HEMATOLOGY 2

PLATELET DISORDERS
i. SEBASTIAN SYNDROME iv. MYH9 RELATED DISORDERS
ii. INTRODUCTION The following conditions, once thought to be
 A rare genetic disease that results in impaired separate, are now known to be part of MYH9RD.
blood clotting function and abnormal platelet
formation.
 An extremely rare autosomal dominant
thrombocytopenia characterized by giant
platelets, neutrophil inclusions, mild bleeding
disorder, and no other clinical manifestations.
 Genetic studies in the year 2000 proved that
Sebastian syndrome is due to a mutation in
the gene that encodes a specific enzyme
known as nonmuscle myosin heavy chain 9
(the MYH9 gene). The gene locus is 22q11.2,
or, the eleventh band of the q arm of
chromosome 22
 Sebastian syndrome is extremely rare and
less than 10 affected families have been
reported in the medical literature. Both males
and females appear to be affected with the
same probability.
 Affected individuals have been identified in
Caucatian, Japanese, African-american,
Spanish and Saudi Arabian families
 People affected have mild, non-life
threatening dysfunction of the blood related to
decreased blood clotting function. They may
be bruise easily or be prone to nosebleeds.
v. RESULTS
iii. LABORATORY FEATURES
 It is a rare autosomal dominant disorder CBC - to MILD TO MODERATE
characterized by the presence of : determine the THROMBOCYTOPENIA
Thrombocytopenia, number of platelets (40-120X103/UL)
Macrothrombocytopenia(abnormal platelets), in a blood sample. Mean platelet volume – 18 fl
Neutrophilic inclusion.
BLEEDING TIME Prolonged mildly (10 to 12
minutes)

GENETIC Confirms the presence of a

SEQUENCING mutation on the MYH9 gene

PERIPHERAL Large platelets and faintly

BLOOD SMEAR blue cytoplasmic inclusions
in the neutrophils, similar in
appearance to Dohle bodies
 Caused by mutations in the MYH9( myosin ELECTRON Enlarged platelets
heavy chain 9 gene on chromosome 22q 12- MICROSCOPY neutrophils show 1- to 3 um
13 which codes for the non-muscle myosin cytoplasmic areas of
heavy chain IIA (NMMHC-IIA) randomly dispersed
 It is a part of MYH9 related disorder ribosome clusters
 Consists of giant platelets, leukocyte PLATELET Normal in response to ADP,
inclusions and thrombocytopenia. AGGREGATION collagen, and ristocetin.
 In a majority of individuals, MYH9- related TEST
disorders is inherited in an autosomal
dominant pattern, in which a single copy of
the mutated gene is sufficient to cause the
disorder.

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 vi. INDICATION x. EPSTEINSYNDROME
The clinical signs and symptoms are variable
Patients are usually: xi. INTRODUCTION
* Asymptomatic Causes of Epstein Syndrome
* Easy bruising • Caused by a mutation in MYH9 gene more
* Mild bleeding diathesis (occurring early in specifically on the R702 codon
childhood) • It is an autosomal dominant mutation thereby
* Heavier than normal menstrual bleeding it is inherited if one or both parents carry the
* Severe postoperative hemorrhage mutated gene (however there have been
***Some individuals with Sebastian syndrome may cases wherein the syndrome is sporadic or
not have an observable physical signs of the non-congenital)
disorder. • The mutations are found in the nonmuscle
vii. CORRELATION TO PLATELET myosin heavy chain IIA (MYHIIA).
QUALITY/ FUNCTION • The MYH9 gene encodes for tissues including
• At the ultrastructural level, the platelets are platelets, cochlea, renal cells, neutrophils, and
enlarged but have normal structural elements. eyes.
• Has a low blood platelet count than normal
• MPV is low for the normal range. xii. Signs and Symptoms
• BT is high within the normal range. • The initial symptoms are described as
viii. TREATMENT bleeding tendency and thrombocytopenia.
• PLATELET TRANSFUSION Bleeding tendency may be observed in
• DESMOPRESSIN epistaxis and purpura.
• ANTIFIBRINOLYTIC DRUGS OR • Other symptoms may include
ELTROMPOBAG macrothrmobocytopenia, protenuria,
nephropathy, sensorineural hearing loss, low
NOTE: No treatment is required for the majority of platelet count, oral lesions, and cataracts.
people affected with Sebastian syndrome. After
surgery, platelet transfusion may be required in
order to avoid the possibility of hemorrhage.
People diagnosed with Sebastian syndrome
should be made aware of the risks associated with
excessive bleeding.
ix. CONCLUSION
Sebastian syndrome is rare, autosomal dominant
disorder resulting in thrombocytopenia with giant
platelets, leukocytes inclusions and absence of • The most common symptoms include
nephritis, sensorineural hearing loss, and macrothrombocytopenia, sensorineural
cataracts. hearing loss, and nephritis. (The symptoms
and severity of these symptoms vary between
NOTES: extremely rare condition particularly patients where most patients experience
affecting platelets nephritis in childhood and then progress to
giant platelets - most common attribution kidney failure in adolescence).
Neutrophilic inclusion - similar to dohle bodies  • In macrothrombocytopenia, the size of the
Very mild bleeding disorder and no other clinical platelets can reach upto 6.6 um compared to
manifestation
a normal size which is 2.5 um (30% of the
Epistaxis - mostly appear to children
platelets can reach the size of an
Adult- mostly affected is right after surgery kaya nga
prolonged bleeding time erythrocytes)
• Macrothrombocytopenia

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 xiii. LABORATORY FEATURES xv. TREATMENT
Diagnosis • Since Epstein Syndrome is regarded as a
• The cardinal symptom in Epstein syndrome is refreactory disease. Treatments include renal
thrombocytopenia with giant platelets transplantation, however, this may become
(macrothrombocytopenia). A peripheral blood problematic as patient’s low platelet count
smear is taken from the patient and a light (thrombocytopenia) increase the risks of
microscope is used to these identify giant complications in surgery.
platelets. • To minimize the risk of patient's losing too
• Hematology analyzers or a hemocytometer much blood during the perioperative period,
can be used to determine the number of HLA-matched platelet infusions can be used
platelets. A small number of platelets in blood to maintain satisfactory platelet levels.
smears compared to the normal • In order to ensure the transplanted kidney is
range of 150,000 to 450,000 platelets in recognized as ‘self’ by Major
microliter of blood suggest thrombocytopenia, Histocompatibility cells, immunosuppression
which is a symptom in Epstein syndrome. drugs are used post operation.
• A urine sample is often collected where a Immunosuppresion drugs such as calcineurin
urinalysis can be used to determine the inhibitor or antimetabolite.
volume of proteins excreted in urine.
Abnormal amounts of protein detected means MAINTENANCE
the patient has proteinuria. (Patients with • As a result of nephritis, a healthy blood
Epstein syndrome often have large proteinuria pressure becomes difficult to maintain
where they excrete above 3.5g of protein in and hence medication including
their urine in a day). This is one of the vasopressin may be prescribed to maintain
initial signs of renal disease. blood pressure. (Severe nephritis may mean
• Easy bruising and abnormal bleeding kidney dialysis is required to ensure the
tendencies are also described in initial blood is being filtered)
diagnosis. This supports the common • This may include either peritoneal dialysis or
misdiagnosis for chronic idiopathic hemodialysis, however, hemodialysis is most
thrombocytopenia purpura in patients with common Epstein syndrome patients will
Epstein syndrome. These symptoms are often often eventually have renal transplants.
noticed in early childhood due to the • Sensorineural hearing loss is a common
congenital cause of the disease. symptom in Epstein syndrome and can
be treated with cochlea implants.
xiv. Correlation to Platelet Quantity / Cochlea implants have four main parts
Function including the electrode array, the
• There are less platelets to coagulate in transmitter, the receiver/stimulator and the
presence of a damaged blood vessel, which microphone.
can result in bleeding problems NOTES: several sign and symptoms
• Platelet survival is normal however Affect kidneys causing nephritis, hearing loss 
They have persistant proteinuria, hematuria and
aggregation and secretion in response to
moderate hypertension and mild bleeding
collagen, adenosine, and thrombin are all
decreased.
• Platelet function may vary from normal to
grossly impaired.
• The large or giant size of the platelets also
affect their ability to bind to each other to seal
the damaged blood vessel and stop bleeding

Giant Platelet in a Peripheral Blood

Normal Peripheral
Smear
Blood Smear (Macrothrombocytopenia)

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 xvi. MEDITERRANEAN  their subsequent factor association is
MACROTHROMBOCYTOPENIA essential for efficient transport of overall
• It as an acquired defects of platelet adhesion complex to the platelet surface.
• It is under Inherited Giant Platelet Disorders  the GP1BA gene that encodes for GP1BB
• It is an autosomal benign anomaly usually is located commonly deleted region.
affect Mediterranean population such as  only single allele of a component of GPlB-
Greeks, Italian and Balkans IX-V complex, which has an important role
• It is under Macrothrombocytopenia , the in platelet activation by VWF is mutated,
phenomenon of reduced platelet count than which accounts for the thrombocytopenia.
normal (< 150,000/µL) with a significant xviii. Treatment
increase in platelet size (> 12 fl). There is no general recommendation about
PHYSICAL EXAMINATION treatment for patients with Inherited Giant Platelet
 Mostly asymptomatic Disorders, but in severe cases of bleeding, the
 No bleeding or other symptoms following may be used:
 Episodes of Hemolytic Anemia may be  Platelet Transfusion is the treatment of
present (very rare). choice with bleeding symptoms.
 It may reveal mild splenomegaly (very rare).  DDAVP (1-deamino-8-arginine vasopressin)
Therapy it causes the release of VW’s antigen
xvii. Laboratory Results from the platelets and the cells that line the
blood vessels where it stored.
THROMBOCYTOPENIA MILD  Splenectomy for patients with splenomegaly
PLATELET COUNT 89-290X10⁹/L OR Notes: The incidence or the disorder has prevalence
290 × 103/ΜL among person from Greece, Italy and 
PLATELET BIOMASS NORMAL Mainly characterized by mild thrombocytopenia and
(PLATELET SIZE × large platelets 
PLATELET COUNT) No bleeding, No aggregation abnormality and no
UNDER PERIPHERAL STOMATOCYTES structural defect
BLOOD SMEAR AND
LARGE
PLATELETS
UNDER ELECTRON LARGE
MICROSCOPIC PLATELETS
EXAMINATION WITH NO OTHER
ABNORMALITIES

Under Peripheral Blood Smear showing giant

platelet and stomatocyte

Gene Mutation
• Mutations in GP1BA gene and GP1BB
gene
 result in defective platelet surface
expression of GPlb-IX-V, resulting to a
decreased ability of platelets to adhere to
subendothelial VWF as well as decreased
in vitro response of platelets to thrombin
and ristocetin.

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 xix. Hermansky-Pudlak Syndrome

Introduction
 Describe in 1959 by Hermansky and Pudlak
 Disorder which results in oculocutaneous
albinism, bleeding problems due to a platelet
abnormality and storage of an abnormal fat-
protein compound.
 HPS is a rare disorder that affects males and
females in equal numbers. It is most prevalent
in persons from northwest Puerto Rico.
 HPS does occur in other populations as well.
It is the third most prevalent form of albinism.

• Hermansky-Pudlak
syndrome (HPS) is
a hereditary disorder
–autosomal
recessive

Three characteristics: Indication

1. Decreased pigmentation (albinism) with visual • Difficult for cuts and wound to heal
impairment • Frequent nosebleed, gum bleeding
2. Blood platelet dysfunction with prolonged • Excessive bleeding
bleeding due to the lower amount of dense • Excessive bleeding during menstruation or
bodies seen in storage pool disease labor in women
3. Some patients have lung fibrosis, colitis, or an • Difficulty in breathing
abnormal storage of a fatty-like
substance (ceroid lipofuscin) in various
tissues of the body.

• Characterized by a condition called

OCULOCUTANEOUS ALBINISM, which
causes an abnormal light coloring
pigmentation of the skin, hair, and eyes.
Those affected by the syndrome, have fair
skin and either white or light colored hair.
• Excessive sun exposure increases the risk of
skin damage or cancer.
Causes
 HPS is inherited as an autosomal
recessive genetic disease. Mutations in HSP1
gene are responsible for this disorder.
 Mutations in the genes associated with
Hermansky-Pudlak syndrome prevent the
formation of LROs or impair the functioning of
these cell structures. Correlation
 HSP1 are responsible for production and • The most accurate test for the diagnosis of
control of melanosomes, dense granules, and HPS is platelet electron microscopy.
lysosomes. • HPS platelets show virtual absence of Dense
Bodies.
xx. Laboratory result • DB are needed for the second phase of
- Normal PT/PTT platelet aggregation. When there is a low
- Platelet count normal-except for severe bleeding amount of dense bodies or granules, the
problems contents to be secreted are also affected
- BT variably normal to prolonged causing a dysfunction in aggregation that
-Diagnosis made by EM is absence of dense could also affect the formation of platelet plug.
granules
-Platelet aggregation shows blunted response in
biphasic curves-abnormal
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 Treatment xxi. CHEDIAK-HIGASHI SYNDROME
There is no cure for HPS, no treatment but there is • a rare, autosomal recessive, complex, platelet
standard therapy: disorder, and a immune disorder of
• Treatment with vitamin E and the generalized cellular dysfunction involving
antidiuretic DDAVP. fusion of cytoplasmic granules
• Transfusions of normal blood platelets. • caused by mutation in CHS1/LYST gene
• Oral contraceptives. located on chromosome 1 which encodes
• The drug desmopressin acetate lysosomal trafficking regulator (protein)
(DDAVP) can also be administered to • onset in early childhood and death often
patients with acute bleeding and has occurs before the age of 7
proved effective for some patients with • adults can be affected but only in atypical
this symptom. form
• Individuals with HPS should avoid blood • initially described by Beguez-Caesar,
anticoagulants, such as aspirin. Chediak, and Higashi
xxii. CHARACTERISTICS OF CHS
1. Partial Oculocutaneous Albinism
● enlarged melanosomes that reduces
production of melanin in the skin, hair
and eyes
● metallic or "silvery" appearance of the
hair
● photosensitive
● nystagmus (rapid and involuntary
movement of eyes)
2. Pyogenic Bacterial Infection
● Pyogenic bacteria- bacteria that
produces pus
3. Giant Lysosomal Granules in Leukocytes
4. Coagulation Defect (deficiency in platelet
dense granules)
● mucosal or gum bleeding, easy bruising,
and bleeding
5. Neurological Problems
● Tremors
● Ataxia (difficulty with balance)
● Peripheral neuropathy

xxiii. ACCELERATED PHASE OF CHS

● arises in 85 % of the individuals affected
● Severe phase of disease and believed to
be triggered by a viral infection
● It is marked by lymphocytic proliferation
in the liver, spleen, bone marrow
● Associated with fever, pancytopenia,
overwhelming infections, episodes of
abnormal bleeding, and organ failure
Notes: can cause various conditions, can manifest ● Results to death at early age
other conditions
In particular, it affects mainly dense granules
wherein there is deficiency or absence in totality
If there are no dense, it can affect the secretion of
the platelet
Swiss cheese platelets – because of marked
dilation
Tortuosity - there is curving that is why it is Swiss
cheese platelets
No treatment but u can do therapy to prevent or
not to worsen
CHG is correlated with HPS
ADP and calcium for aggregation
The other one for bleeding
Aside from dense granules deficiency, it could
cause oculocutaneous albinism there is deficiency
in melanin - mainly for protection specially in the
skin

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 xxiv. LABORATORY FEATURES Therefore, less or no clotting activity of platelets,
there will be severe or prolonged bleeding
Laboratory Test Result
WBC Count Decreased: <12,000
WBC Differential WBC/cumm
Count neutropenia: <2500
neutrophils/cumm
Peripheral Blood Giant lysosomal granules in
Smear WBCs
Platelet Count Decreases as the condition
worsens
Platelet Structure: deficiency xxvii. TREATMENT
of dense granules
• HIGH DOSE OF VITAMIN C- to improve
Bleeding Time Prolonged
phagocytic activity
Modified Duke’s Method
• PLATELET TRANSFUSION
(exceeds 7 minutes)
• ANTIBIOTICS, ANTI-FUNGAL, AND ANTI-
Ivy Method (exceeds 7
minutes) VIRAL DRUGS- when bacterial or viral
Platelet Decreased platelet infections occur
Aggregation Test aggregation in response to • BONE MARROW TRANSPLANT- for
collagen accelerated phase
Bone Marrow Large peroxidase-positive
Biopsy inclusion bodies in leukocyte SUMMARY
precursor cells • Chediak-Higashi Syndrome is a rare,
autosomal recessive, immune disorder of
generalized cellular dysfunction involving
fusion of cytoplasmic granules caused by
mutation in CHS1/LYST gene.
• It occurs mostly in children and death often
occurs before the age of 7.
• It is characterized by partial oculocutaneous
albinism, pyogenic bacterial infection, giant
lysosomal granules in leukocytes, coagulation
defect, and neurological manifestations.
• Accelerated Phase, as the severe stage of
CHS is believed to be triggered by a viral
infection and is life threatening.
• Laboratory Results include neutropenia,
xxv. INDICATION thrombocytopenia, prolonged bleeding time,
● Low WBC count, neutropenia and decreased platelet aggregation, giant
abnormal morphology, neutrophils lysosomal granules in WBCs and deficiency of
demonstrate defective phagocytic activity dense granules in platelets.
which increases susceptibility to bacterial • Low platelet count, and lack of dense
infection. granules means lack of storage sites for
● Thrombocytopenia, prolonged clotting substances that leads to slow platelet
bleeding time, and deficiency of aggregation and prolonged bleeding.
platelet dense granules can lead to • Treatment: vitamin C, antibiotics,
easy bruising and bleeding. antifungal/antiviral, platelet transfusion, and
xxvi. CORRELATION TO PLATELET bone marrow transplant
QUALITY/FUNCTION
Platelet Quality NOTES: Episodes of chg
• Dense granules of platelets release ATP, could range from mild to moderate but could
serotonin, and calcium in the clotting worsen as platelet count decreases
process and help platelets to stick
together to form clot.
• In CHS, lack of dense granules means
lack of storage sites for clotting
substances.
• Leads to slow platelet activation and
prolonged bleeding.
Platelet Quantity
• Normal value of platelets in children is
250,000- 450,000 platelets/cumm that
can help in normal coagulation.
• In CHS, decreased value of platelets
means decreased platelet function.