Quebec platelet disorder is an autosomal

dominant bleeding disorder that results from a

deficiency of multimerin (a multimeric protein
that is stored complexed with factor V in a-
granules). Even though a-granule structure is
maintained, many a-granule proteins show signs
of protease-related degradation.
Thrombocytopenia may be present, although it is
not a consistent feature. Quebec platelet disorder

(QPD) is a rare autosomal dominant bleeding

disorder first described in a family from the
province of Quebec in Canada. The disorder is
characterized by large amounts of the fibrinolytic
enzyme urokinase-type plasminogen activator
(uPA) in platelets.

Hermansky-Pudlak syndrome. In addition to

occurring as an isolated problem, dense granule
deficiency is found in association with several
disorders. Hermansky-Pudlak syndrome is an
autosomal recessive disorder characterized by
tyrosinase positive oculocutaneous albinism,
defective lysosomal function in a variety of cell
types, ceroid-like deposition in the cells of the
reticuloendothelial system, and a profound
platelet dense granule deficiency. Several of the
mutations responsible for Hermansky-Pudlak
syndrome have been mapped to chromosome 19.
Mutations in at least seven genes individually can
give rise to Hermansky-Pudlak syndrome. These
genes encode for proteins that are involved in
intracellular vesicular trafficking and are active in
the biogenesis of organelles. The bleeding
associated with most dense granule deficiencies
is rarely severe; however, Hermansky-Pudlak
syndrome can be an exception. Although most
bleeding episodes in Hermansky-Pudlak
syndrome are not severe, lethal hemorrhage has
been reported, and in one series hemorrhage
accounted for 16% of deaths in affected patients.
For extensive surgery or prolonged bleeding both
red blood cell (RBC) and platelet transfusions are
required. Thrombin-soaked Gelfoam can be
used to treat skin wounds that fail to
spontaneously clot. Oral contraceptives can limit
the duration of menstrual periods. A unique
morphologic abnormality has been described in
the platelets of four families with Hermansky-
Pudlak syndrome. This abnormality consists of
marked dilation and tortuosity of the surface-
connecting tubular system (the so called Swiss
cheese platelet).
HPS was first described in 1959 by Dr. Frantisek
Hermansky and Dr. Paulus Pudlak
Chédiak-Higashi syndrome. This is a rare
autosomal recessive disorder characterized by
partial oculocutaneous albinism, frequent
pyogenic bacterial infections, giant lysosomal
granules in cells of hematologic and
nonhematologic origin, platelet dense granule
deficiency, and hemorrhage. The disorder is
accompanied by severe immunologic defects and
progressive neurologic dysfunction in patients
who survive to adulthood. The gene for the
Chédiak-Higashi syndrome protein is located on
chromosome 1 (1q42.3). A number of nonsense
and frameshift mutations result in a truncated
Chédiak-Higashi syndrome protein that gives rise
to a disorder of generalized cellular dysfunction
involving fusion of cytoplasmic granules. In 85%
of patients with Chédiak-Higashi syndrome the
disorder progresses to an accelerated phase that is
marked by lymphocytic proliferation in the liver,
spleen, and marrow with macrophage
accumulation in tissues. During this stage the
pancytopenia worsens, leading to hemorrhage
and ever-increasing susceptibility to infection;
the result is death at an early age. Initially
bleeding is increased because of dense granule
deficiency and consequent defective platelet
function. During the accelerated phase, however,
the thrombocytopenia also contributes to a
prolonged bleeding tendency. Bleeding episodes
vary from mild to moderate but worsen as the
platelet count decreases
Although Chediak-Higashi syndrome (CHS)
bears the names of the French physician Moises
Chediak and the Japanese physician Ototaka
Higashi, it was Antonio Beguez-Cesar, a Cuban
physician, who described the initial family with
atypical enlarged granules
Wiskott-Aldrich syndrome (WAS). This is a
rare X-linked disease caused by mutations in the
WAS gene on the short arm of the X chromosome
Xp11.23 that encodes for a 502-amino acid
protein – the Wiskott-Aldrich syndrome protein
(WASp) – that is found exclusively in
hematopoietic cells, including lymphocytes.
WASp plays a crucial role in actin cytoskeleton
remodeling. T cell function is defective due to
abnormal cytoskeletal reorganization, leading to
impaired migration, impaired adhesion, and
insufficient interaction with other cells. Disease
severity associated with WAS gene mutations
ranges from the classic form of WAS with
autoimmunity and/or malignancy, to a milder
form with isolated microthrombocytopenia (X-
linked thrombocytopenia [XLT]) (Chapter 38), to
X-linked neutropenia (XLN). Approximately
50% of patients with WAS gene mutations have
the WAS phenotype, and the other half have the
XLT phenotype. WAS gene mutations causing
XLN are very rare.50 Homozygous mutations of
the WIPF1 gene on chromosome 2 that encodes
WASp-interacting protein (WIP) – a cytoplasmic
protein required to stabilize WASp – can also
cause a WAS phenotype.51 The classic form of
WAS, alternatively called the eczema
thrombocytopenia immunodeficiency syndrome,
is characterized by susceptibility to infections
associated with immune dysfunction, with
recurrent bacterial, viral, and fungal infections,
microthrombocytopenia, and severe eczema.
Thrombocytopenia is present at birth, but the full
expression of WAS develops over the first 2 years
of life. Individuals with this disorder lack the
ability to make antipolysaccharide antibodies,
which results in a propensity for pneumococcal
sepsis. Patients with classic WAS tend to develop
autoimmune disorders, lymphoma, or other
malignancies, often leading to early death.
Bleeding episodes are typically moderate to
severe. In WAS a combination of ineffective
thrombocytopoiesis and increased platelet
sequestration and destruction accounts for the
thrombocytopenia. As with all X-linked recessive
disorders, it is found primarily in
males.11,20,33,52 Wiskott-Aldrich platelets are
also structurally abnormal. The number of dense
granules is decreased, and the platelets are small
(microthrombocytes), a feature of diagnostic
importance. Other than in WAS, such small
platelets are seen only in association with
TORCH (toxoplasma, other agents, rubella virus,
cytomegalovirus, herpesvirus) infections.
Diminished levels of stored adenine nucleotides
are reflected in the lack of dense granules
observed on transmission electron micrographs.
In laboratory testing the platelet aggregation
pattern in WAS is typical of a storage pool
deficiency. The platelets show a decreased
aggregation response to ADP, collagen, and
epinephrine and lack a secondary wave of
aggregation in response to these agonists
(Chapter 41). The response to thrombin is normal,
however. The most effective treatment for the
thrombocytopenia seems to be splenectomy,
which would be consistent with a mechanism of
peripheral destruction of platelets. Platelet
transfusions may be needed to treat hemorrhagic
episodes. Bone marrow transplantation also has
been attempted, with some success.
Wiskott-Aldrich syndrome was first described
in 1937 by Dr. Alfred Wiskott
Wiskott Aldrich Syndrome
WATER
Wiskott Aldrich Syndrome
Thrombocytopenia
Eczema
Recurrent bacterial infection
IgM s low
IgG is normal
IgA And IgE are elevated