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2052 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2053

GLYCOPROTEIN VI DEFICIENCY δ-STORAGE POOL DEFICIENCY
GPVI can mediate platelet adhesion to collagen and is important in Definition and History
collagen-induced signal transduction (Chap. 112). Twelve patients In 1969, a family with impaired platelet aggregation was described
with mild to moderate bleeding disorders and variable deficiencies of whose platelets displayed decreased levels of ADP. Holmsen and
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platelet GPVI or signaling have been described; one had concomitant Weiss subsequently established that the defect was a deficiency in the
GPS (α-granule deficiency). 341–350 The others had selective abnormal- nonmetabolic pool or “storage pool” of ADP present in the dense gran-
ities in platelet–collagen interactions. Platelet GPVI deficiency asso- ules. δ-SPD is a heterogeneous disorder characterized by a bleeding
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ciated with an autoantibody to GPVI has been described in several tendency, abnormalities in the second wave of platelet aggregation, and
patients, one of whom also had systemic lupus erythematosus and variable deficiencies of platelet dense granule contents.
another of whom had coexisting antibodies to integrin α β . 351–353
IIb 3
Antibody to GPVI may be detectable in eluates prepared from patient Etiology and Pathogenesis
platelets even when it is not detectable in patient plasma. Acquired Normal platelets contain two pools of adenine nucleotides that exchange
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forms of GPVI-specific signal transduction have also been described in very slowly. One pool is a metabolic nongranule pool in which the
patients with myelodysplastic syndromes and chronic lymphocytic leu- ratio of ATP to ADP content is 8 to 10:1. The second pool is the “stor-
kemia. Studies in mice and primates demonstrated that antibodies age pool” present in the dense granules and contains 65 percent of the
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to GPVI can result in loss of GPVI from the platelet surface through platelet adenine nucleotides with an ATP-to-ADP ratio of 2:3. It is this
either proteolytic shedding or a cyclic adenosine monophosphate storage pool that is deficient in δ-SPD. Dense granules also contain
(cAMP)-mediated internalization mechanism, even though the plate- serotonin, which is taken up from plasma at a ratio of approximately
lets continue to circulate. 346,355 Thus, it is likely that the deficiency of 1000:1 via a pH-dependent amine trapping mechanism. Platelet seroto-
GPVI most commonly results from the autoantibodies. It is unclear nin levels are also decreased in δ-SPD.
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whether the patients reported earlier as having GPVI deficiency might δ-SPD can be a primary, inherited platelet disorder or a compo-
also have had an immune basis for their GPVI deficiency. nent of a multisystem (syndromic) disorder, such as the Hermansky-
Three different inherited forms of GPVI deficiency have been Pudlak syndrome (HPS) 361–365 (variable oculocutaneous albinism, hemor-
described. One patient with a lifelong history of “mild” mucocuta- rhagic disorder, and neurologic manifestations), the Chédiak-Higashi
neous, posttraumatic, and postsurgery bleeding had a marked defi- syndrome 361,365,366 (partial oculocutaneous albinism, giant lysosomal
ciency of platelet membrane GPVI resulting from both a 16-base granules, and frequent pyogenic infections), and the Wiskott-Aldrich
out-of-frame deletion and a S175N missense mutation. The patient’s syndrome 361,367,368 (see below and Chap. 80). Other diseases associated
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platelets failed to respond to collagen, convulxin, or collagen-related with δ-SPD are Ehlers-Danlos syndrome, osteogenesis imperfecta,
peptide. Of note, FcRγ expression was normal. Another patient with and TAR syndrome. 361,371 The mode of inheritance in δ-SPD is not well
easy bruising, a prolonged bleeding time, abnormal PFA-100 closure defined, but an autosomal dominant pattern for the primary form has
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time to collagen/epinephrine, and no platelet aggregation in response been identified in some patients. The inheritance pattern of the syn-
to collagen had a combination of a R38C mutation in one allele and dromic forms follows the autosomal recessive and X-linked patterns
a five-nucleotide duplication insertion in the other, leading to a non- characteristic of those disorders. Essential criteria for the diagnosis of
sense codon. The R38C mutation led to misfolding of the protein, HPS are the tyrosinase-positive oculocutaneous albinism and the δ-SPD
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reduced surface expression, and a qualitative defect in collagen bind- in platelets. The hallmarks of albinism are diffuse hypopigmentation
ing. Five subjects from four apparently unrelated families in Chile of skin, iris, hair and retina, although there is phenotypic heterogeneity.
with variable histories of easy bruising, epistaxis, excessive bleeding Studies from animal models and, particularly, in patients with
after minor trauma, and gingival bleeding were found to have no the syndromic variants indicate that defects in biogenesis of lysosome-
platelet aggregation in response to collagen, convulxin, or collagen-re- related organelles form the basis of the disorders. 361,374 These organelles
lated peptide. DNA analysis showed a homozygous adenine inser- share features with lysosomes but have distinct morphology, composi-
357
tion between bases 711 and 712. Heterozygotes were asymptomatic tion, and functions, and include melanosomes in melanocytes, platelet
and had nearly normal platelet function. δ-granules, and Weibel-Palade bodies in endothelial cells. 361,374 In δ-SPD
associated with HPS, there may be a total failure of δ-granule formation
as judged by electron microscopy of platelets and megakaryocytes and
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the absence of CD63 (granulophysin; ME491; LIMP-1; LAMP-3), a lys-
ABNORMALITIES OF PLATELET osomal and dense granule membrane protein of Mr 40,000 that is also
GRANULES found in melanosomes. 361,363,376,377 The defect in melanosomes accounts
for the oculocutaneous albinism. The defect in lysosomes results in
Platelets contain at least three types of granules: dense or δ granules accumulation of ceroid lipofuscin, a lipid-protein complex leading to
containing ADP, ATP, calcium, serotonin, and pyrophosphate; α gran- granulomatous colitis and pulmonary fibrosis, which are variably mani-
ules containing a variety of proteins, some derived from plasma, oth- fest in these patients. Abnormalities of nine genes have been implicated
ers synthesized by the megakaryocyte; and lysosomes containing acid in causing HPS (Fig. 120–5). Ultrastructural studies in patients with a
hydrolases. Following platelet activation, the contents of the α and variety of types of HPS indicate that α granules and other organelles
dense granules are secreted. Inability to release these granule contents are unaffected. Mutations in HPS-associated genes result in defects
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by virtue of a deficiency of the granules or their contents or in the cel- in intracellular protein trafficking and in the biogenesis of lysosomes
lular mechanisms governing the secretory process is associated with and lysosomes-related organelles. The HPS gene products operate in
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impaired platelet function. A heterogeneous group of disorders involv- distinct complexes termed biogenesis of lysosome-related organelles com-
ing platelet granules has been described. They are broadly categorized plexes (BLOCs), which consist of multiple proteins. HPS is unusually
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into defects affecting dense granules (δ-storage pool deficiency [SPD]), common in patients from northwest Puerto Rico (frequency: 1:1800),
α granules (α-SPD, or GPS), or both dense bodies and α granules and linkage analysis of these patients led to the identification of the
(αδ-SPD). Another disorder affecting granules is the Quebec platelet abnormality in HPS gene (HPS1). The gene encodes a 700-amino-acid
disorder, which affects the α-granules. protein that participates in the complex of proteins called BLOC-3. 361,363

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