Megakaryocyte Cytoskeletal Proteins in Platelet Biogenesis and Diseases

Mbiandjeu, Serge; Balduini, Alessandra; Malara, Alessandro

doi:10.1055/s-0041-1731717

Cited by 10 publications

(12 citation statements)

References 167 publications

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“…For the production of platelets MKs undergo a series of remodeling events that result in thousands of platelets being released from a single cell [76]. All the proteins found to be interact with THPO protein are known to regulate the platelet formation and functions [77][78][79]. The interaction of THPO protein with other proteins suggested that there might be potential alternate mechanisms that could affect platelet production, morphology and function.…”

Section: Discussionmentioning

confidence: 99%

Genomic Variation Affecting MPV and PLT count in association with development of Ischemic Stroke and its Subtypes

Ludhiadch

Sulena

Singh

et al. 2022

Preprint

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Background Platelets play a significant role in pathophysiology of ischemic stroke since they are involved in the formation of intravascular thrombus after erosion or rupture of the atherosclerotic plaques. Platelet (PLT) count and Mean platelet volume (MPV) are the two significant parameters that affect functions of the platelets. Methods In the current study MPV and PLT count was evaluated using flow cytometry and cell counter. SonoClot analysis was carried out to evaluate Activated Clot Timing (ACT), Clot Rate (CR) and Platelet Function (PF). Genotyping was carried out GSA and Sanger sequencing and expression analysis was carried out using RT-PCR. In silico analysis was carried out using GROMACS tool and UNAFold. The interaction of significant proteins with other proteins was predicted using STRING database. Results 96 genes were analyzed and a significant association of THPO (rs6141) and ARHGEF3 (rs1354034) was observed with the disease and its subtypes. Altered genotypes were associated significantly with increased MPV, decreased PLT count and CR. Expression analysis revealed a higher expression in patients bearing the variant genotypes of both the genes. In silico analysis revealed that mutation in THPO gene leads to the reduced compactness of protein structure. mRNA encoded by mutated ARHGEF3 gene increases the half-life of mRNA. The two significant proteins interact with many other proteins especially the ones involved in the platelet activation, aggregation, erythropoiesis, megakaryocyte maturation, and cytoskeleton rearrangements suggesting that they could be important player in determination of MPV values. Conclusions In conclusion the current study demonstrated the role of higher MPV affected by genetic variation in the development of IS and its subtypes. The results of the current study also indicate that higher MPV can be used as a biomarker for the disease and altered genotypes and higher MPV can be targeted for better therapeutic outcomes.

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Section: Discussionmentioning

confidence: 99%

Genomic Variation Affecting MPV and PLT count in association with development of Ischemic Stroke and its Subtypes

Ludhiadch

Sulena

Singh

et al. 2022

Preprint

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“…activation of platelets, accompanied by endothelial damage, subsequent fibrin deposition and the formation of thrombosis 21 . In Lemierre's syndrome direct evidence of pus collections surrounding the internal jugular vein as well as pus within the thrombi have been described 22 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Actin-binding protein. Suggested to be a negative regulator of megakaryocyte platelet production, meaning high levels could cause thrombocytopenia 20,21 .…”

Section: Plastin-2mentioning

confidence: 99%

Proteomic Characterization of Plasma in Lemierre's Syndrome

Nygren,

Torisson,

Happonen

et al. 2023

Thromb Haemost

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Background The underlying mechanisms of thrombosis in Lemierre’s syndrome and other septic thrombophlebitis are incompletely understood. Therefore, in this case-control study we aimed to generate hypotheses on its pathogenesis by studying the plasma proteome in patients with these conditions. Methods All patients with Lemierre’s syndrome in the Skåne Region, Sweden were enrolled prospectively during 2017-2021 as cases. Age-matched patients with other severe infections were enrolled as controls. Patient plasma samples were analyzed using label-free data-independent acquisition liquid chromatography tandem mass spectrometry. Differentially expressed proteins in Lemierre’s syndrome vs. other severe infections were highlighted. Functions of differentially expressed proteins were defined based on a literature search focused on previous associations with thrombosis. Results Eight patients with Lemierre’s syndrome and 15 with other severe infections were compared. Here, 20/449 identified proteins were differentially expressed between the groups. Of these, 14/20 had functions previously associated with thrombosis. 12/14 had a suggested prothrombotic effect in Lemierre’s syndrome, whereas 2/14 had a suggested antithrombotic effect. Conclusion Proteins involved in several thrombogenic pathways were differentially expressed in Lemierre’s syndrome compared to other severe infections. Among identified proteins, several were associated with endothelial damage, platelet activation and degranulation and warrant further targeted studies.

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“…Although WASP is involved in all main stages of megakaryocyte (MK) maturation—invaginated membrane system (IMS) formation, podosome formation, migration and proplatelet release, 13 the MKs in WAS patients remain largely unexamined.…”

Section: Introductionmentioning

confidence: 99%

“…an increased tendency to undergo programmed cell death, which in case of platelets results in a shortened lifespan and accelerated clearance. 12 Although WASP is involved in all main stages of megakaryocyte (MK) maturation-invaginated membrane system (IMS) formation, podosome formation, migration and proplatelet release, 13 the MKs in WAS patients remain largely unexamined.…”

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confidence: 99%

Accelerated death of megakaryocytes from Wiskott–Aldrich syndrome patients

et al. 2023

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Summary Wiskott–Aldrich syndrome (WAS) is an X‐linked recessive disorder caused by WAS gene mutations resulting in haematopoietic/immune cell defects. Recent studies report accelerated death of WAS platelets and lymphocytes. Data on megakaryocyte (MK) maturation, viability and their possible role in thrombocytopenia development in WAS are limited. In this study we evaluate the MK viability and morphology in untreated, romiplostim‐treated WAS patients compared with normal controls. The study included 32 WAS patients and 17 healthy donors. MKs were captured from bone marrow aspirates by surface‐immobilized anti‐GPIIb‐IIIa antibody. Viability (by phosphatidylserine [PS] externalization), distribution by maturation stages and size of MK were determined by light microscopy. MK distribution by maturation stages in patients differed from controls. 40 ± 22% of WAS MKs versus 23 ± 11% of normal MKs were at maturation stage 3 (p = 0.02), whereas 24 ± 20% in WAS and 39 ± 14% in controls had megakaryoblast morphology (p = 0.05). Romiplostim treatment changed the MK maturation stages distribution close to normal. PS‐positive (PS+) MK in WAS was significantly higher (21 ± 21%) than in healthy controls (2 ± 4%, p < 0.01). WAS patients with more damaging truncating mutations and higher disease score had higher PS+ MK fraction (Spearman r = 0.6, p < 0.003). We conclude that WAS MKs have increased cell death tendency and changes in maturation pattern. Both could contribute to thrombocytopenia in WAS patients.

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Megakaryocyte Cytoskeletal Proteins in Platelet Biogenesis and Diseases

Cited by 10 publications

References 167 publications

Genomic Variation Affecting MPV and PLT count in association with development of Ischemic Stroke and its Subtypes

Genomic Variation Affecting MPV and PLT count in association with development of Ischemic Stroke and its Subtypes

Proteomic Characterization of Plasma in Lemierre's Syndrome

Accelerated death of megakaryocytes from Wiskott–Aldrich syndrome patients

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