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Clonal hematopoiesis and platelet traits
bleeding. Mice with Gata1low mutation resemble this phe- notype, demonstrating similar megakaryocyte abnormali- ties, such as abnormal P-selectin localization, and throm- bo-hemorrhagic events. The prothrombotic state was ascribed to increased platelet-leukocyte interactions through P-selectin.91
In cultured megakaryocytes, GATA1 has been shown to regulate the expression of GPIIb (fibrinogen receptor) and GPIb (von Willebrand factor receptor). Markedly, in GATA1-deficient megakaryocytes, expression levels of GPIIb can be maintained by GATA2 substitution, whereas those of GPIb are decreased.54 As expected, inherited mutations of GATA1 are accompanied by a bleeding phe- notype rather than by an increased risk of thrombosis. On the other hand, high levels of GATA1 transcripts are found in patients with ET or PV.92 Overexpression of GATA1 in mice results in a similar phenotype.93 Regarding CHIP, somatic gain-of-function may increase the cardiovascular risk including atherothrombosis, whereas loss-of-function may be more associated with bleeding.
TET2
The protein Tet oncogene family member 2 (TET2) has a key role in DNA methylation, explaining how it functions as a tumor suppressor, maintaining normal hematopoiesis. The TET gene product in particular represses the transcrip- tion of inflammatory molecules, such as interleukin-6 and -8, which are known as pro-atherogenic mediators.1,94 This explains why somatic loss-of-function mutations in TET2 are associated with an increased inflammation tendency. Similarly, as described for DNMT3A, the mutations may increase the burden of atherosclerosis and arterial CVD.
Murine Tet2-null models are used to confirm that CHIP- like mutations lead to inflammation-driven cardiovascular pathologies,7,95 markedly without changes in blood cell counts. In the aging population, clonal hematopoietic mutations of TET2 have a prevalence of 2.5%.16 On the other hand, such mutations are found in approximately 25% of patients with myeloid neoplasms, and are then associated with an increased cardiovascular risk.7 It is still not clear to what extent the mutations affect megakary- opoiesis or platelet function, either directly or indirectly via enhanced inflammation.
Conclusions and perspectives
As outlined above, somatic mutations in multiple genes affecting hematopoiesis contribute as a risk factor to the development of CVD. So far, studies have focused on the effects of somatic and CHIP-linked mutations on blood cells, linking to increased inflammation, atherosclerotic disease and thrombosis risk. In this review, we provide evidence that many of the common CHIP genes are involved in quantitative (count) and/or qualitative (func- tion) platelet traits, and therefore in this way can influence CVD, in particular triggered by thrombo-inflammatory mechanisms. On the other hand, insight is gained in a link between mutations in CHIP genes and impairment of hematopoiesis and hemostatic function.
Reactive (secondary) thrombocytosis, which is not due
to a primary hematologic disorder but driven by inflam- matory stimuli, trauma or acute bleeding, does not seem to increase the risk of thrombotic or hemorrhagic com- plications.96 In line with this, the degree of elevation in the platelet count does not correlate with the thrombosis risk in myeloproliferative disease, where clonal (primary) thrombocytosis has been demonstrated.97 This indicates that the platelet count as such is not the only determi- nant of the increased thrombosis risk in myeloprolifera- tive disorders.98,99 Also, several CHIP mutations (e.g. DNMT3A mutations) can indirectly cause a rise in platelet count by inducing increased expression of inflammatory molecules that subsequently upregulate the thrombopoietin production by the liver. However, the combination of alterations in count and function may play an essential role in CHIP mutations related to thrombosis. So far, we have found evidence of seven CHIP-related genes (ABCB6, ASXL1, DNMT3A, GATA1, JAK2, SF3B1, SH2B3) with elevated platelet counts and an associated thrombotic risk (Figure 1). For the other genes, there is not enough evidence to make estimates of this kind; only for ABCB6, JAK2 and SH2B3 mutations is it known that the elevated platelet count is accompanied by a hyper-reactive platelet phenotype. Apparently, information regarding the functional status of platelets in the context of CHIP mutations is still scarce and further studies are needed to elucidate the contribution of platelets to the risk of thrombosis.
One of the most thoroughly investigated conditions, demonstrating the consequences of altered platelet traits due to somatic driver mutations, is essential thrombo- cythemia. Markedly, in these patients, there appears to be no direct correlation between platelet count and thrombo- sis. On the other hand, the JAK2 V617F mutation is known to increase the thrombosis risk in ET patients, when compared to patients without the mutation.100 The reported enhanced activation status of platelets in JAK2 V617F-positive patients provides a strong indication that platelet function changes induced by a CHIP mutation contribute to the risk of thrombosis, thus explaining part of the risk associations of CHIP mutations with CVD. Platelet reactivity also involves interactions with leuko- cytes, secretion of pro-inflammatory mediators and release of extracellular vesicles that may all contribute to CVD, like atherosclerosis and atherothrombosis. Given the increasing prevalence of CHIP mutations in the elderly who are prone to develop CVD (along with malignancies), more thorough investigation of platelet function linked to CHIP mutations would be worthwhile. Greater insight into the functional consequences of such acquired muta- tions may also favor personalized risk assessment, not only with regard to malignancies, but also in relation to thrombotic vascular disease.
Acknowledgments
AV is supported by the Dutch Landsteiner Foundation for Blood Transfusion Research (1711). IDS is supported by a joint PhD scholarship of Maastricht and Reading Universities, and by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement n. 766118.
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