BERNARD-SOULIER SYNDROME
Description
 bleeding disorder; abnormal platelets
 Hemorrhagiparous thrombocytic
dystrophy
History
 Jean Bernard; Jean Pierre Soulier
Main Characteristic Features
 Large platelet, low platelet count
prolonged bleeding time
 Autosomal recessive
 1 in 1M individuals
Pathophysiology
 Decreased expression of GPIb/V/IX
(receptor of vWF) in the surface of
platelets
 deficient binding w/ vWF 
defective platelet adhesion
Lack of platelet plug formation 
increased bleeding tendency
Signs and Symptoms
 Easy bleeding and bruising
 Epistaxis
 Petechial rash
 Purpura
 GIT bleeding
 Menorrhagia
Lab Diagnosis
 Bleeding Time (prolonged) – <10-20
mins
 Clot Retraction – normal
 Platelet Survival – normal
 Blood Smears – larger than 4 um–10
um (normal value size: 2-3 um)
 Platelet Count - >30,000 to 200,000/ul
– low to normal
 Platelet Aggregation Studies – Normal
in collagen, epinephrine, ADP; fail to
aggregate in ristocetin or absent
 Flow Cytometry – reduce amount of
GP1b-IX-V complex
Treatment
 Platelet transfusion
 Desmopressin acetate – shortens
bleeding time
 Antifibrinolytic agents – useful for
mucosal bleeding (tranexamic acid)
 Restrictions of activity
 Antifibrinolytic drugs
 Recombinant factor VIIa
 Fibrin sealants
 Hormonal contraceptives (to control
excessive menstrual bleeding)
 Iron replacement (if necessary, to treat
anemia caused by excessive or
prolonged bleeding)
FETCHNER SYNDROME
Description
 Autosomal dominant
 Macrothrombocytopenia, w/ leukocyte
inclusion bodies assoc with Alport-Like
Syndrome
Main Characteristic Features
 Hematuria, Proteinuria, Cataract,
Hearing Loss, Macrothrombocytopenia
and Kidney Failure
 Platelets (about 7 µm in diameter)
 Mild to moderate bleeding tendency
 Mutation in the nonmuscle myosin
heavy chain 9 gene (MYH9)
Pathophysiology
 Mutation in MYH9 gene  Defect
expression of Glycophorin A 
Defective Megakaryopoesis 
Release of Macrothrombocytes 
Lack of Platelet plug formation 
Prolonged bleeding time
Laboratory Diagnosis
 Peripheral Blood Smear – decrease
platelet, macrothrombocytopenia
 Platelet Aggregation Test - normal
 Bleeding Time - prolonged
 Clotting Time - prolonged
 Platelet Count - decreased
 Urine Analysis – protein and blood
(increase rbc)
Treatment
No cure but symptoms can be manage.
 Dialysis
 Hearing Aid
 GLANZMANN THROMBASTHENIA
Description
 genetic platelet disorder
 qualitative or quantitative deficiencies
of the fibrinogen receptor GPIIb/GP3a
 chromosome 17
 50% activity of each protein - support
normal platelet aggregation
 leads to defective platelet aggregation
and subsequent bleeding
History
 autosomal recessive
 Eduard Glanzmann, 1918
Pathophysiology
 Mutation in ITGA2b & ITGB3  Defect
in GP2b/GP3a  Defective
aggregation in response to ADP,
Epinephrine and collagen  Increased
bleeding
Laboratory Diagnosis
 Platelet Count- Normal
 RBC Count- decreased
 Bleeding time- prolonged
 PFA 100 testing- the platelets fail to
plug the collagen-based filter
 Flow cytometry and monoclonal
antibodies- confirm the diagnosis of
Glanzmann thrombasthenia.
 Platelet aggregation studies- the
primary platelet aggregation response
to platelet agonists such as adenosine
diphosphate (ADP), epinephrine, and
collagen are decreased.
Treatment
 Platelet transfusion
 HepaB vaccine (for risk of multiple
transfusions)
 Avoid medications that affect platelet
func (Aspirin & NSAIDs)
 Oral contraceptives (control
menorrhagia)
Prognosis
 Good prognosis
MAY-HEGGLIN ANOMALY (MHA)
Description
 Autosomal dominant
 Giant platelet disorder
History
 Richard May
o Inclusion bodies in leukocytes
o May-Grunwald stain
 Robert Hegglin
o Three Novel Points of the
disorder
 presence of
abnormalities in two
distinct lineages of blood
cells: leukocytes and
platelets
 Thrombocytopenia
 Familial nature of the
disorder- transmitted
dominantly by a single
gene mutation
Main Characteristic Features
• characterized by:
• leukocytes with abnormal
cytoplasmic inclusion
bodies/Dohle like bodies
(mainly neutrophils)
• large/giant platelets (w/ few
granules)
• variable thrombocytopenia (that
may be associated with purpura
and bleeding)
• Symptomatic or asymptomatic
Pathophysiology
 Mutation in MYH9 gene (chromosome
22q12.3-13.2)  Overproduction of
NMMHCII-A (responsible for cell
diameter and architecture) 
Abnormal platelet diameter
(macrothrombocytopenia)  mild to
severe bleeding tendency
Laboratory Studies
 CBC – low platelet count
 PBS – leukocyte inclusion bodies,
macrothrombocytes
 Family history
 Bone Marrow Exam – normal
 Platelet Aggregation studies – normal
 Additional findings – prolonged
bleeding
  Differential diagnosis
 Immunofluorescence analysis of
neutrophil NMMHC-IIA localization
 MYH9 sequencing
Treatment and Management
 Platelet transfusion
 MonitorIing for abnormal bleeding
and/or hemorrhages.
 Genetic counseling
 Mild cases do not require therapy
 Preoperative Desmopressin
 Administration of corticosteroids,
immunosuppressive agents or
splenectomy is not indicated.
Prognosis
 It is not always easy to detect MHA
o Occasionally, patients with this
disorder have been
misdiagnosed and managed as
idiopathic thrombocytopenic
purpura.
o About half of the reported
patients are asymptomatic, and
the other half have platelet
counts < 50 K/uL and abnormal
bleeding.
o A special circumstance when
MHA should be considered in
pregnancy.
SCOTT CARDIODIGITAL SYNDROME
History
 Weiss (1994) – Anne Scott
 Autosomal recessive
 Congenital bleeding disorder- defect
in a platelet mechanism required for
blood coagulation.
 Provoked bleeding that includes:
a. menorrhagia
b. epistaxis
c. trauma induced hematomas
d. oral bleeding after tooth extractions
e. post-partum hemorrhage
f. defective wound healing
coagulation factors and also have
catalytic activity in the formation of
clots
 Procoagulant - refers to their ability to
flip the negatively charged
phosphatidylserine (PS) to their outer
membrane following activation,
localizing coagulation complexes near
the developing blood clot.
 Factor X -plays a role in blood clotting
 Thrombin - It catalyzes the conversion
of fibrinogen to fibrin
Pathophysiology
 Normal Pathway
Vascular injury  Platelet activated 
Phosphatidylserine in the inner leaflet
is transferred to the outer leaflet of the
membrane  Plasma protein
complexes bind to the surface/serves
as a procoagulant surface  acts to
the activation of factor X  thrombin
formation
 Abnormal Pathway
Unknown cause  Phosphatidyl
serine remains sequestered in the
inner leaflet of the membrane  No
procoagulant surface  No activation
of Factor X  No thrombin  No fibrin
clot formation  Increased bleeding
Laboratory Diagnosis
 Clotting Time - prolonged
 Bleeding time – prolonged
 Platelet count – normal
 Platelet coagulant activity assessment
– abnormal
 Platelet Aggregation Activity- normal
Treatment
 Normal Platelet Transfusion

Definition of Terms
 Phosphatidylserine -serves as
procoagulant surface; when exposed
to the outer leaflet of the platelet
membrane, PS serve as binding
sites for circulating protein
 SEBASTIAN SYNDROME
Characteristics
Description  Mild bleeding tendency due to platelet
 one of the inherited giant platelet dysfunction, thrombocytopenia,
disorders (IGPDs) anemia, asplenia, tubular aggregate
 improper platelet function and myopathy, congenital miosis &
increased platelet cell size ichthyosis
 autosomal dominant  Headaches and recurrent stroke-like
 mutation in the gene that encodes a episodes
specific enzyme known as nonmuscle Terms
myosin heavy chain 9 (the MYH9  STIM1- Stromal interaction molecule
gene). The gene locus is 22q11.2 1
o involved in controlling the entry
Pathophysiology of positively charged calcium
 Mutation in MYH9 gene (chromosome atoms (calcium ions) into cells
22q11.2)  Alteration in NMMHC-IIA when levels of the ions are low
 Macrothrombocytopenia  specifically through channels
MH FT EP SP called calcium-release activated
A S S S calcium (CRAC) channels.
MACROTHROMBOC + + + +  ORAI1- Calcium release-activated
YTOPENIA calcium channel protein 1
INCLUSION BODIES + + - + o A calcium selective ion channel
(LARGE) (L) (S) (S) that in humans is encoded by
HEARING LOSS - + + (+) the ORAI1 gene. It mediates
NEPHRITIS - + + - Ca2+ influx following depletion of
CATARACTS - + - (+) intracellular Ca2+ stores and
Increased bleeding tendency channel activation by the
Signs and symptoms Ca2+sensor
 Epistaxis
 Bleeding from the gums Pathophysiology
 Increased Bleeding Time  Normal Pathway
o Calcium levels are low  Upon
 Thrombocytopenia
Menorrhagia sensing Ca2+, STIM1
undergoes a conformational
 CBC – decreased platelet count
change enabling it to interact
 Bleeding Time- prolonged
with ORAI1 ORAI1 opens 
 Clotting Time- prolonged Calcium influx  adequate Ca
 PBS – macrothrombocytes, leukocyte ions  ORAI1 closes
inclusion bodies  Abnormal Pathway
 Platelet Count - decreased o Gain-of-function mutation of
 Genetic Sequencing – MYH9 Gene STIM  STIM1 senses calcium
sequencing  STIM1 undergoes a
conformational change enabling
Treatment and Management it to interact with ORAI1
 Platelet transfusion ORAI1 opens  Calcium influx
 STIM1 activated  does not
STORMORKEN SYNDROME close ORAI1  continuous
Other Names calcium influx  platelet
 Stormorken-Sjaastad-Langslet breakdown  increased
Syndrome bleeding tendency
 York Platelet Syndrome (YPS)
 Thrombocytopathy, Asplenia, Miosis Laboratory Diagnosis
 STRMK   Genetic Testing:
 o Molecular genetic tests
o Chromosomal genetic tests
o Biochemical genetic tests
 New Born testing (CentoICU)
(Germany)
 CentoICU platinum plus (Germany)
 Hereditary ichthyosis (NGS panel of
53 genes) (Portugal)
 Hereditary ichthyosis (NGS panel of
53 genes) (Portugal)
 STIM1 Deletion/duplication
analysis(United States)
Treatment
 Meloxicam for TAM
 Platelet transfusion
 Calcium Gluconate
THROMBOXANE PATHWAY DISORDERS
Terms
 Thromboxane-a member of a family of
lipids (eicosanoids)
 Thromboxane A2 (TxA2)-is a type of
thromboxane produced by activated
platelets that has prothrombotic
properties
 Thromboxane Synthase-an enzyme
found in platelets
 Arachidonic Acid-precursor of
thromboxane
 Adenosine Diphosphate (ADP)-
causes platelets to undergo shape
change, release granule contents, and
aggregate
 Collagen-substrate for adhesion of
platelets
 Epinephrine- potentiates the effects of
other agonists and at higher
concentrations, initiate platelet
responses including aggregation,
serotonin secretion and arachidonic
pathway activation
Pathophysiology
 Normal Pathway
o Phospholipid membrane ---
(Phospholipase A2)
Arachidonic Acid ---
(Cyclooxygenase) 
Prostaglandin H2 ---
(Thromboxane Synthase) 
Thromboxane A2
 Abnormal Pathway results to:
o ASPIRIN-LIKE DEFECTS
-Hereditary absence or
abnormalities of the components of
the thromboxane pathway
-Abnormal Aggregation seen with:
 Impaired release of
(ADP)
 Epinephrine
 Collagen
o Collagen Receptor Deficiency
• GP Ia/IIa or a2β1 Integrin
deficiency
-lacked an aggregation
response to collage
-platelets do not adhere to
collagen
• Glycoprotein VI deficiency
- responsible for platelet
signaling and activation
leading to TxA2 formation
-Platelets failed to aggregate
in response to collagen
-adhesion to collagen is also
impaired
-decreased ability to
form bloodclots.
o Adenosine Receptor Deficiency
• P2x1 Receptor Deficiency
- ion channel that upon
activation causes an influx of
calcium. Calcium activates
phospholipase A2, which
liberates arachidonic acid.
-It causes platelet shape
change and aids in the
activation process of other
agonists. Platelet shape
changes facilitate aggregation
-no calcium influx
-arachidonic acid is not
liberated
• P2Y1 Receptor Deficiency
-difficulty in platelet change
shape, aggregation,
thromboxane A2 generation
and thrombus formation.
• P2Y12 (P2TAC) receptor
deficiency
- is important for:
 platelet shape change
  thromboxane
generation
 procoagulant activity
 adhesion to immobilized
fibrinogen
 thrombus formation
under shear conditions.
-no platelet activation
• Epinephrine Receptor Deficiency
• a2–Adrenergic Receptor
Deficiency
-decreased platelet
activation and aggregation
in response to epinephrine
are known
- located on blood vessels
and sympathetic terminals
where they mediate
vasoconstriction and inhibit
norepinephrine release.
Laboratory Diagnosis
 Bleeding time (BT) - prolonged
 Activated Partial Thromboplastin Time
(APTT)- prolonged
 Prothrombin time (PT)- prolonged
 Platelet count direct and indirect-
slightly decrease
Treatment
 Desmopressin
 Blood Transfusion
WISKOTT-ALDRICH SYNDROME
Background
 X-linked disorder
 thrombocytopenia, eczema, and
immune deficiency.
 AKA eczema-thrombocytopenia-
immunodeficiency syndrome
 1937- Alfred Wiskott
 1954- Robert Aldrich
Pathophysiology
 Gene mutation or defect in WAS Gene
(Xp11.22-23) ----Missense/Frameshift
mutation- Formation of WAS protein
 Thrombocytopenia
A2
 Missense Mutation
o a point mutation in which a
single nucleotide change results
in a codon that codes for a
different amino acid
 Frameshift Mutation
o deletion or insertion in a DNA
sequence that shifts the way the
sequence is read
Signs and Symptoms
 Eczema
 Immunodeficiency
 Bleeding
 Recurrent Infections
Laboratory Diagnosis
 Platelet Count
 Genetic Test
 Immunoglobulin Test
Treatment
 Antimicrobial
 Platelet transfusions to prevent
bleeding
 Topical steroid to prevent eczema
GRAY PLATELET SYNDROME
Description
 It is an inherited bleeding disorders
characterized with abnormal platelet
which involves in blood coagulation.
 Due to absence of alpha-granules in
platelet and resulting the appearing of
gray when viewed under microscope
 The platelet appears to be large and
fewer than unusual
(macrothrombocytopenia) due to
mutation that disrupting in production
of alpha-granules.
Pathophysiology
 It has autosomal recessive pattern of
inheritance
 The proteins stored in alpha-granules help
platelet stick to one another
 A lack of a-granules impairs the normal
activity of platelets during clotting
Signs and Symptoms
 Low platelet count
 Spleenomegaly
 Easy bruising
 Myelofibrosis
 Nosebleed
 Menorrhagia
Laboratory Diagnosis
 Low platelet count
 Normal full blood count.
 Electron microscopy showing absence
alpha granules.
 Bleeding time is prolonged.
 Blood smear showing large gray
hypogranular platelets
Laboratory Test
 Platelet Aggregation Studies
 Molecular Genetic Testing
Treatment
 Platelet Transfusion
 Administration of Demopressin
 Splenectomy
Notes:
another blood component to be transfused is
the CRYOPRECIPITATE- component of the
plasma.
- It helps to control/ minimize bleeding.
COMPONENT PREPERATION- separation
of different blood component
Light spin-2000 gravitational force
Heavy spin-5000
-after blood collection, whole blood is
subjected to centrifugation to separate
plasma and packed rbc
-frozen fresh blood or ffb is towed at 4C
-Subject for another spin – observe white
mass-Cryoprecipitate
- in 450 ml whole blood- 15 ml
cryoprecipitate.
Notes:
-absence of plasma syndrome
- Platelet morphology is gray and large
- poor blood clotting, increase risk of bleeding
-associated with myelofibrosis
-Can be detected when born.
-NBEAL2- found in chromosome 3
MONTREAL PLATELET SYNDROME
Description
• Over 45 years ago, Montreal Platelet
Syndrome was first described as a rare
inherited platelet disorder.
• Ccharacterized by
macrothrombocytopenia with spontaneous
platelet clumping, abnormal platelet shape
change upon stimulation and a defect in
platelet calpain.
• This syndrome has now been reclassified
as type 2B von Willebrand disease with
the V1316M VWF mutation in the only
kindred ever reported.
Frequency and Inheritance
• Lacombe and d’Angelo first described this
disorder in 1963.
• Inherited as an autosomal dominant trait,
it has been reported in 3 generations of
Canadian families.
Clinical Manifestations
 Patients with MPS have a significant
bruising tendency and episodes of
hemorrhage
Laboratory Findings
• Autosomal dominants
• Platelet count ranges: 5 to 40K
• The platelet diameter is increased
(median, 3 μm)
• The bleeding time is prolonged, but the
clot retraction and the thromboplastin
generation are normal
• There is spontaneous platelet
aggregation,
• A hypervolumetric change in shape
associated with platelet activation also is
seen.
• The platelet aggregation in response to
ADP, collagen, AA, and ristocetin is
normal. However, the platelet aggregation
in response to thrombin is decreased
slightly, and it seems to be even more
pronounced at lower platelet counts.
The peripheral blood smear shows large
platelets with no neutrophil.
 means the patient has proteinuria.
Treatment (Patients with Epstein syndrome often
• No medications are needed. have large proteinuria where they
• Treatment is about managing the excrete above 3.5g of protein in their
symptoms urine in a day). This is one of the
• Stopping bleeding episodes from initial signs of renal disease.
becoming too extreme. • Easy bruising and abnormal bleeding
EPSTEIN SYNDROME tendencies are also described in initial
diagnosis.
Causes of Epstein Syndrome
• Caused by a mutation in MYH9 gene Treatment
more specifically on the R702 codon  Blood or Platelet Transfusion
• It is an autosomal dominant mutation
 Renal Transplantation
thereby it is inherited if one or both
 Immunosuppresion Medication
parents carry the mutated gene (however
there have been cases wherein the
Maintenance
syndrome is sporadic or non-congenital)
• The mutations are found in the nonmuscle  Cochlea Implants
myosin heavy chain IIA (MYHIIA).  Peritoneal Dialysis or Hemodialysis
The MYH9 gene encodes for tissues  Medication
including platelets, cochlea, renal cells,
neutrophils, and eyes. MEDITERRANEAN
MACROTHROMBOCYTOPENIA
Signs and Symptoms
Description:
• The initial symptoms are described as
• It as an acquired defects of platelet
bleeding tendency and thrombocytopenia.
adhesion
Bleeding tendency may be observed in
• It is under Inherited Giant Platelet
epistaxis and purpura.
Disorders
• Other symptoms may include
• It is an autosomal benign anomaly usually
macrothrmobocytopenia, protenuria,
affect Mediterranean population such as
nephropathy, sensorineural hearing loss,
Greeks, Italian and Balkans
low platelet count, oral lesions, and
• It is under Macrothrombocytopenia, the
cataracts.
phenomenon of reduced platelet count
• The most common symptoms include
than normal (< 150,000/µL) with a
macrothrombocytopenia, sensorineural
significant increase in platelet size (> 
hearing loss, and nephritis. (The
12 fl).
symptoms and severity of these
symptoms vary between patients where
Physical Examination
most patients experience nephritis in
 Mostly asymptomatic
childhood and then progress to kidney
 No bleeding or other symptoms
failure in adolescence).
 Episodes of Hemolytic Anemia may be
• In macrothrombocytopenia, the size of the
present (very rare).
platelets can reach upto 6.6 um compared
 It may reveal mild splenomegaly (very
to a normal size which is 2.5 um (30% of
rare).
the platelets can reach the size of an
erythrocytes)
Laboratory Results
• Macrothrombocytopenia
 Thrombocytopenia – mild
Laboratory Diagnosis:  Platelet Count – normal
• The cardinal symptom in Epstein  PBS – Stomatocytes & Large Platelets
syndrome is thrombocytopenia with  Electron Microscopic Examination –
giant platelets (macrothrombocytopenia). Large Platelets with no other
• A urine sample is often collected where a abnormalities
urinalysis can be used to determine the
volume of proteins excreted in urine. Treatment
Abnormal amounts of protein detected
There is no general recommendation about
treatment for patients with Inherited Giant
Platelet Disorders, but in severe cases of
bleeding, the following may be used:
 Platelet Transfusion
 DDAVP(1-deamino-8-arginine
vasopressin) Therapy
 Splenectomy
Notes: The incidence or the disorder has
prevalence among person from Greece, Italy
and mainly characterized by mild
thrombocytopenia and large platelets, no
bleeding, no aggregation abnormality and no
structural defect.
HERMANSKY-PUDLAK SYNDROME
Description
 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:
1. Decreased pigmentation (albinism) with
visual impairment
2. Blood platelet dysfunction with prolonged
bleeding due to the lower amount of
dense bodies seen in storage pool
disease
3. Some patients have lung fibrosis, colitis,
or an 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.
 HSP1 are responsible for production and
control of melanosomes, dense granules,
and lysosomes.
Laboratory Results
 Normal PT/PTT
 Platelet count normal-except for
severe bleeding problems
 BT variably normal to prolonged
 Diagnosis made by EM is absence of
dense granules
 Platelet aggregation shows blunted
response in biphasic curves-abnormal
Indication
• Difficult for cuts and wound to heal
• Frequent nosebleed, gum bleeding
• Excessive bleeding
• Excessive bleeding during menstruation
or labor in women
• Difficulty in breathing
Treatment
There is no cure for HPS, no treatment but
there is standard therapy:
• Treatment with vitamin E and the
antidiuretic DDAVP.
• Transfusions of normal blood platelets.
• Oral contraceptives.
• The drug desmopressin acetate
(DDAVP) can also be administered to
patients with acute bleeding and has
proved effective for some patients with
this symptom.
• Individuals with HPS should avoid
blood anticoagulants, such as aspirin.
Notes:
 can cause various conditions, can manifest
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 minutes)
dilation
Platelet Decreased platelet
 Tortuosity - there is curving that is why it is Swiss
cheese platelets Aggregation aggregation in response to
 No treatment but u can do therapy to prevent or Test collagen
not to worsen Bone Large peroxidase-positive
 CHG is correlated with HPS Marrow inclusion bodies in
 ADP and calcium for aggregation
 The other one for bleeding
Biopsy leukocyte precursor cells
 Aside from dense granules deficiency, it could
cause oculocutaneous albinism there is
deficiency in melanin - mainly for protection
specially in the skin
CHEDIAK-HIGASHI SYNDROME Indication
Description ● Low WBC count, neutropenia and
• a rare, autosomal recessive, complex, abnormal morphology, neutrophils
platelet disorder, and a immune disorder demonstrate defective phagocytic
of generalized cellular dysfunction activity which increases susceptibility
involving fusion of cytoplasmic granules to bacterial infection.
• caused by mutation in CHS1/LYST gene ● Thrombocytopenia, prolonged
located on chromosome 1 which encodes bleeding time, and deficiency of
lysosomal trafficking regulator (protein) platelet dense granules can lead to
• onset in early childhood and death often easy bruising and bleeding.
occurs before the age of 7
• adults can be affected but only in atypical Treatment
form • High Dose of Vitamin C
• initially described by Beguez-Caesar, • Platelet Transfusion
Chediak, and Higashi • Antibiotics, Anti-Fungal, and Anti-Viral
Drugs
Characteristics of CHS • Bone Marrow Transplant
1. Partial Oculocutaneous Albinism
2. Pyogenic Bacterial Infection MYELOPROLIFERATIVE NEOPLASM
3. Giant Lysosomal Granules in
Introduction
Leukocytes
 Myeloproliferative neoplasms (MPNs),
4. Coagulation Defect (deficiency in
formerly known as myeloproliferative
platelet dense granules)
diseases, are a rare type of blood cancer.
5. Neurological Problems
MPNs cause the overproduction of blood
cells by the bone marrow, including white
Laboratory Features
blood cells, red blood cells, or platelets.
Laboratory Result
The overproduction of cells can
Test
compromise blood flow and cause the
WBC Count Decreased: <12,000 various signs and symptoms common in
WBC WBC/cumm MPNs
Differential neutropenia: <2500  the term "myeloproliferative disorder"
Count neutrophils/cumm (MPD) was first used to described
Peripheral Giant lysosomal granules polycythemia vera and related disorders in
Blood Smear in WBCs 1951. In 2008, the World Health
Platelet Decreases as the Organization reclassified MPDs to
Count condition worsens "myeloproliferative neoplasms" (MPNs) to
Platelet Structure: reflect the consensus that these diseases
deficiency of dense are blood cancers (neoplasms). This
granules group of disorders is characterized by the
Bleeding Prolonged overproduction (proliferation) of one or
Time Modified Duke’s Method more of the three main blood cell lines -
(exceeds 7 minutes) red or white blood cells or platelets
Ivy Method (exceeds 7
Four Predominant Disorders Bone marrow biopsy
 Generalized
 Chronic Myeloid Leukemia (CML) hypocellularity
 Primary Myelofibrosis (PMF)  Megakaryocyte
 Polycythemia Vera (PV) hypertrophy and
 Essential Thrombocythemia (ET) hyperplasia
Genetic test Mutated JAK2, MPL,
CALR
Thrombopoietin level
Decreased

Prothrombin time Normal

Signs and Symptoms

• progressive fatigue Secondary Causes of Thrombocytosis
• low-grade fever  Iron deficiency
• anorexia  Infection
• weight loss  Inflammation
• bone pain.  Splenectomy
• Night sweats and fever associated with an  Trauma
increased metabolism caused by  Surgery
granulocytic cell turnover, may occur.  Ischemia
Laboratory Features Major Criteria
Erythrocytes (RBC) Megakaryocyte proliferation with large and
 Mild anemia mature morphology, little to no granulocyte or
 Polychromatophilia erythroid proliferation
 Elevated reticulocyte count • Rarely, minor (Grade 1) increase in
reticulin fibers
Leukocytes (WBC) • Must not meet any criteria for CML, PV,
 WBC Count is INCREASED PMF, MDS or other Myeloid neoplasms
• Must demonstrate JAK2 V617F, CALR, or
Platelets MPL mutations
 Giant dysplastic platelets
 Thrombocytosis Minor Criteria
• Presence of clonal marker or absence of
Bone Marrow evidence or reactive thrombocytosis
 Hypocellular
Treatment
Pathogenetic Mechanism of 3 Mutations  Plateletpheresis
1. JAK 2  Hydroxyurea
2. MPL  Cytoreduction
3. CALR  Anagrelide

Laboratory Results Notes:

TEST RESULT  ET- slow progressive
Complete blood count  Produces many platelets (platelets
 RBC: increased
 WBC: increased produced are abnormal or has defect in
 Platelets: increased their morphology)
 There is an increase megakaryopoiesis
Peripheral blood
smear
 High number of  Correlation of ET, PV, and MF- jak2
platelets mutation, 90-95% PV 56-60 % ET and
 Many large platelets MF.
Bleeding time  Prolonged
  Menorrhagia and postpartum
hemorrhage
 Heavy bleeding after injury or surgery
 Spontaneous rupture of the spleen
 Bleeding inside the skull (intracranial
hemorrhage) - very rare
 Miscarriage

Laboratory Features
 Prolonged prothrombin time
 and thrombin time
 Prolonged activated partial
thromboplastin time
 Undetectable functional fibrinogen
 Absence or immunoreactive fibrinogen
HEREDITARY AFIBROGENEMIA  Platelet defects may be secondary to the
metabolic defect
Introduction  Prolonged bleeding time
 Afibrinogenemia is considered as rare  Induced platelet aggregation
hereditary bleeding disorder with
autosomal recessive genetic WALDENSTORM MACROGLOBULINEMIA
transmission, caused by mutations of
any one out of the three genes located Introduction
on chromosome 4, responsible for  Waldenstrom Macroglobulinemia or
lymphoplasmacytic lymphoma is a
coding of three polypeptide chains,
monoclonal gammopathy that causes
constituents of fibrinogen. excessive B cell production of IgM and
 Afibrinogenemia, is a rare hereditary decreased production of the other
bleeding disorder having autosomal immunoglobulins.
recessive genetic transmission and  It is a very uncommon, slow-growing
prevalence of 1:1,000,000 live birth. cancer that begins in the immune system.
 It is a rare congenital coagulopathy  Increased IgM production thickens the
that leads to life-threatening bleeding. blood.
 Characterized by the absence of
fibrinogen (also known as coagulation Epidemiology
factor I) in the blood, a protein that is  AGE SPECIFIC: varies between 63-68
essential in the blood clotting years of age
(coagulation) process.  RACE: higher incidence among white
 Affected individuals may be people
susceptible to severe bleeding  SEX: more common in older men than
women
(hemorrhaging) episodes, particularly
during infancy and childhood. Prognosis
- Patient's Age
Etiology
- B2-Microglobulin Level
It is caused by:
- Monoclonal Protein Level
1. FGA Gene
- Hemoglobin Concentration
2. FGB Gene
- Platelet Count
3. FGG Gene
Etiology
Signs and Symptoms 1. There is B-cell neoplasm in WM
 Nosebleeds that are difficult to stop characterized by lymphoplasmo-
 Bleeding in the mucus membranes proliferative disorder with infiltration of the
 Bleeding in the joints bone marrow and IgM protein.
 Bruising easily
 Gastrointestinal bleeding
2. This proliferative disorder is associated
with production of abnormally large
amounts of IgM.
3. The basic abnormality in this
macroglobulinemia is uncontrolled
proliferation of lymphocyte and plasma
cells.
Signs and Symptoms
 weakness
 fatigue attributable to anemia
 chronic anemia and bleeding episodes
 increased blood viscosity
 lymphadenopathy &
hepatosplenomegaly
Presence of Malignant Cells with
Lymphoid and Plasmacytoid Morphology
 Specimen: Bone Marrow Aspirate
Serum Protein Electrophoresis (SPEP)
 presence of M spike
Other Lab Results
 Platelet dysfunction is observed in
approximately 1/3 of patients with WM.
This results from coating of platelet
membranes by paraprotein. Paraprotein
may interfere with fibrin polymerization
and the function of other coagulation
proteins.
 Almost all patients with malignant
paraprotein disorders have clinically
significant bleeding but thrombocytopenia
is still the most likely cause of bleeding in
these patients.
Treatments
1. Chemotherapy
Medicines are used that attack
abnormal cells to reduce their effect on
healthy bone marrow and lower the level of
abnormal protein. It can be taken
intravenously or in the form of a pill.
2. Plasma exchange
If thickening of the blood causes
problems, plasma exchange can be used
to wash the IgM protein out of your
bloodstream and replace it with healthy
plasma. It is very effective procedure
which requires only one or two treatments
to lower blood protein levels.
3. Biotherapy
Biotherapy may be used alone or in
coordination with chemotherapy. Biological
therapy, as it is often known, boosts your
immune system's ability to fight cancer and
help decrease side effects from certain types
of cancer treatments.
4. Radiation Therapy
It uses high-energy rays to kill cancer
cells. However, this type of treatment is not
used often to treat Waldenstrom
macroglobulinemia.
 Therapy is postponed for asymptomatic
patients, and progressive anemia is the
most common indication for initiation of
treatment.
 Main therapeutic options include: alkylating
agents - affects the ability of the cancer
cell to multiply.
 Nucleoside analogues- act as chain
terminators to stop DNA from multiplying.
 rituximab - binds to CD20 on surface of B
cell and triggers cell death.
 Novel agents, for example, bortezomib
shows promise as a targeted therapy
option for Waldenstrom Macroglobulinemia
Bortezomib is used to treat multiple
myelomas and mantle cell lymphoma.