ReviewThe gray platelet syndrome: Clinical spectrum of the disease
Introduction
Raccuglia1 is generally recognised to have first described the gray platelet syndrome (GPS), although earlier reports described patients with platelets that may have been symptomatic of it.2, 3, 4 A rare disease of platelets and megakaryocytes (MK), GPS is characterised by mild to moderate thrombocytopenia and the presence of large morphologically abnormal platelets lacking α-granules and their constituents. The platelets show a unique ghost-like and gray appearance on May-Grünwald-Giemsa stained blood smears. GPS is also known as α-storage pool disease (α-SPD).5 The associated bleeding syndrome is usually mild to moderate but can be severe. Current data suggests that the basic defect concerns α-granule biogenesis. Proteins that would normally be stored in these organelles are spontaneously released from MKs into the marrow. Bone marrow fibrosis is the consequence for many patients. GPS has yielded information on the function of α-granules, it has also helped characterise the storage protein pool of platelets (recently called the secretome).6
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Seminal reports on patients with GPS
Major case reports and associated studies on patients or families that have contributed to the definition of GPS are first serially reviewed. Common findings for these patients are compared in Table I. Raccuglia1 originally described a young American boy with petechiae, a bruising tendency, and recurrent knee pain presumably from intra-articular bleeding (case 1 in Table I). Thrombocytopenia (35,000/μL and 65,000/μL on first examinations) was noted and an immune cause was suspected.
A French family with GPS and autosomal dominant inheritance
In this review, we will illustrate characteristics of GPS by reference to case 13 and to a previously unreported family where the disease appears to represent the second report (see case 10) of autosomal dominant inheritance. The patients, an adult woman (case 19), and her elderly father (case 20, now deceased) have been followed by us for many years. Members of a large French gypsy family, they both presented with thrombocytopenia (case 19: her platelet count currently ranges from 51–90 G/L),
Ultrastructure of gray syndrome platelets
EM has often been used to to confirm the diagnosis of GPS and the characteristic morphology of the platelets is shown in Fig. 1. It was the pioneering work of Breton-Gorius and her colleagues9, 10 and White7, 30 which led the way in EM studies. Results from both groups highlighted normal numbers of mitochondria, dense bodies, peroxisomes and lysosomes but few or no α-granules. Platelet morphology can be quite heterogeneous, and platelets show wide size variations. Smaller platelets tend to be
Platelet function, Ca++ stores and signaling mechanisms
Platelet aggregation in GPS has been widely studied (Table I). GPIbα-mediated platelet agglutination by ristocetin is mostly normal, but there is considerable heterogeneity between patients in the response to physiologic agonists. Aggregation by ADP in citrated PRP is normal in most reports, although it is reduced for some. There is no evidence for a decreased αIIbβ3 activation. Occasionally, all aggregations are basically normal as was the case for the Australian patients.16 Yet for many
Patient heterogeneity
The data that we have reviewed so far clearly indicates that GPS is a heterogeneous disorder. While platelets of some patients aggregate normally, other patients have a generally reduced response, for some activation by thrombin appears specifically affected while for others the response to collagen is most defective. For case 13, a much reduced aggregation with collagen was accompanied by a virtually absent expression of GPVI, as measured by flow cytometry using FITC-labeled convulxin, a
Proteins stored in α-granules
Proteins stored in α-granules and reduced in platelets of GPS patients include those synthesised in MKs such as PF4, βTG and VWF, and those endocytosed by MKs and circulating platelets such as Fg, albumin and IgG. Studies on GPS patients have helped identify proteins that are part of the storage pool. Thus osteonectin was localised to α-granules after it was found to be missing from the platelets of a GPS patient.24 Osteonectin binds to the platelet surface on release by thrombin and together
Cellular specificity
VWF is stored in the Weibel Palade bodies of endothelial cells as well as in the α-granules of MKs and platelets. This fact led Gebrone-Younés et al.46 to study the dermis capillary network in GPS, skin biopsies being taken from cases 3 and 4. Their endothelial cells normally contained VWF and P-selectin and the general morphology of the cells was normal. Falik-Zaccai et al29 also performed a skin biopsy and excluded pigmentary defects during their study of the Israeli patients.
Megakaryocytes and myelofibrosis
MK numbers are often normal in GPS despite the myelofibrosis that is seen for many patients (Table I). Like the platelets they produce, mature MKs from GPS patients are highly vacuolated. Other platelet organelles including dense bodies, catalase-containing granules and lysosomes are normally present although their distribution may be abnormal with areas of cytoplasm devoid of organelles. Smooth ER develops normally. The presence of ‘dense’ material in the distended DMS and/or vacuoles was
Other human disorders with platelet storage pool deficiency
In 1979, Weiss et al.5 showed that while many patients with ’storage pool’ disease had selective deficiencies of dense granules and their contents (δ-SPD), in others the abnormality also extended to α-granules and their stored proteins. Patients who combined dense granule defects with partial α-granule deficiencies included two families with probable autosomal dominant inheritance while a single patient of South American ancestry and with a long history of bleeding combined a severe deficiency
Potential animal models for GPS
The Wistar Furth rat was claimed to be an animal model of the GPS and indeed a deficiency of both α-granules and their contents featured in an early report.64 However, later studies highlighted an abnormal subcellular distribution of the cytoskeletal proteins, myosin and talin and defective filopodia formation.65, 66 These are abnormalities not seen in GPS. White57 and others67 subsequently failed to observe a reduced α-granule number in platelets of Wistar Furth rats, instead they highlighted
Packaging of α-granule proteins and GPS
Proteins synthesised in MKs are sorted in the trans-Golgi network. Evidence for a targeting of soluble proteins to preformed vesicles has been obtained by El.Golli et al.79 who showed that the amino acid sequence LKNG has a direct role in α-granule capture of PF4 mutants. This sequence promotes the formation of a surface-exposed hydrophilic turn/loop similar to that found in other chemokines such as RANTES. In the GPS, all evidence points to a normal production of endogenously synthesised α
Management
The bleeding tendency in GPS is basically mild to moderate although trauma-related intracranial haemorrhage has been reported in a child.85 Adult patients mostly tend to bleed at times of haemostatic stress. Platelet transfusion is the standard treatment. DDAVP (1-deamino-8-arginine vasopressin) shortened the bleeding time in a GPS patient who typically showed no detectable platelet VWF but whose plasma pool was normal.18 This implied a protective effect through an increase in plasma VWF levels
Final conclusions
GPS is a unique disease in that it allows an appreciation of the consequences of specific loss of the α-granule storage pool of proteins in platelets. Proteomics is currently revealing a whole range of new proteins in the platelet secretome.91, 92 Proteins such as calumenin, an inhibitor of the vitamin K epoxide reductase-warfarin interaction; secretogranin III, a potential monocyte chemoattractant precursor; and cyclophilin A, a vascular smooth muscle cell growth factor, are of unknown role
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2020, BloodCitation Excerpt :All patients were thrombocytopenic, and α-granule deficiency was noted in the platelets of all cases assessed by electron or light microscopy (Figure 2A; supplemental Figure 2.1; supplemental Table 2). Consistent with previous reports,17,40,41 a wide spectrum of bleeding symptoms was reported, ranging from subcutaneous to intracranial hemorrhage. Five patients were notable for their lack of a bleeding diathesis.