Can Novel Insights into the Pathogenesis of Myeloproliferative Neoplasm-Related Thrombosis Inform Novel Treatment Approaches?
Abstract
:1. Introduction
2. The Scope of the Problem: Thrombosis in MPNs
3. Current Risk Assessment for Thrombosis in MPNs: Established and Suggested Models
4. Pathogenetic Pathways Promoting Thrombosis in MPNs
4.1. RBC’s and Hematocrit
4.2. Platelets
4.3. Leukocytes
4.4. Endothelium
4.5. Thrombo-Inflammation and Clonal Hematopoiesis
4.6. COVID-19, MPNs and Thrombosis-(Mechanistic) Lessons Learned from the Pandemic
5. Current Strategies to Prevent Thrombosis
5.1. Aspirin
5.2. Hematocrit
5.3. Cytoreduction
5.4. JAK Inhibitors
5.5. Anticoagulation
6. Novel Targets to Prevent Thrombosis
6.1. Targeting the JAK/STAT Pathway
6.2. Targeting Cell-Cell Interaction
6.3. Targeting Cell Activation
6.4. Targeting Inflammation
Pathway/Target | Target | Drug/Compound | Effect | Context | Ref. |
---|---|---|---|---|---|
JAK-STAT | JAK1/2 | Ruxolitinib | Pro-inflammatory cytokines ↓ | MF, Clinical trial | [179] |
Neutrophil: ROS ↓ NETs ↓ | Ex-vivo studies, Murine models | [76,84] | |||
RBC: HCT ↓, Lu/BCAM ↓ | Clinical trial Ex-vivo studies | [33] [50] | |||
Monocyte: TF expression ↓ | Ex-vivo studies | [180] | |||
Endothelial activation ↓ | Pre-clinical HUVEC model | [181] | |||
Selectins | P-selectin | P-selectin blocking antibodies | Thrombosis ↓ NETs ↓ PLT-endothelial ↓ PLT-leukocyte ↓ | Murine models Crizanlizumab is a clinically available Ab | [94,182,185] |
Integrins | VLA4 LFA1 | VLA4 and LFA1 blocking antibodies | Thrombosis ↓ | Murine models | [101] |
Neutrophil functions* | NETs | NAC | Thrombosis ↓ NETs ↓ PLT-leukocyte ↓ Arterial dysfunction ↓ | Ex-vivo studies, Murine models | [192] [51] |
PAD4 | Thrombosis ↓ NETs ↓ | Ex-vivo studies, Murine models | [76] [193,203] | ||
DNAse | Thrombosis ↓ NETs ↓ | Murine models | [196,197,198] | ||
RBC’s | Plek2 | Plek2 inhibitor | Thrombosis ↓ RBC mass ↓ | Murine models | [53,201] |
Inflammation | Vasoconstriction | simvastatin | Arterial dysfunction ↓ | Murine models | [51] |
7. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Wolach, O.; Shacham Abulafia, A. Can Novel Insights into the Pathogenesis of Myeloproliferative Neoplasm-Related Thrombosis Inform Novel Treatment Approaches? Hemato 2021, 2, 305-328. https://doi.org/10.3390/hemato2020018
Wolach O, Shacham Abulafia A. Can Novel Insights into the Pathogenesis of Myeloproliferative Neoplasm-Related Thrombosis Inform Novel Treatment Approaches? Hemato. 2021; 2(2):305-328. https://doi.org/10.3390/hemato2020018
Chicago/Turabian StyleWolach, Ofir, and Adi Shacham Abulafia. 2021. "Can Novel Insights into the Pathogenesis of Myeloproliferative Neoplasm-Related Thrombosis Inform Novel Treatment Approaches?" Hemato 2, no. 2: 305-328. https://doi.org/10.3390/hemato2020018