Page 2079 - Williams Hematology ( PDFDrive )

2054 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2055

and, therefore, this reagent may distinguish between δ-SPD (dimin- attributed to failure of α-granule maturation during MK differentia-
ished release) and abnormalities of platelet secretory mechanisms, tion, transport or targeting of proteins to α granules, and/or synthesis of
wherein the release may be normal or near-normal. granule membranes. 412,415 Proteomic studies in a GPS patient suggested
Measurement of platelet granule contents can establish further a failure to incorporate endogenously synthesized MK proteins into
415
412
the platelet abnormality. The total platelet content of adenine nucleo- α granules. Some GPS patients have elevated plasma PF4
tides is reduced in δ-SPD, and the ratio of total platelet ATP to ADP suggesting that PF4 synthesis was normal and the primary defect
is increased because it more closely reflects the ratio in the cytoplas- was impaired granule biogenesis with leakage of PF4. Some patients
mic, “metabolic” pool of adenine nucleotides (approximately 8:1) with decreased α-granule contents have a mutation in the gene for the
than in the “storage” pool in dense granules (approximately 2:3). 360,401 transcription factor RUNX1 372,390 and PF4 is a transcriptional target
402
417
Platelet serotonin is variably reduced. Serotonin is taken up by plate- of RUNX1. This suggests that decreased platelet PF4 levels in these
lets of patients with δ-SPD, but because it cannot be stored in dense patients represents a defect in transcriptional regulation and syn-
402
granules, it is rapidly catabolized. Abnormalities in platelet secretion thesis of PF4. GPS has been reported in association with a X-linked
and arachidonic acid metabolism have been identified, but are quite thrombocytopenia, thalassemia, and an R216N mutation in GATA-1,
variable. Reduced plasma and platelet VWF activity in association a major regulator of megakaryopoiesis. Autosomal dominant GPS
403
418
with a decrease in plasma high-molecular-weight multimers has been resulting from mutations in transcription factor gene GFI1B has been
reported in HPS, 404,405 and may reflect abnormalities involving the endo- reported in two kindreds. 419,420
thelial Weibel-Palade bodies. Three groups 10–12 have reported mutations in NBEAL2 in patients
The decrease or absence of platelet dense bodies can be confirmed by with GPS, a gene that encodes for a protein linked to vesicle transport
electron microscopy, using either whole mounts or thin sections of plate- in neuronal cells. These studies implicate defective vesicle transport
lets fixed in the presence of calcium, although it requires expertise to inter- as a major mechanism in many forms of GPS. Studies in Nbeal2-
pret the results. 5,406 Some patients have abnormal granules. Uranaffin and deficient mice provide evidence 421,422 that Nbeal2 is required for
osmium may help to identify dense granules. The fluorescent amine mepa- α-granule biogenesis, platelet function, and MK survival, devel-
crine can be used to quantify dense bodies by fluorescent microscopy or by opment and platelet production—key evidence linking GPS and
flow cytometry. 407,408 Immunoblot analysis of skin fibroblasts in HPS may Nbeal2. These mice were also found to have abnormalities in arterial
facilitate identification of the protein responsible for the defect. 409 thrombosis, inflammation, and wound repair. A mutation in the gene
encoding the VPS33B protein (a member of the Sec1/Munc18 protein
family) involved in vesicle trafficking has also been associated with
Therapy, Course, and Prognosis human α-granule deficiency in the arthrogryposis multiplex congen-
The general principles of patient management are similar to those ital, renal dysfunction, and cholestasis (ARC) syndrome. A muta-
423
described for all patients with platelet function defects. Patients with tion in VPS16B gene has also been linked to α-granule deficiency in
HPS suffer from a number of specific problems related to their albi- the ARC syndrome, and it appears that VPS16B and VPS33B interact
373
nism, colitis, and pulmonary fibrosis. In particular, they should avoid with each other. Thus, multiple mechanisms can lead to GPS. The
424
sun exposure. An antifibrotic agent, pirfenidone, demonstrated modest inheritance of α-granule deficiency has been autosomal recessive in
410
411
benefit in the initial study. A second study failed to confirm this and most reports, but autosomal dominant and sex-linked cases have also
was terminated because of futility. been described. 372,390,412,418
GRAY PLATELET SYNDROME Clinical Features
(α-STORAGE POOL DEFICIENCY) GPS patients have a lifelong mild to moderate bleeding diathesis, which
Definition and History is variable in its manifestations. 412
The GPS is a markedly heterogeneous bleeding disorder characterized
by selective deficiency of platelet α-granules and their contents, in com- Laboratory Features
bination with thrombocytopenia and large platelet size. 412,413 The name Platelets appear as larger-than-normal, pale, ghost-like, oval forms on
414
derives from the initial observation by Raccuglia, in 1971, of the gray blood films and often difficult to identify (Fig. 120–6). Thrombocytope-
appearance of platelets with paucity of granules on peripheral blood nia is variable but can be moderately severe, with counts below 50,000/μL.
films from a patient with a life-long bleeding disorder. Platelet aggregation abnormalities vary considerably. 343,412,413,425–427 ADP-
and epinephrine-induced aggregation is normal or nearly normal.
Etiology and Pathogenesis Collagen- and thrombin-induced aggregation tend to be more abnor-
Normal platelets contain approximately 50 spherical or elongated α mal, but this is not a consistent finding. Concomitant GPVI deficiency
granules that contain a large number of proteins, some relatively specific was reported in one patient and if the association is more widespread,
for platelets (platelet factor 4 [PF4], β-thromboglobulin [βTG]), others it may explain the variable abnormalities in collagen-induced aggrega-
that are also found in plasma, and yet others whose role in platelets is tion. Studies in one patient showed flow-dependent thrombus for-
343
8
poorly understood. 412,415,416 Plasma proteins present in α granules include mation to be decreased. Additional abnormalities in PI metabolism,
fibrinogen, VWF, albumin, coagulation factor V, immunoglobulin (Ig) protein phosphorylation, calcium mobilization, platelet factor Va, and
G, fibronectin, and several protease inhibitors. Some of these proteins, platelet secretion have been described 428–430 and may contribute to the
such as VWF are synthesized by megakaryocytes, whereas others, such platelet aggregation abnormalities and clinical symptoms. The failure
as albumin and IgG, are incorporated into platelets by endocytosis. The of exogenous α-granule proteins to fully correct the aggregation defects
α-granule membrane contains several proteins present in the platelet suggests that these abnormalities may be important in the overall plate-
plasma membrane (integrin α β , GPIb-IX-V) and some specific for α let dysfunction in GPS. 425
IIb 3
granules (P-selectin and osteonectin). Under the electron microscope platelets and megakaryocytes
The molecular mechanisms leading to α-granule deficiency in GPS from GPS patients reveal absent or markedly decreased α granules
and the combined αδ-SPD are also heterogeneous; thus, they have been (Fig. 120-6). The platelets are deficient in α-granule proteins: PF4,
412

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