Page 2084 - Williams Hematology ( PDFDrive )

2058 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2059

and VIIIa-IXa, 505,506 thus leading to impaired blood coagulation. Ery- macrothrombocytopenia; the polymorphism could not account fully
throcytes and lymphocytes also demonstrate similar defects in both for the macrothrombocytopenia because of the difference in inheri-
microvesicle formation and coagulant activity. 505,512 In a French family tance and its presence in approximately 11 percent of the normal pop-
508
with Scott syndrome, the propositus’ platelets were found to have a ulation. Individuals heterozygous for the polymorphism had normal
520
defect in protein tyrosine phosphorylation, suggesting an additional platelet counts, relatively high mean platelet volume values, abnormally
defect in signal transduction. 510 rounded platelets with abnormal marginal bands of microtubules, and
Apart from the above patients with the Scott syndrome, four mild abnormalities of platelet aggregation, secretion, and adhesion to col-
patients from three unrelated families have been reported to have lagen. One study found the polymorphism was associated with decreased
abnormal PCA, a bleeding disorder, impaired serum prothrombin con- collagen-induced platelet aggregation and increased risk of intracerebral
516
sumption, and reduced microparticle formation. However, in contrast hemorrhage in men. 521
to the Scott syndrome, the prothrombinase activity was normal. Subsequently, two patients with macrothrombocytopenia from a
The inheritance pattern in the Scott syndrome appears to be single kindred were reported to be heterozygous for a R318W β tubu-
1
522
autosomal recessive. 505,508 A heterozygous missense mutation has lin mutation. The mutation is strategically located at the α–β tubulin
been reported in one patient in the gene ABCA1, which encodes the interface. Of note, the Q43P polymorphism and an R207H substitution
ATP-binding cassette transporter protein implicated in PS transloca- were also found in this family, but neither was judged to be responsible
517
tion; the significance of this remains unclear. Mutations in TMEM16F for the macrothrombocytopenia.
have been identified in two patients with Scott syndrome. The patient Filamins are large dimeric actin-binding proteins that stabilize
Scott was found to have a homozygous mutation at the splice acceptor actin filament networks. Filamin A is the predominant platelet fil-
site for intron 12 of TMEM16F, resulting in a frameshift and premature amin. Several patients have been reported with dominant mutations of
518
termination of protein translation. A second patient had compound X-linked Filamin A (FLNA) gene associated with thrombocytopenia,
heterozygosity for a mutation at the donor splice site of intron 6 and a and abnormalities in platelet aggregation, secretion, GPVI signaling
single nucleotide insertion in exon 12, causing a frameshift and prema- and thrombus growth on collagen. 522A
ture termination of translation. While these findings constitute strong
13
evidence linking TMEM16F mutations to Scott syndrome, they leave
open whether TMEM16F is itself the membrane scramblase or a protein ABNORMALITIES OF CYTOSKELETAL
that regulates the scramblase. LINKING PROTEINS

CLINICAL AND LABORATORY FEATURES WISKOTT-ALDRICH SYNDROME PROTEIN
The bleeding symptoms in patients with the Scott syndrome are simi- The Wiskott-Aldrich syndrome (WAS) is an X-chromosome–linked
lar to those with other platelet defects. In contrast to other qualitative inherited disorder characterized by small platelets, thrombocytopenia,
platelet abnormalities, the bleeding time in Scott syndrome patients is recurrent infections, eczema, and an increased incidence of autoim-
523,524
normal. 508,509,514 The serum PT, which reflects the completeness of clot- munity and malignancies. In addition, a variety of immunologic
ting of whole blood and consumption of prothrombin, is abnormally, abnormalities affecting T-lymphocyte function, Ig levels, cellular immu-
indicating incomplete coagulation. 507–509 More specific assays of “platelet nity, and responsiveness to polysaccharide antigens are commonly
factor 3,” the phenomenologic designation of the platelet contribution present. Death from infection, hemorrhage, or malignancy is common
to accelerating clot formation, are also abnormal. 519 before adulthood. Some patients with WAS mutations may have only
Patients with the Scott syndrome have normal platelet aggregation thrombocytopenia (X-linked thrombocytopenia [XLT]) without other
and secretion in response to the usually used agonists. The patient features. WAS is caused by mutations in the WAS gene which encodes
505
Scott also had normal platelet phospholipid content, normal to the WAS protein (WASP), a multidomain protein that relays signals
505
enhanced platelet adhesion to subendothelium with diminished throm- from the cell surface to the actin skeleton and modulates the latter’s
524,525
bus formation, diminished factor Va binding to platelets and platelet reorganization. In platelets, WASP is localized to the cytoskeleton.
microparticles, and diminished platelet acceleration of both factor X It is phosphorylated on platelet activation by several different protein
524
activation and prothrombin activation. Abnormalities in exposure of kinases, including Btk, Grb2, PLC-γ , PKC-θ, and SGK1.
2
negatively charged phospholipids and shedding of microparticles have Microthrombocytopenia is a consistent feature of WAS and XLT
been consistent findings in all patients described. 506,508–512 and the major contributor to the bleeding diathesis, which may be
life-threatening in some patients because of gastrointestinal hemor-
rhage or intracranial hemorrhage. Marrow megakaryocytes are normal
TREATMENT in number, but platelet formation is abnormal and platelet survival is
Platelet or whole blood transfusions have been effective as prophylaxis decreased. 523,524
and as therapy for bleeding episodes. 505,507–509 Prothrombin complex Abnormalities in platelet surface glycoprotein sialophorin (CD43,
concentrates were effective in the patient Scott, but these preparations gp115, leukosialin), GPIb, platelet integrin α , integrin α β , and GPIV
392
IIb 3
2
may be associated with thrombotic complications. have been reported in some WAS patients. 526,527 Platelets from patients
with WAS also have qualitative defects, including SPD 367,368,528 and
impaired energy metabolism. 528,529
ABNORMALITIES OF A CYTOSKELETAL mal, or enhanced. 524,530–533 Interpreting these studies is confounded by
Platelet aggregation in WAS has been reported to be reduced, nor-
STRUCTURAL PROTEIN: β -TUBULIN the low platelet count, methodological differences, and timing in rela-
1
AND FILAMIN A tion to splenectomy. Despite the role of WASP in cytoskeletal reor-
524
ganization, shape change and actin polymerization are normal in WAS
Megakaryocytes and platelets express primarily and selectively the platelets. 531,534,535
β isoform of tubulin. A heterozygous β -tubulin Q43P polymor- WASP has been implicated in regulating responses dependent
1
1
phism was identified in a group of patients with a recessive form of on integrin α β outside-in signaling. Although Pac-1 binding is
536
IIb 3

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