BERNARD-SOULIER SYNDROME  Antifibrinolytic drugs

Description  Recombinant factor VIIa

 bleeding disorder; abnormal platelets  Fibrin sealants
 Hemorrhagiparous thrombocytic  Hormonal contraceptives (to control
dystrophy excessive menstrual bleeding)
 Iron replacement (if necessary, to treat
History anemia caused by excessive or
 Jean Bernard; Jean Pierre Soulier prolonged bleeding)

Main Characteristic Features FETCHNER SYNDROME

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

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  Abnormal Pathway results to:
 New Born testing (CentoICU) o ASPIRIN-LIKE DEFECTS
(Germany) -Hereditary absence or
 CentoICU platinum plus (Germany) abnormalities of the components of
 Hereditary ichthyosis (NGS panel of the thromboxane pathway
53 genes) (Portugal) -Abnormal Aggregation seen with:
 Hereditary ichthyosis (NGS panel of  Impaired release of
53 genes) (Portugal) (ADP)
 STIM1 Deletion/duplication  Epinephrine
analysis(United States)  Collagen
o Collagen Receptor Deficiency
Treatment • GP Ia/IIa or a2β1 Integrin
 Meloxicam for TAM deficiency
-lacked an aggregation
 Platelet transfusion
response to collage
 Calcium Gluconate
-platelets do not adhere to
collagen
• Glycoprotein VI deficiency
THROMBOXANE PATHWAY DISORDERS
- responsible for platelet
signaling and activation
Terms
leading to TxA2 formation
 Thromboxane-a member of a family of -Platelets failed to aggregate
lipids (eicosanoids) in response to collagen
 Thromboxane A2 (TxA2)-is a type of -adhesion to collagen is also
thromboxane produced by activated impaired
platelets that has prothrombotic -decreased ability to
properties form bloodclots.
 Thromboxane Synthase-an enzyme o Adenosine Receptor Deficiency
found in platelets • P2x1 Receptor Deficiency
 Arachidonic Acid-precursor of - ion channel that upon
thromboxane
activation causes an influx of
 Adenosine Diphosphate (ADP)-
calcium. Calcium activates
causes platelets to undergo shape
change, release granule contents, and phospholipase A2, which
aggregate liberates arachidonic acid.
 Collagen-substrate for adhesion of -It causes platelet shape
platelets change and aids in the
 Epinephrine- potentiates the effects of activation process of other
other agonists and at higher agonists. Platelet shape
concentrations, initiate platelet changes facilitate aggregation
responses including aggregation,
serotonin secretion and arachidonic -no calcium influx
pathway activation -arachidonic acid is not
liberated
Pathophysiology • P2Y1 Receptor Deficiency
 Normal Pathway -difficulty in platelet change
o Phospholipid membrane --- shape, aggregation,
(Phospholipase A2) thromboxane A2 generation
Arachidonic Acid --- and thrombus formation.
(Cyclooxygenase)  • P2Y12 (P2TAC) receptor
Prostaglandin H2 --- deficiency
(Thromboxane Synthase)  - is important for:
Thromboxane A2  platelet shape change
  thromboxane A2
generation
 procoagulant activity
 adhesion to immobilized  Missense Mutation
fibrinogen o a point mutation in which a
single nucleotide change results
 thrombus formation
in a codon that codes for a
under shear conditions.
different amino acid
-no platelet activation
 Frameshift Mutation
• Epinephrine Receptor Deficiency o deletion or insertion in a DNA
• a2–Adrenergic Receptor sequence that shifts the way the
Deficiency sequence is read
-decreased platelet
Signs and Symptoms
activation and aggregation
in response to epinephrine  Eczema
are known  Immunodeficiency
- located on blood vessels  Bleeding
and sympathetic terminals  Recurrent Infections
where they mediate
Laboratory Diagnosis
vasoconstriction and inhibit
 Platelet Count
norepinephrine release.
 Genetic Test
 Immunoglobulin Test
Laboratory Diagnosis
 Bleeding time (BT) - prolonged Treatment
 Activated Partial Thromboplastin Time  Antimicrobial
(APTT)- prolonged  Platelet transfusions to prevent
 Prothrombin time (PT)- prolonged bleeding
 Platelet count direct and indirect-  Topical steroid to prevent eczema
slightly decrease

Treatment
GRAY PLATELET SYNDROME
 Desmopressin
 Blood Transfusion Description
 It is an inherited bleeding disorders
characterized with abnormal platelet
WISKOTT-ALDRICH SYNDROME which involves in blood coagulation.
 Due to absence of alpha-granules in
Background platelet and resulting the appearing of
 X-linked disorder gray when viewed under microscope
 thrombocytopenia, eczema, and  The platelet appears to be large and
immune deficiency. fewer than unusual
 AKA eczema-thrombocytopenia- (macrothrombocytopenia) due to
immunodeficiency syndrome
mutation that disrupting in production
 1937- Alfred Wiskott
of alpha-granules.
 1954- Robert Aldrich
Pathophysiology
Pathophysiology
 It has autosomal recessive pattern of
 Gene mutation or defect in WAS Gene inheritance
(Xp11.22-23) ----Missense/Frameshift  The proteins stored in alpha-granules help
mutation- Formation of WAS protein platelet stick to one another
 Thrombocytopenia
 A lack of a-granules impairs the normal -NBEAL2- found in chromosome 3
activity of platelets during clotting

Signs and Symptoms

 Low platelet count MONTREAL PLATELET SYNDROME
 Spleenomegaly
 Easy bruising Description
 Myelofibrosis • Over 45 years ago, Montreal Platelet
 Nosebleed Syndrome was first described as a rare
inherited platelet disorder.
 Menorrhagia
• Ccharacterized by
macrothrombocytopenia with spontaneous
Laboratory Diagnosis
platelet clumping, abnormal platelet shape
 Low platelet count
change upon stimulation and a defect in
 Normal full blood count. platelet calpain.
 Electron microscopy showing absence • This syndrome has now been reclassified
alpha granules. as type 2B von Willebrand disease with
 Bleeding time is prolonged. the V1316M VWF mutation in the only
 Blood smear showing large gray kindred ever reported.
hypogranular platelets
Frequency and Inheritance
• Lacombe and d’Angelo first described this
Laboratory Test
disorder in 1963.
 Platelet Aggregation Studies
• Inherited as an autosomal dominant trait,
 Molecular Genetic Testing it has been reported in 3 generations of
Canadian families.
Treatment
 Platelet Transfusion Clinical Manifestations
 Administration of Demopressin  Patients with MPS have a significant
 Splenectomy bruising tendency and episodes of
hemorrhage
Notes:
another blood component to be transfused is Laboratory Findings
the CRYOPRECIPITATE- component of the • Autosomal dominants
plasma. • Platelet count ranges: 5 to 40K
- It helps to control/ minimize bleeding. • The platelet diameter is increased
COMPONENT PREPERATION- separation (median, 3 μm)
of different blood component • The bleeding time is prolonged, but the
Light spin-2000 gravitational force clot retraction and the thromboplastin
Heavy spin-5000 generation are normal
-after blood collection, whole blood is • There is spontaneous platelet
subjected to centrifugation to separate aggregation,
plasma and packed rbc • A hypervolumetric change in shape
-frozen fresh blood or ffb is towed at 4C associated with platelet activation also is
-Subject for another spin – observe white seen.
mass-Cryoprecipitate • The platelet aggregation in response to
- in 450 ml whole blood- 15 ml ADP, collagen, AA, and ristocetin is
cryoprecipitate. normal. However, the platelet aggregation
in response to thrombin is decreased
Notes: slightly, and it seems to be even more
-absence of plasma syndrome pronounced at lower platelet counts.
- Platelet morphology is gray and large The peripheral blood smear shows large
- poor blood clotting, increase risk of bleeding platelets with no neutrophil.
-associated with myelofibrosis
-Can be detected when born.
 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  Excessive sun exposure increases the
treatment for patients with Inherited Giant risk of skin damage or cancer.
Platelet Disorders, but in severe cases of
bleeding, the following may be used: Causes
 Platelet Transfusion  HPS is inherited as an autosomal
 DDAVP(1-deamino-8-arginine recessive genetic disease. Mutations in
vasopressin) Therapy HSP1 gene are responsible for this
 Splenectomy disorder.
Notes: The incidence or the disorder has  Mutations in the genes associated with
prevalence among person from Greece, Italy Hermansky-Pudlak syndrome prevent the
and mainly characterized by mild formation of LROs or impair the
thrombocytopenia and large platelets, no functioning of these cell structures.
bleeding, no aggregation abnormality and no  HSP1 are responsible for production and
structural defect. control of melanosomes, dense granules,
and lysosomes.

HERMANSKY-PUDLAK SYNDROME Laboratory Results

 Normal PT/PTT
Description  Platelet count normal-except for
 Describe in 1959 by Hermansky and severe bleeding problems
Pudlak  BT variably normal to prolonged
 Disorder which results in oculocutaneous  Diagnosis made by EM is absence of
albinism, bleeding problems due to a dense granules
platelet abnormality and storage of an  Platelet aggregation shows blunted
abnormal fat-protein compound. response in biphasic curves-abnormal
 HPS is a rare disorder that affects males
and females in equal numbers. It is most Indication
prevalent in persons from northwest • Difficult for cuts and wound to heal
Puerto Rico. • Frequent nosebleed, gum bleeding
 HPS does occur in other populations as • Excessive bleeding
well. It is the third most prevalent form of • Excessive bleeding during menstruation
albinism. or labor in women
 Hermansky-Pudlak syndrome (HPS) is a • Difficulty in breathing
hereditary disorder –autosomal recessive
Treatment
There is no cure for HPS, no treatment but
Three Characteristics: there is standard therapy:
1. Decreased pigmentation (albinism) with • Treatment with vitamin E and the
visual impairment antidiuretic DDAVP.
2. Blood platelet dysfunction with prolonged • Transfusions of normal blood platelets.
bleeding due to the lower amount of • Oral contraceptives.
dense bodies seen in storage pool • The drug desmopressin acetate
disease (DDAVP) can also be administered to
3. Some patients have lung fibrosis, colitis, patients with acute bleeding and has
or an abnormal storage of a fatty-like proved effective for some patients with
substance (ceroid lipofuscin) in this symptom.
various tissues of the body. • Individuals with HPS should avoid
 Characterized by a condition called blood anticoagulants, such as aspirin.
OCULOCUTANEOUS ALBINISM, Notes:
which causes an abnormal light  can cause various conditions, can manifest
coloring pigmentation of the skin, hair, other conditions
and eyes. Those affected by the  In particular, it affects mainly dense granules
syndrome, have fair skin and either wherein there is deficiency or absence in totality
white or light-colored hair.  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 abnormal protein. It can be taken
with production of abnormally large intravenously or in the form of a pill.
amounts of IgM.
3. The basic abnormality in this 2. Plasma exchange
macroglobulinemia is uncontrolled If thickening of the blood causes
proliferation of lymphocyte and plasma problems, plasma exchange can be used
cells. to wash the IgM protein out of your
bloodstream and replace it with healthy
Signs and Symptoms plasma. It is very effective procedure
 weakness which requires only one or two treatments
 fatigue attributable to anemia to lower blood protein levels.
 chronic anemia and bleeding episodes
 increased blood viscosity 3. Biotherapy
 lymphadenopathy & Biotherapy may be used alone or in
hepatosplenomegaly coordination with chemotherapy. Biological
therapy, as it is often known, boosts your
Presence of Malignant Cells with immune system's ability to fight cancer and
Lymphoid and Plasmacytoid Morphology help decrease side effects from certain types
 Specimen: Bone Marrow Aspirate of cancer treatments.

Serum Protein Electrophoresis (SPEP) 4. Radiation Therapy

 presence of M spike It uses high-energy rays to kill cancer
cells. However, this type of treatment is not
Other Lab Results 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
 Platelet dysfunction is observed in cell and triggers cell death.
approximately 1/3 of patients with WM.  Novel agents, for example, bortezomib
This results from coating of platelet shows promise as a targeted therapy
membranes by paraprotein. Paraprotein option for Waldenstrom Macroglobulinemia
may interfere with fibrin polymerization Bortezomib is used to treat multiple
and the function of other coagulation myelomas and mantle cell lymphoma.
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