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Haematologica 2020 Volume 105(8):2020-2031
Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding
Alicia Veninga,1,* Ilaria De Simone,1,* Johan W.M. Heemskerk,1 Hugo ten Cate,1,2,3 and Paola E.J. van der Meijden1,2
1Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht; 2Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht and 3Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
*AV and IDS contributed equally as co-first authors.
ABSTRACT
Platelets are key elements in thrombosis, particularly in atherosclero- sis-associated arterial thrombosis (atherothrombosis), and hemosta- sis. Megakaryocytes in the bone marrow, differentiated from hematopoietic stem cells are generally considered as a uniform source of platelets. However, recent insights into the causes of malignancies, includ- ing essential thrombocytosis, indicate that not only inherited but also somatic mutations in hematopoietic cells are linked to quantitative or qualitative platelet abnormalities. In particular cases, these form the basis of thrombo-hemorrhagic complications regularly observed in patient groups. This has led to the concept of clonal hematopoiesis of indetermi- nate potential (CHIP), defined as somatic mutations caused by clonal expansion of mutant hematopoietic cells without evident disease. This concept also provides clues regarding the importance of platelet function in relation to cardiovascular disease. In this summative review, we present an overview of genes associated with clonal hematopoiesis and altered platelet production and/or functionality, like mutations in JAK2. We con- sider how reported CHIP genes can influence the risk of cardiovascular disease, by exploring the consequences for platelet function related to (athero)thrombosis, or the risk of bleeding. More insight into the func- tional consequences of the CHIP mutations may favor personalized risk assessment, not only with regard to malignancies but also in relation to thrombotic vascular disease.
Introduction
Atherosclerotic cardiovascular disease is a chronic inflammatory condition that frequently occurs in the aging population.1 Current understanding is that upon rup- ture or erosion of an atherosclerotic plaque, a thrombus is formed of aggregated platelets and fibrin which can become vaso-occlusive.2 Furthermore, platelets con- tribute to ensuing thrombo-inflammatory reactions through their multiple interac- tions with vascular cells, leukocytes and the coagulation system, thereby promot- ing disease progression.3
Platelets are formed from megakaryocytes in the bone marrow (BM) through a differentiation and maturation process known as megakaryopoiesis. Several tran- scription factors have been identified over the years that regulate megakaryopoiesis and platelet production, and understanding of key transcriptional regulators is still expanding. Mutations in genes encoding for these transcription factors, along with epigenetic regulators, are accompanied with quantitative and/or qualitative platelet abnormalities, causing thrombo-hemorrhagic complications.4 Multiple growth fac- tors control megakaryopoiesis and platelet production, of which thrombopoietin and its binding to the thrombopoietin receptor plays a primary role.5 Megakaryocytes undergo endomitosis to become polyploid and during maturation
Correspondence:
P.E.J. VAN DER MEIJDEN
p.vandermeijden@maastrichtuniversity.nl
Received: January 31, 2020. Accepted: May 4, 2020. Pre-published: June 18, 2020.
doi:10.3324/haematol.2019.235994
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2020
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