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Updated: Nov 19, 2025
Comprehensive Analysis of Procoagulant Platelets Exhibiting Features of Necrosis, Apoptosis and Platelet Activation
Published on: May 23, 2025
The necroptotic cell death pathway operates in megakaryocytes, but not in platelet synthesis
Diane Moujalled1,2, Pradnya Gangatirkar1, Maria Kauppi1,2
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Abstract:
Necroptosis is a pro-inflammatory cell death program executed by the terminal effector, mixed lineage kinase domain-like (MLKL). Previous studies suggested a role for the necroptotic machinery in platelets, where loss of MLKL or its upstream regulator, RIPK3 kinase, impacted thrombosis and haemostasis. However, it remains unknown whether necroptosis operates within megakaryocytes, the progenitors of platelets, and whether necroptotic cell death might contribute to or diminish platelet production. Here, we demonstrate that megakaryocytes possess a functional necroptosis signalling cascade. Necroptosis activation leads to phosphorylation of MLKL, loss of viability and cell swelling. Analyses at steady state and post antibody-mediated thrombocytopenia revealed that platelet production was normal in the absence of MLKL, however, platelet activation and haemostasis were impaired with prolonged tail re-bleeding times. We conclude that MLKL plays a role in regulating platelet function and haemostasis and that necroptosis signalling in megakaryocytes is dispensable for platelet production.
Insights
Mixed lineage kinase domain-like (MLKL) executes necroptosis. While MLKL is dispensable for platelet production by megakaryocytes, it is crucial for normal platelet function and haemostasis.
Area of Science:
- Cellular biology
- Immunology
- Hematology
Background:
- Necroptosis is a programmed cell death pathway involving mixed lineage kinase domain-like (MLKL).
- Previous research indicated MLKL's role in platelets, affecting thrombosis and hemostasis.
- The function of necroptosis in megakaryocytes and its impact on platelet production remained unclear.
Purpose of the Study:
- To investigate the presence and function of necroptosis signaling in megakaryocytes.
- To determine the role of MLKL-mediated necroptosis in platelet production.
- To assess the impact of necroptosis on platelet function and hemostasis.
Main Methods:
- Functional analysis of necroptosis signaling cascade in megakaryocytes.
- Assessment of platelet production under steady-state and thrombocytopenic conditions in MLKL-deficient models.
- Evaluation of platelet activation and hemostasis parameters, including tail bleeding times.
Main Results:
- Megakaryocytes possess a functional necroptosis signaling pathway, leading to MLKL phosphorylation, cell swelling, and loss of viability upon activation.
- Platelet production was unaffected in the absence of MLKL during steady-state and following antibody-induced thrombocytopenia.
- Absence of MLKL resulted in impaired platelet activation and prolonged tail re-bleeding times, indicating defective hemostasis.
Conclusions:
- MLKL-dependent necroptosis signaling is functional in megakaryocytes but is not essential for platelet production.
- MLKL plays a significant role in regulating platelet function and ensuring proper hemostasis.
- These findings highlight a distinct role for MLKL in platelet biology beyond its function in necroptosis-mediated cell death during platelet formation.
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