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A.T. Nurden and P. Nurden
gain-of-function mutations within exon 28 of VWF result in multimers that bind spontaneously to GIba.27 Enlarged platelets and thrombocytopenia are features and the cross- linking of platelets by adsorbed VWF multimers leads to platelet clumping in many patients. Megakaryocytes in cul- ture appear to bind VWF multimers leaking from their own cells; the mature megakaryocytes have larger platelet terri- tories while proplatelet-like protrusions are fewer, shorter and the swellings larger.28 Patients of French-Canadian descent with what was called the “Montreal platelet syn- drome”, an inherited macrothrombocytopenia, in fact pos- sessed the VWF p.V1316M mutation. Recent studies on both a mouse model and platelets from a patient with VWF V1316M have shown that platelet aggregation is also reduced due to the loss of essential signaling requirements for aIIbb3 activation.29 With regards to a possible loss of sialic acid from platelets of these patients, the same group showed that while endogenous neuraminidase translocated to the platelet surface, the desialylation threshold required for thrombocytopenia in vivo was not reached; intriguingly, N-glycans on aIIb and b3 and not GPIba, were most target- ed.30 But both platelet-type von Willebrand disease and type 2B von Willebrand disease are disorders in which increased platelet turnover contributes to the thrombocytopenia.
MYH9-related disease
Myosin, heavy chain 9 (MYH9), a subunit of myosin
IIA, mediates intracellular contractile forces generated through ATP hydrolysis and the actin cytoskeleton. AD- inherited MYH9 variants are a common cause of moderate to severe macrothrombocytopenia and platelets can be very large.31 Cytochemical or immunofluorescence detec- tion of inclusions (Döhle-like bodies) in leukocytes on blood smears facilitates the diagnosis.32 Myosin IIA is expressed in many tissues and MYH9-related disease will often become syndromic with age; symptoms include glomerulonephritis, potentially leading to renal failure (requiring dialysis or transplantation), sensorial hearing loss, early cataracts and elevated circulating liver enzymes indicating hepatic damage. Historically, combinations of macrothrombocytopenia with these conditions were known as May-Hegglin anomaly, and Epstein, Fechtner and Sebastian syndromes but all were later linked to mutations in MYH9.33 Disease-causing variants are mostly missense but variants of all types have been described and affect both the N-terminal head or motor domain and C- terminal tail (responsible for dimerization and containing phosphorylation sites).33,34 Some residues are mutational hotspots, for example S96 and R702 in the head and R1165 and D1424 in the tail and genotype-phenotype cor- relations have been linked to disease evolution in MYH9- related disease. Notwithstanding the AD inheritance, some of the mutations are sporadic and somatic germinal mosaicism has been reported. Lacking contractile force, affected megakaryocytes show reduced migration to the vascular sinus and, together with altered proplatelet for- mation, this results in ectopic but reduced platelet release in the marrow.35 Treatment includes slowing the extra- hematologic effects with cochlear or kidney transplanta- tion and renin-angiotensin inhibitors in some cases.
Gray platelet syndrome and related disorders.
A qualitative disorder characterized by moderate macrothrombocytopenia with “gray-colored” platelets on a stained blood smear, gray platelet syndrome has mostly
AR inheritance. Patients have enlarged platelets lacking a- granules and their storage pool of proteins.36 Thrombocytopenia is often progressive and bleeding highly variable. Enlarged spleens, myelofibrosis, high serum vitamin B12 levels and reduced platelet function help define the phenotype.37 In 2011, three groups using different approaches including next-generation WES and RNA profiling showed that mutations in NBEAL2 caused gray platelet syndrome in large, but distinct cohorts of patients (data reviewed by Chen et al.38). NBEAL2 is a scaf- folding protein involved in a-granule ontogeny. Mouse Nbeal2-/- models recapitulated the gray platelet syndrome phenotype and showed how the lack of the secretory pool of biologically active proteins affects wound healing, and has consequences for thrombosis and inflammation.39 Cultured megakaryocytes from patients with NBEAL2 mutations interacted abnormally with extracellular matrix proteins, including type I collagen, with reduced pro- platelet formation and branching.40 Extensive emperipole- sis of neutrophils by the megakaryocytes is another fea- ture of gray platelet syndrome. Although altered neu- trophil structure and increased infections were reported in early studies on this syndrome, only recently was a role for NBEAL2 in immunity confirmed.41 New avenues for research on autoimmunity and inflammation in gray platelet syndrome have now opened.
The absence of platelet a-granules is also a characteristic of children with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, a severe AR multisystem dis- order especially affecting the kidneys and linked to muta- tions in VPS33B and VPS16B, genes encoding proteins involved in a-granule biogenesis; however, platelet count and size are often normal and this syndrome is not includ- ed in Online Supplementary Table S1.38 A paucity of a-gran- ules in platelets of patients with X-linked mutations in GATA1 is explained by its long-distance regulation of NBEAL2.42 The transcription factor, GATA1, in complex with its cofactor FOG1 acts as a gene repressor in hematopoietic cell lineages including megakaryocytes and red blood cells. It was first identified as a cause of macrothrombocytopenia with moderate to severe bleed- ing by Nichols et al., who found a p.V205M mutation in siblings with severe thrombocytopenia and dyserythro- poietic anemia.43 Most GATA1 mutations result in dys- megakaryopoiesis with the marrow often containing an abundance of small megakaryocytes; the red blood cell abnormalities include features that can be observed in b- thalassemia and also congenital erythropoietic porphyr- ia.21 Phenotypic variation is considerable and the condition often improves with age. A loss of collagen-induced platelet aggregation in some patients remains unex- plained. Macrothrombocytopenia, an absence of platelet a-granules and red blood cell defects variably characterize patients with AD germline mutations in GFI1B, a tran- scriptional repressor and key regulator of hematopoiesis.44,45 The macrothrombocytopenia can be accompanied by platelet function defects and myelofibro- sis; bleeding is mostly mild or even absent but may be severe after trauma. Abnormal megakaryocyte maturation and proplatelet formation contribute to the macrothrom- bocytopenia. The phenotype depends on the site and nature of the mutation and the GFI1B isoform affected.46 Haploinsufficiency or non-functioning of GATA1 or GFI1B will change the activation of a number of genes coding for proteins maintaining platelet function.
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haematologica | 2020; 105(8)