Department of Medicine, Division of Hematology and Oncology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Curr Hematol Malig Rep. 2021 Jun;16(3):304-313. doi: 10.1007/s11899-021-00630-8. Epub 2021 Apr 19.
Thrombosis remains a leading cause of morbidity and mortality in BCR/ABL negative myeloproliferative neoplasms (MPN). Circulating blood cells are both increased in quantity and qualitatively abnormal in MPN, resulting in an increased thrombotic risk. Herein, we review recently elucidated mechanisms of MPN thrombosis and discuss implications of drugs currently under investigation for MPN.
Recent studies highlight that in JAK2 granulocytes and platelets, thrombo-inflammatory genes are upregulated. Furthermore, in JAK2 granulocytes, protein expression of integrin CD11b, tissue factor, and leukocyte alkaline phosphatase are all increased. Overall, myeloid cells, namely neutrophils, may contribute in several ways, such as through increased adhesion via β1 integrin binding to VCAM1, increased infiltration, and enhanced inducibility to extrude neutrophil extracellular traps. Non-myeloid inflammatory cells may also contribute via secretion of cytokines. With regard to red blood cells, number, rigidity, adhesion, and generation of microvesicles may lead to increased vascular resistance as well as increased cell-cell interactions that promote rolling and adhesion. Platelets may also contribute in a similar fashion. Lastly, the vasculature is also increasingly appreciated, as several studies have demonstrated increased endothelial expression of pro-coagulant and pro-adhesive proteins, such as von Willebrand factor or P-selectin in JAK2 endothelial cells. With the advent of molecular diagnostics, MPN therapeutics are advancing beyond cytoreduction. Our increased understanding of pro-inflammatory and thrombotic pathophysiology in MPN provides a rational basis for evaluation of in-development MPN therapeutics to reduce thrombosis.
在 BCR/ABL 阴性骨髓增殖性肿瘤（MPN）中，血栓仍然是发病率和死亡率的主要原因。MPN 中循环血细胞数量和质量均异常增加，导致血栓形成风险增加。在此，我们综述了 MPN 血栓形成的最新阐明机制，并讨论了目前正在研究的药物对 MPN 的影响。
最近的研究强调，在 JAK2 粒细胞和血小板中，血栓炎症基因上调。此外，在 JAK2 粒细胞中，整合素 CD11b、组织因子和白细胞碱性磷酸酶的蛋白表达均增加。总的来说，髓样细胞，即中性粒细胞，可能通过多种方式发挥作用，例如通过 β1 整合素与 VCAM1 的结合增加黏附、增加浸润和增强挤出中性粒细胞细胞外陷阱的诱导性。非髓样炎症细胞也可能通过分泌细胞因子发挥作用。就红细胞而言，数量、刚性、黏附性和微泡的产生可能导致血管阻力增加，以及促进滚动和黏附的细胞-细胞相互作用增加。血小板也可能以类似的方式发挥作用。最后，血管也越来越受到重视，因为几项研究表明 JAK2 内皮细胞中促凝和促黏附蛋白（如血管性血友病因子或 P 选择素）的内皮表达增加。随着分子诊断的出现，MPN 治疗正在超越细胞减少。我们对 MPN 中促炎和血栓形成病理生理学的认识不断提高，为评估正在开发的 MPN 治疗药物以减少血栓形成提供了合理的依据。
