Page 2085 - Williams Hematology ( PDFDrive )

2060 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2061

normal in WAS platelets, there is decreased spreading on fibrinogen production. 419,420,544 They interact in a combinatorial manner in regulat-
544
and decreased clot retraction associated with enhanced PS exposure. 536 ing megakaryocytic genes. A single transcription factor mutation may
Splenectomy usually improves the thrombocytopenia. 523,524 Hemato- alter expression of numerous genes, affect diverse cellular mechanisms,
poietic stem cell transplantation is the accepted curative approach for and lead to defects in both platelet number and function. Until recently
WAS and can correct all aspects of the disease provided reconstitution is the pursuit of the molecular mechanisms in patients with platelet dys-
achieved. 523,524 Autologous gene-modified hematopoietic stem cell trans- function has focused on delineating mutations in the genes encoding
plantation is an emerging therapy for WAS patients. 523,524 postulated candidate proteins. Therefore, the increasing spotlight on
transcription factor mutations to explain platelet dysfunction is a para-
digm shift. 9,545,545A
KINDLIN-3 (LEUKOCYTE ADHESION
DEFECT-3; LEUKOCYTE ADHESION RUNX1 (FAMILIAL PLATELET DISORDER WITH
DEFECT—1 VARIANT; INTEGRIN PREDISPOSITION TO ACUTE MYELOGENOUS

ACTIVATION DEFICIENCY DISEASE) LEUKEMIA)
DEFINITION AND HISTORY/ETIOLOGY An association between inherited platelet dysfunction, thrombocytope-
nia, and a predisposition to acute myeloid leukemia has been reported
AND PATHOGENESIS in several families in which the platelet abnormalities antedated the leu-
A syndrome with the features of both mild LAD-1 and GT was first kemia. 390,490,546–551 Inherited mutations in RUNX1 (AML1, CBFA2) is the
537
described in 1997 and termed LAD-1 variant or LAD-3. Since basis for this constellation, which is inherited as an autosomal dominant
then more than 10 families have been reported, with several from trait, because of haploinsufficiency. Patients generally display mild
490
Turkey. 538–541 The etiology is a deficiency or defect in the cytoskeletal thrombocytopenia from birth and a bleeding disorder disproportionate
linking protein kindlin-3 (FERMTS3). Kindlin-3 is a protein expressed to the thrombocytopenia. Approximately one-third of patients develop
exclusively in hematopoietic cells with homology to talin that also binds leukemia, with a median age of onset of 33 years. 552
to the cytoplasmic domain of the β subunit of integrin α β (Chap. 112). Platelet abnormalities reported in patients with RUNX1 muta-
3
IIb 3
It has been implicated in the inside-out activation of integrin α β tions include decreased aggregation, secretion, protein phosphorylation
IIb 3
542
in mice. It also participates in the activation of leukocyte integrins, (myosin light chain and pleckstrin), production of 12-hydroxyeicosap-
which accounts for the defects in immune function. It may also affect entaenoic acid; decreased integrin α β activation upon platelet acti-
IIb 3
red blood cell structure. Defects in CALDAGGEF1, the gene for another vation; δ and/or α-granule SPD; and a selective decrease in one PKC
exchange factor, also cause abnormalities in platelet function and are isoform (PKC-θ). 372,390,553–555 Of note, several patients described earlier as
discussed in the section on Guanosine Triphosphate-Binding Protein having SPD (δ or α granules) have been subsequently shown to harbor
Defects. 538,543 RUNX1 mutations. 358,372,390,391 In one patient, platelet albumin and IgG
The disorder is characterized by a hemorrhagic diathesis in com- were diminished, suggesting a defect in the uptake and packaging of
bination with a variable predisposition to infections and inflamma- these proteins into α granules. 481,489
tion without pus formation, poor wound healing, delayed umbilical Most mutations of RUNX1 have been in the conserved Runt
390
cord stump detachment, and variable osteopetrosis. Intracerebral domain, although a mutation in the transactivating domain (Y260X)
hemorrhage at birth or soon thereafter has been reported in several of has been reported. Platelet transcript expression profiling in a patient
390
the patients, as well as relatively severe mucosal and gastrointestinal with RUNX1 haploinsufficiency revealed downregulation of numer-
bleeding. Thus, the bleeding diathesis is more severe than is found ous genes involved in platelet structure and function, including MYL9
in patients with GT, perhaps because of additional abnormalities in (myosin light chain), ALOX12 (12-lipoxygenase), PF4, and PRKCQ
blood vessels. The need for red blood cell transfusions in infancy (PKC-θ). 491,554–556 ALOX12, PRKCQ, PF4, and MYL9 554–556 are direct
has been reported in several patients as a result of blood loss from transcriptional targets of RUNX1. Patients with RUNX1 haploinsuf-
mucosal surfaces and perhaps red blood cell abnormalities. Leukocy- ficiency also have impaired megakaryopoiesis and decreased plate-
490
551
tosis, as is found in other LAD syndromes is a constant finding. Nor- let thrombopoietin receptors (Mpl). Targeted correction of RUNX1
mal platelet counts are the usual finding, but thrombocytopenia has mutation in induced pluripotent stem cells (iPSCs) developed from skin
been reported. Platelet aggregation studies demonstrate defects simi- fibroblasts from two patients resulted in normalization of the defect in
391
lar to those observed in GT. 541–543 Hematopoietic stem cell transplan- megakaryopoiesis. These studies raise the potential for targeted gene
tation has been successful in restoring normal hematopoietic function therapy for this disorder. Using next-generation sequencing, Stockley
9
in patients with life threatening hemorrhagic and infectious compli- and colleagues identified mutations in RUNX1 and FLI1, in six of
cations of the disease. 541 13 patients with excessive bleeding, and impaired aggregation and
platelet dense granule secretion in response to multiple agonists. Thus,
transcription factor mutations are an important mechanism for inher-
TRANSCRIPTION FACTOR MUTATIONS ited platelet dysfunction. 545,545A
AND ASSOCIATED PLATELET
DYSFUNCTION GATA-1
GATA-1 is a critical regulator of both megakaryocyte and erythroid
Transcription factors, and the cis-regulatory sequences to which they development. GATA-1 mutations have been associated with an X-linked
bind, regulate lineage-specific gene expression. Transcription factors syndrome consisting of dyserythropoiesis, anemia, thrombocytopenia,
RUNX1, FLI1 (a member of the ETS [E-twenty-six] family), GATA-1, and large platelets ; selectively impaired responses to collagen and ris-
2
and GFI1B (growth factor independent 1B) are important regulators of tocetin related to abnormalities in GPIbβ 557,558 ; diminished platelet Gαs
hematopoietic lineage differentiation, megakaryopoiesis, and platelet protein and mRNA ; and a form of GPS (with R216N mutation). 418
557

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