Blood clot contraction: Mechanisms, pathophysiology, and disease

Litvinov, Rustem I.; Weisel, John W.

doi:10.1016/j.rpth.2022.100023

Cited by 34 publications

(19 citation statements)

References 125 publications

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“…Its loss in type I GT and its mutation-dependent modification in type II and type III GT has recently been reviewed by us, 9 and will not be further detailed here. Furthermore, Litvinov and Weisel 30 have elegantly described the molecular details of the basic mechanics and dynamics of how αIIbβ3 transmits forces to the cytoskeleton and mediates the contraction. The clot retraction in type II GT and some type III patients is certainly controlled by the density of the residual αIIbβ3 that must provide a critical level of outside-in signaling.…”

Section: Platelet Function Testing and The Biology Of Gtmentioning

confidence: 99%

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

Nurden,

Nurden

2024

Semin Thromb Hemost

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Glanzmann thrombasthenia (GT) is the most common inherited platelet disorder (IPD) with mucocutaneous bleeding and a failure of platelets to aggregate when stimulated. The molecular cause is insufficient or defective αIIbβ3, an integrin encoded by the ITGA2B and ITGB3 genes. On activation αIIbβ3 undergoes conformational changes and binds fibrinogen (Fg) and other proteins to join platelets in the aggregate. The application of next-generation sequencing (NGS) to patients with IPDs has accelerated genotyping for GT; progress accompanied by improved mutation curation. The evaluation by NGS of variants in other hemostasis and vascular genes is a major step toward understanding why bleeding varies so much between patients. The recently discovered role for glycoprotein VI in thrombus formation, through its binding to fibrin and surface-bound Fg, may offer a mechanosensitive back-up for αIIbβ3, especially at sites of inflammation. The setting up of national networks for IPDs and GT is improving patient care. Hematopoietic stem cell therapy provides a long-term cure for severe cases; however, prophylaxis by monoclonal antibodies designed to accelerate fibrin formation at injured sites in the vasculature is a promising development. Gene therapy using lentil-virus vectors remains a future option with CRISPR/Cas9 technologies offering a promising alternative route.

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Section: Platelet Function Testing and The Biology Of Gtmentioning

confidence: 99%

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

Nurden,

Nurden

2024

Semin Thromb Hemost

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“…Compaction of RBCs makes them change shape to become polyhedrocytes with very tight packing, which helps to create an impermeable seal at the site of vessel injury to prevent bleeding. 4 Contraction can modulate effects of fibrinolytic enzymes by decreasing clot permeability, impeding access to these enzymes, and increasing spatial proximity of the fibrin fibres. In experiments with haemophilia A mice lacking factor VIII, clots have less fibrin and a correspondingly higher proportion of platelets and microvesicles, as expected from the lower amount of thrombin generated.…”

Section: Clot Contractionmentioning

confidence: 99%

Unresolved hemostasis issues in haemophilia

Sidonio,

Weisel,

Stafford

2024

Haemophilia

Self Cite

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Despite rapid technological advancement in factor and nonfactor products in the prevention and treatment of bleeding in haemophilia patients, it is imperative that we acknowledge gaps in our understanding of how hemostasis is achieved. The authors will briefly review three unresolved issues in persons with haemophilia (PwH) focusing on the forgotten function that red blood cells play in hemostasis, the critical role of extravascular (outside circulation) FIX in hemostasis in the context of unmodified and extended half‐life FIX products and finally on the role that skeletal muscle myosin plays in prothrombinase assembly and subsequent thrombin generation that could mitigate breakthrough muscle hematomas.

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“…30 In line with this, heterozygous point mutations of myosin-II gene, affecting myosin-II contractility, result in macrothrombocytopenia and decrease platelet adhesion, causing impaired clot retraction and consequent prolonged bleeding time. 31…”

Section: αIibβ3 Integrinmentioning

confidence: 99%

Platelet Mechanotransduction: Regulatory Cross Talk Between Mechanosensitive Receptors and Calcium Channels

Mammadova‐Bach

Gudermann

Braun

2023

ATVB

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Blood flow–induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating cells, triggering the rapid activation of receptors, calcium channels, and related signaling mechanisms. Shear stress can also modify the folding of extracellular molecules and directly activate mechanosensitive receptors and calcium channels. The mechanical movement of the ECM (extracellular matrix) and the intracellular cortical actin cytoskeleton can change the conformation of platelet receptors and gate channel pores in the plasma membrane. Mechanosensitive platelet receptors and their downstream signaling events and metabolic products can also indirectly activate calcium channels. While the molecular composite of mechanotransduction pathways has been described in mammals, shear stress–induced platelet receptors and their cross talk with calcium channels have been incompletely characterized. In this review, we discuss current knowledge about the role of mechanosensitive platelet receptors and calcium channels in shear-dependent platelet activation and arterial thrombus formation.

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Blood clot contraction: Mechanisms, pathophysiology, and disease

Cited by 34 publications

References 125 publications

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

Unresolved hemostasis issues in haemophilia

Platelet Mechanotransduction: Regulatory Cross Talk Between Mechanosensitive Receptors and Calcium Channels

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