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A.T. Nurden and P. Nurden
hepatocyte Ashwell-Morell receptor, an act that stimu- lates the synthesis of thrombopoietin.14 Subsequent stud- ies using a mouse model additionally pointed to clearance by Kupffer cells in the liver sinusoids; here N-acetyl-galac- tosamine was recognized by the lectin, CLEC4A.15 State- of-the-art microscopy then pinpointed how Küpffer cells also recognized b-galactose on aged mouse or human platelets with a galactose-binding lectin mediating the phagocytosis.16 Most importantly, Küpffer cells were shown to continually scan circulating platelets with touch- and-go interactions as these latter pass through sinusoidal endothelial fenestrae.
In megakaryocytes, the role of apoptosis during pro- platelet formation and platelet biogenesis is controversial and largely unproven although it may intervene after platelet release or during stress situations such as infec- tions and inflammation.17 In a classic paper, the pro-sur- vival protein, Bcl-XL, was proposed to constrain the pro- death Bak in platelets; the balance acting as a molecular clock for platelet survival.18 Others have shown how apoptotic pathways and necrosis engage pro-death pro- teins triggering mitochondrial membrane permeabiliza- tion, cytochrome C release and caspase activation leading to Ca2+-dependent exposure of phosphatidylserine, which is not only recognized by phagocytic cells but also leads to procoagulant activity.19
The following sections of this review will describe familial defects of platelet production and megakary- opoiesis; affected genes will be shown to interfere with HSC proliferation, megakaryocyte maturation and migra- tion and the alteration of platelet lifespan. Many are
accompanied by an increased platelet size (Figure 2) while others have a normal platelet size or even small platelets (Figure 3). Platelet function is variably affected. While some thrombocytopenias are isolated, many are syn- dromic and/or associated with other conditions that may be of major clinical importance. Bleeding is mostly muco- cutaneous, severe in some disorders, but infrequent or even absent in others, particularly when the decrease in platelet count is modest. A summary of the genes involved and the principle characteristics of each disorder are pre- sented in Online Supplementary Table S1.
Classic inherited thrombocytopenias
We begin with a series of named inherited thrombocy- topenias whose characterization has marked the history of inherited platelet disorders. In many of these syn- dromes, thrombocytopenia, defined as a platelet count <150x109/L, is accompanied by platelet function defects that aggravate bleeding. In early studies genotyping most- ly involved candidate gene sequencing and linkage stud- ies.
Bernard-Soulier syndrome
The “GPI” lesion in BSS platelets was quickly shown to involve a complex of four distinct subunits each encoded by a distinct gene. The large, heavily glycosylated GPIba is attached by a disulfide to the small GPIbb, while GPIX and GPV are non-covalently associated, all in a 2:2:2:1 sto- ichiometry. Bleeding in BSS patients is disproportionate to
Figure 2. A cartoon showing genes causing non-syndromic and syndromic macrothrombocytopenias. The causative genes are grouped according to the nature of the encoded protein and/or the secondary condition(s) that may accompany the macrothrombocytopenia. MTP: macrothrombocytopenias; BSS: Bernard-Soulier syn- drome; pl-type VWD: platelet-type von Willebrand syndrome; VWD2B: von Willebrand disease type 2B; GPS: gray platelet syndrome.
2006
haematologica | 2020; 105(8)