Advances in understanding the pathogenesis of hereditary macrothrombocytopenia

Abstract

Low platelet count, or thrombocytopenia, is a common haematological abnormality, with a wide differential diagnosis, which may represent a clinically significant underlying pathology. Macrothrombocytopenia, the presence of large platelets in combination with thrombocytopenia, can be acquired or hereditary and indicative of a complex disorder. In this review, we discuss the interpretation of platelet count and volume measured by automated haematology analysers and highlight some important technical considerations relevant to the analysis of blood samples with macrothrombocytopenia. We review how large cohorts, such as the UK Biobank and INTERVAL studies, have enabled an accurate description of the distribution and co-variation of platelet parameters in adult populations. We discuss how genome-wide association studies have identified hundreds of genetic associations with platelet count and mean platelet volume, which in aggregate can explain large fractions of phenotypic variance, consistent with a complex genetic architecture and polygenic inheritance. Finally, we describe the large genetic diagnostic and discovery programmes, which, simultaneously to genome-wide association studies, have expanded the repertoire of genes and variants associated with extreme platelet phenotypes. These have advanced our understanding of the pathogenesis of hereditary macrothrombocytopenia and support a future clinical diagnostic strategy that utilises genotype alongside clinical and laboratory phenotype data.

“CHildren with Inherited Platelet disorders Surveillance” (CHIPS) retrospective and prospective observational cohort study by Italian Association of Pediatric Hematology and Oncology (AIEOP)

“…Furthermore, some of ITs (i.e., MYH9 and Bernard–Soulier syndrome) may present platelets that, due to their increased size, are unrecognized by the electronic counter, which therefore underestimates the MPV ( 54 ). In the last few years, new genes and de novo mutations responsible for inherited thrombocytopenia are continuously detected, and the classification of hereditary thrombocytopenias is updated constantly ( 55 , 56 ). Therefore, pathogenicity could be due to different predisposing genetic variants in a polygenic setting.…”

Biological, clinical features and modelling of heterozygous variants of glycoprotein Ib platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit beta (GP1BB) genes responsible for constitutional thrombocytopenia

“…For example, a network involving two genes encoding the GPIb‐IX‐V receptor, GP1BB and GP9 , and eight other highly co‐expressed genes can be mentioned. These genes are all trans‐regulated by the rho guanine nucleotide exchange factor 3 ( ARHGEF3 ) gene, which is one of the main genes regulating megakaryopoiesis and could therefore influence the severity of thrombocytopenia as well as platelet size 47,48 …”

“…These genes are all trans-regulated by the rho guanine nucleotide exchange factor 3 (ARHGEF3) gene, which is one of the main genes regulating megakaryopoiesis and could therefore influence the severity of thrombocytopenia as well as platelet size. 47,48 The pathophysiological mechanisms of the impact of these mutations on megakaryopoiesis remain to be elucidated. For this, it would be necessary to analyse larger series of patients and to carry out directed mutagenesis studies.…”

A novel nonsense variant in TPM4 caused dominant macrothrombocytopenia, mild bleeding tendency and disrupted cytoskeleton remodeling

“…These MCTs are mainly caused by genetic defects affecting early megakaryopoiesis and proplatelet formation 7,10 . In particular, proplatelet formation is highly dependent on cytoskeletal proteins, including myosin IIA, actin filaments and tubulins 2,7,10,11 6,12 .…”

“… 7 , 10 In particular, proplatelet formation is highly dependent on cytoskeletal proteins, including myosin IIA, actin filaments and tubulins. 2 , 7 , 10 , 11 Thus, genetic changes affecting genes of the actomyosin cytoskeleton, such as MYH9 , ACTN1 , or in recent years, FLNA , DIAPH1 or TUBB1 associate with MCT. 6 , 12 In 2017, the first five patients from two unrelated pedigrees with mild bleeding and TPM4 ‐related thrombocytopenia ( TPM4 ‐RT) due to the nonsense variant p.Arg69* (NM_003290.3) were identified.…”