobilizes high level of cytosolic calcium, which is taken up by mitochondria through mitochondrial calcium uniporter (MCU). A significant rise in mitochondrial calcium results in the depolarization of mitochondrial membrane potential, which triggers the opening of mitochondrial permeability transition pore (mPTP) to achieve the supramaximal cytosolic calcium level required for PS exposure. Thus, in this study, we aimed to explore the function of MCU in the generation and modulation of procoagulant COAT platelets.

Method Platelets were activated with thrombin (THR) or convulxin (CVX, collagen GPVI agonist) or a combination of these. Flow cytometry was employed to monitor procoagulant and aggregatory properties of platelets using Annexin-V and PAC-1 binding, respectively. Function of MCU was modulated with specific inhibitors, namely mitoxantrone (MTX) or Ru265.

Results Our results demonstrated that MTX had non-significant effect on single THR stimulated platelets as this agonist triggered poor procoagulant platelet formation. In contrast, platelets stimulated with single CVX generated moderate procoagulant platelets and MTX showed a significant inhibition in the generation of Annexin V positive platelets. Furthermore, when we co-stimulated the platelets with THR-plus-CVX, our results demonstrated that MTX exhibited significant decrease (-23%±1.26) in Annexin V positive platelets and inversely increase (+36%±4.6) in PAC-1 positive platelets. Data were replicated and validated by blocking MCU with Ru265.

Conclusion Altogether, the present study revealed that CVX pathway alone and synergistically with THR enhances the formation of procoagulant platelets through MCU-driven mitochondrial calcium uptake. MCU is as a key regulator in the generation of procoagulant platelets.



Publication History

Article published online:
26 February 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany