[TRANS] LECTURE UNIT 11: PLATELET DISORDERS

QUANTITATIVE PLATELET DISORDERS o Ecchymosis

• Bleeding disorders resulting from platelet abnormalities ▪ Irregular
whether they may be quantitative or qualitative, may ▪ 1 cm
usually manifest as bleeding into the skin or mucous
membranes or both (mucocutaneous bleeding). • Small vessel bleeding can
• Common presenting symptoms include: be seen in skin, mucous
membranes of nose and
o Petechiae mouth, GI, urinary and resp.
o Purpura tracts (common sites)
o Ecchymoses • Hemorrhage in CNS most serious site
o Epistaxis • severity of bleeding is related to the degree of
o Gingival bleeding thrombocytopenia
▪ These similar findings are also seen in vascular o > 50,000/uL - unusual for clinical significant
disorders (e.g., Ehlers-Danlos syndrome) which bleeding to occur
are relatively rare o < 60 x 109/L: significant bleeding
• Deep tissue bleeding, such as hematoma and o severity of bleeding = degree of thrombocytopenia
hemarthrosis, is associated with clotting factor o < 20 x 109/L spontaneous bleeding into skin and
deficiencies mucous membrane
o < 10 000 uL platelet counts – high risk of developing
• Quantitative Platelet Disorders
spontaneous bleeding (Rodak’s)
o Thrombocytopenia
o Thrombocytosis • Laboratory Findings
o Prolonged Bleeding Time
Thrombocytopenia
o Abnormal Clot retraction
• Platelet count of fewer than 100,000/μL Etiologies
• Most common cause of clinically important bleeding
o True thrombocytopenia has to be differentiated from • Generalized BM suppression
the thrombocytopenia artifact that can result from:
o Aplastic Anemia
▪ poor specimen collection o Acquired: toxic chemical or physical agents (e.g.,
▪ poorly prepared blood films ionizing radiation or chemotherapeutic agents)
▪ automated cell counts
• Selective suppression of megakaryocyte
▪ platelet clumping or platelet satellitosis
o Associated with an intake of diuretic agents such as
I. Decreased Production chlorothiazide but the mechanism is still unclear
• Abnormalities in platelet production can result from • Myelophthisic process
megakaryocyte hypoplasia in the bone marrow or o it is a space occupying lesion such as tumor, fibrosis
ineffective thrombopoiesis. or leukemia
• Factors causing decreased platelet production can be o the thrombocytopenia in this condition is related to
congenital or acquired. the abnormal cells that are crowding out the normal
• Small-vessel bleeding in the skin attributed to bone marrow elements
thrombocytopenia manifests as hemorrhages of
different sizes. It may include the following: • Ineffective thrombopoiesis that could be associated
with:
o Petechiae
o Ethanol abuse with or without malnutrition
▪ small, pinpoint o Megaloblastic states wherein there is an impairment
hemorrhages of DNA synthesis
▪ 1 mm in o Could be due to severe iron deficiency anemia
diameter
▪ iron is essential in platelet synthesis
o Purpura
o Paroxysmal nocturnal hemoglobinuria
▪ round
▪ 3 mm in diameter ▪ wherein the stem cell is abnormally sensitive to
C3b
o Due to viral infections such as in HIV

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 LECTURE UNIT 11: PLATELET DISORDERS
II. Dilutional Loss
• Extensive blood transfusion
o The degree of thrombocytopenia is also directly
proportional to the number of units that has been
transfused
o There are two mechanisms for thrombocytopenia.
Could be due to:
▪ Dilution of own platelet pull
▪ Acute blood loss
III. Non-Immune Destruction
• Artificial surfaces can induce platelet adherence and
platelet microaggregates in cases of:
o Cardiovascular prosthetic devices
o Prosthetic vascular grafts
o Dialysis membranes
o Can also induce platelet adherence and platelet
microaggregates
• Activation of the coagulation System
o In diffuse intravascular coagulation there is an
activation of coagulation system that will lead to:
▪ intravascular thrombin generation platelet
aggregation
 thrombin mediated reaction will trap platelets
in the fibrin networks and will eventually
destroy them.
▪ consumption of Factors I, V, VIII and XIII.
• Hemolytic Uremic Syndrome (HUS) and Thrombotic
Thrombocytopenic Purpura (TTP)
• Pathophysiology for thrombus formation:
o Intravascular aggregation (e.g., Endothelial
prostacyclin deficiency)
o Endothelial Injury (e.g., Endotoxins)
IV. Immune Platelet Destruction
• Associated with IgG or complement on platelet surfaces
o Previously called as “Idiopathic thrombocytopenic
purpura” because it describes the cases of
thrombocytopenia arising without apparent reasons.
o Since acute and chronic ITP are immunologically
mediated, the word idiopathic has been replaced
with immune.
• Causes:
o Isoimmune (alloantibodies)
o Autoimmune (autoantibodies)
o Drugs
Isoimmune
• Post-transfusion (Isoimmune) Purpura
o Rare complication of post transfusion characterized
by a sudden profound self-limiting thrombocytopenia
• Neonatal Isoimmune Thrombocytopenia
o Caused by transplacental passage of maternal IgG
directed against fetal platelet antigens
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o Analogous to Rh Hemolytic Disease
• Patients’ refractory to Platelet transfusion
o Alloimmunization
o Characterized by failure to achieve adequate
increments in the circulating platelet count after
several transfusions
o Alloantibodies are directed against the HLA antigens
o Patients resists the treatment
▪ Can be observed in patients who have received
long-term platelet support
Autoimmune
• Primary Autoimmune Thrombocytopenia
o E.g., Immune Thrombocytopenic Purpura (ITP)
• Acute Immune Thrombocytopenic Purpura (ITP)
o Primarily a disorder of children
▪ there is a similar condition seen occasionally in
adults
o Characterized by an abrupt onset of bruising,
petechiae and mucosal bleeding (sometimes) in a
previously healthy child
o Primary Hematologic Feature: Thrombocytopenia
▪ Often occurs one to three weeks after an
infection
o Acquired and self-limiting
o Preceded by various infections or vaccinations in
more than half of pediatric patients in the 4 weeks
before the diagnosis
▪ Measles Mumps Rubella (MMR) vaccine
▪ Diphtheria Tetanus and Pertussis (DTP)
▪ Other vaccines: Polio, Hepatitis A and B
o Observation: Often follows a viral illness or
vaccination suggests that some children will produce
antibodies and immune-complexes against the viral
antigens
▪ Platelet destruction results from the binding of
these antibodies or immune complexes to the
platelet surface
• Immune Thrombocytopenic Purpura
o Enhanced platelet consumption
o Idiopathic
▪ Causes appear to be related to antibodies
against platelets
• Drug-Induced Thrombocytopenic Purpura
o Certain drugs can stimulate production of
immunoglobulin that will bind to platelet membrane
antigen
o Heparin-induced Thrombocytopenia
▪ Patients develop antibodies that appear to bind
by their Fab region to platelet factor 4 (PF-4)
o Certain drugs can stimulate formation of
autoantibodies that will bind to specific platelet
membrane glycoprotein with no requirement for the
presence of free drug
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 LECTURE UNIT 11: PLATELET DISORDERS

▪ Gold salts ▪ In severe cases with clinical bleeding,

▪ Procainamide transfusion with platelets is necessary.
▪ Levodopa
• Other Conditions
o Certain drugs induce antibodies which is analogous
o Fetcher syndrome
to drug-induced hemolytic anemia
o Epstein syndrome
▪ Quinidine o Sebastian syndrome
▪ Quinine o Bernard-Soulier syndrome
▪ Sulfa antibiotics o Velocardiofacial/DiGeorge syndrome
▪ Sulfonamides o Paris-Trousseau Thrombocytopenia
▪ Chloroquine o Mutation in transcription factor GATA1
▪ Rifampicin
Small platelets
V. Secondary Autoimmune Thrombocytopenia
• Wiskott-Aldrich Syndrome
• 5-10% of px with chronic lymphocytic leukemia (CLL)
o X-linked thrombocytopenia
and 14-26% of px with SLE
o Due to mutations in WASp gene
VI. Drug-Induced Immune Thrombocytopenia o Characterized by:
▪ Abnormal immune system function
• Can be divided to several types based on mechanisms ▪ Immune deficiency
underlying the interaction of antibodies with the drug ▪ Eczema
and platelets ▪ Inflammatory skin disorders
• Like quinidine
 Patches of red irritated skin
VII. Splenic Sequestration ▪ Reduced ability to form blood clots
• In splenomegaly, either there is o Primarily affects MALE
o increased phagocytosis and destruction of damaged Normal size platelets
platelets
o Increased sequestration of normal undamaged • Familial Platelet Disorder
platelets.
o Predisposition to AML
• Sequestration can be seen in Gaucher disease, o Secondary to mutations in the CBFA/AML1 gene
sarcoidosis, and Felty’s syndrome o Platelets may look paler
o Felty’s syndrome is the adult type of Rheumatoid o Reduce platelet aggregation with collagen
arthritis with splenomegaly. o PLT count may not be always reduced
▪ Uncertain if it has qualitative PLT effect
VIII. Congenital Thrombocytopenia
o Symptoms may vary
Increased platelet size
▪ There are patients with no symptoms of easy
bruising or bleeding
• Arise from mutations in the MYH9 gene encoding the ▪ Some patients have bleeding
nonmuscle myosin heavy chain II
• This is a rare autosomal dominant disorder o Hemoglobin and WBC may be elevated
• May-Hegglin Anomaly Other causes
o Abnormal genetic
condition that is an Dohle body • Congenital Amegakaryocytic Thrombocytopenia
autosomal dominant
disorder whose exact o Autosomal recessive disorder associated with
frequency is unknown. mutations in the thrombopoietin receptor MPL
o It is characterized by • Gray Platelet Syndrome
the presence of Dohle
bodies like inclusions Giant platelets o Rare congenital disorder in which platelets are large
in eosinophils, and have grey appearance on light microscopy due
neutrophils, and to the absence of alpha granules
monocytes. o Lifelong bleeding disorder
o Abnormal giant platelets measuring 20mm in
diameter
o Thrombocytopenia frequently coexists
o Platelet function in response to platelet activating
agents is usually normal.
o In some patients, the number of megakaryocytes is
increased and ultra-structure is abnormal
o Most patients are asymptomatic unless there is a
severe thrombocytopenia

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 LECTURE UNIT 11: PLATELET DISORDERS

IX. Thrombotic Thrombocytopenic Purpura • Clinical picture: resembles thrombocytopenia but

platelet count is within the normal range
• Related to deficient activity of a plasma vWF-cleaving • Clinical manifestations:
metalloproteinase (now known as ADAMTS-13)
o Epistaxis
• Large vWF molecules that are capable of binding to o Menorrhagia
platelets and producing platelet thrombi in the o Easy bruising
microcirculation o Postoperative bleeding
o There is microangiopathic hemolytic anemia
secondary to platelet aggregation in the small blood
vessels
Thrombocytosis

• An increase in number of circulating platelets

• Transient increase: physiologic stress or epinephrine
infusion
• Classification:
o Primary (Autonomous thrombocytosis)
o Secondary (Reactive thrombocytosis)

I. Primary (Autonomous Thrombocytosis)

• Uncontrolled platelet proliferation

o Increased platelet counts and megakaryocyte
numbers and volumes
• Myeloproliferative disorders
o Polycythemia vera Inherited Defects
o Essential thrombocytosis
I. Platelet Vessel Wall Interaction - Disorders of Adhesion
▪ Persistent elevation of platelet 3x the normal
value
• Platelets fail to adhere on exposed subendothelial
o Chronic granulocytic leukemia components such as collagen and basement membrane
o Myelofibrosis
o Chronic Myelogenous leukemia

II. Secondary (Reactive Thrombocytosis)

• Usually transient and benign

o May be a reactive process
o Thrombocytosis is not as pronounced as the primary
• Result from acute or chronic disorders
o Iron deficiency anemia
o Inflammatory diseases
o Malignancy Von Willebrand Disease
o Drugs
o Redistribution of platelets • Deficiency or abnormality in plasma vWF
o Rebound thrombocytosis • Von Willebrand Factor
o Hemolytic anemias
o Acute blood loss o pivotal protein and plays key roles in both primary
o Major surgical procedure, splenectomy hemostasis and secondary hemostasis
o Other pathological conditions o secreted by endothelial cells, specifically the Weibel-
Palade bodies, and alpha granules of platelets
▪ Weibel-Palade bodies – elongated secretory
QUALITATIVE PLATELET DISORDERS
organelles specific to endothelial cells
• excessive bruising and superficial bleeding in patients o It serves as an adhesive platelet ligand that ties the
whose platelet count is normal suggests an acquired or platelet to the exposed collagen at sites of vascular
a congenital disorder of platelet function injury
Thrombocytopathy o Gene is located on chromosome 12
o Partial but nonfunctional duplication – chromosome
• Refers to the platelets with functional defects 22 (vWF pseudogene)
• Inherited or acquired
• Primary or secondary

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 LECTURE UNIT 11: PLATELET DISORDERS
▪ Important consideration in the design of primers
for amplification of vWF gene
• Platelet is functional but incapable of adhering to BV
wall
• Spontaneous bleeding from mucous membranes,
excessive wound bleeding
• Laboratory findings:
o Prolonged bleeding time, normal platelet count
o Decreased Factor VIII – increased PTT
▪ vWF plays a role in secondary hemostasis as it
serves as a carrier protein for Factor VIII
▪ Absence of vWF will rapidly clear Factor VIII
from the plasma
o Normal aggregation: epinephrine, collagen and ADP
o Fails to aggregate at ristocetin
▪ The rate and extend of their aggregation are
measured by the standard platelet aggregometer
and ELISA
• Von Willebrand Disease Classification
o Type 1 - Partial quantitative deficiency of vWF
▪ Most common variant that occurs in about 80%
of the patients
o Type 2 - Qualitative deficiency of vWF
o Type 2A - Decreased platelet-dependent vWF
function w/ selective deficiency of HMW multimers
o Type 2B - Increased affinity for platelet glycoprotein
Ib
o Type 2M - Decreased platelet-dependent vWF
function with HMW multimers present
o Type 2N - Markedly decreased binding of Factor VIII
to vWF
o Type 3 - Complete deficiency of vWF
▪ Absence of the vWF antigen and vWF activity
▪ Very low levels of Factor VIII
Bernard-Soulier Syndrome (Giant Platelet Syndrome)
• Rare autosomal recessive
platelet function resulting from
an abnormality in platelet GP
Ib/IX/V complex
o The glycoprotein Ib/IX/V
complex is missing from
the platelet surface or exhibits abnormal function.
▪ Mediates the binding of vWF to platelets
▪ For platelet adhesion to the subendothelium
• There is an inability to bind to the vWF, which accounts
for the inability of the platelet to adhere to the exposed
subendothelium → bleeding characteristics of this
disorder
• Patients with this type of syndrome usually manifest in
infancy or childhood with hemorrhage characteristic of
defective platelet function such as ecchymosis,
epistaxis, and gingival bleeding.
• There is no specific treatment, but platelet transfusions
are the therapy of choice.
o However, some patients develop alloantibodies so
that further platelet transfusion is no longer possible.
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o Patients tend to do better if platelet apheresis is
used for transfusion because it limits the number of
donors to which the patient is exposed.
▪ Therefore, the rate of alloimmunization is lower
• Treatments:
o desmopressin acetate (DDAVP), a synthetic
analogue of ADH.
o More recently, the recombinant factor VIIa or the
activated factor 7.
• Laboratory Findings
o Bleeding Time (BT) is markedly prolonged.
o Platelet Count (PC) moderately decreased and
increased in size (peripheral smear)
o Normal aggregation: Epinephrine, Thrombin,
Collagen and ADP (ECA)
o Fails at: ristocetin
▪ There is a decreased or absence of aggregation
II. Platelet-Platelet Interaction - Disorders of Aggregation
Congenital Afibrinogenemia
• Deficiency of plasma fibrinogen (Factor I)
• Not a truly platelet function disorder
o Platelet do not exhibit normal function in the
absence of fibrinogen
• Laboratory Findings
o Prolonged PT, aPTT, and Thrombin Time
o Cryoprecipitate or fibrinogen concentrates can be
used to treat bleeding episodes.
▪ Some patients develop antibodies to fibrinogen –
ineffective treatment
Glanzmann’s Thrombasthenia
• Originally described as a bleeding disorder associated
with abnormal in-vitro clot reaction and normal platelet
count
• Autosomal recessive
• Frequently seen in populations with high degree of
consanguinity
• Platelet: Normal size and morphology
• Quantitative and qualitative defect in the GP llb/llla
complex
o Genetic mutations are distributed widely over ITG
A2B and ITGB 3 genes (Chromosome 17)
o Fibrinogen binding to platelets on activation and
aggregation are impared
• Treatment: Transfusion of normal platelet
o The defective platelets may interfere with the normal
transfused platelet and it may be necessary to
infuse more donor platelets (control the bleeding)
o Patients may become alloimmunized.
▪ To reduce alloimmunization:
 single donor platelet apheresis products
 HLA match donor platelets
 ABO match donor platelets
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 LECTURE UNIT 11: PLATELET DISORDERS
• Laboratory Findings
o Prolonged bleeding time
o Impaired clot reaction
o Platelet count is normal in number, with normal size,
morphology, and life span, but without platelet-
platelet clumping
o Absence or marked decrease of platelet aggregation
in the presence of ADP, Collagen, Epinephrine and
Thrombin – diagnostic hallmark
o Normal platelet agglutination in the presence of
ristocetin
III. Platelet Secretion and Abnormalities of Granules -
Storage Pool Deficiency
• Deficiencies in:
o Dense granules (delta-SPD) or Alpha granules
(alpha-SPD) or both (alpha/delta-SPD)
• Clinical Manifestations:
o Mucocutaneous hemorrhage and hematuria,
epistaxis, and easy and spontaneous bruising
o Petechiae are less common than in other qualitative
platelet disorders
• Laboratory Findings
o Prolonged bleeding time
o Platelet count = normal
o Response to ADP and epinephrine – absent or
blunted
o Collagen response – markedly impaired
Delta-Storage Pool Deficiency
• The dense granules are the storage site for serotonin
nucleotides such as ATP and ADP, Calcium and
Pyrophosphate
• In this disorder, there is a diminished platelet
aggregation during the second phase
• Due to the decrease in dense granules materials and
other abnormalities reported in this disorder
o There is a decreased in synthesis (in platelets
activated with collagen and epinephrine, but not
arachidonate)
▪ Prostaglandins
▪ Thromboxane-2
▪ Malondialdehyde
• Dense granule deficiencies can be subdivided into
deficiency states associated with Albinism and those
normal individuals (non-Albinos)
o In the platelets for non-Albinos, there is evidence for
the presence of dense granule membranes in
normal to near normal numbers
▪ Which suggests that this disorder arises from the
inability to package the dense granule contents
• addition of arachidonic acid to platelet-rich plasma, fails
to induce aggregation response
o This is due to the impaired liberation of arachidonic
acid from the membrane phospholipids
• Enhanced ADP but not thrombin-induced rise in
cytoplasmic calcium ion levels
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• Prothrombinase activity (Platelet procoagulant) that is
induced upon activation is reported to be impaired in
association with an inability to maintain elevated
intracellular calcium ion levels
• In association with other inherited disorders
o Hermansky-Pudlak Syndrome (HPS)
▪ aka Oculocutaneous albinism
o Chediak-Higashi Syndrome
o Wiskott-Aldrich Syndrome
o Thrombocytopenia-Absent Radii Syndrome
o Criscelli Syndrome
Hermansky-Pudlak Syndrome (HPS)
• Tyronase-positive
oculocutaneous albinism
• Defective lysosomal function in
a variety of cell types
• Accumulation of ceroid-like
pigments in macrophages
o Lipofuscinosis – ceroid-
like deposition in the cell of
the reticuloendothelial system
▪ A neurodegenerative disorder that results from
excessive accumulation of lipofuscin in the
body’s tissue
• Profound platelet dense granule deficiency
• Due to the mutation of Chromosome 19
• Clinical manifestations
o Bleeding tendency associated with abnormal platelet
function
o Defective lysosomal function
o Bleeding associated with most dense granule
deficiencies is rarely severe
o Causes an abnormally pigmentation of the hair, skin,
and eyes
o A person can have a higher chance or risk of skin
damage and skin cancers caused by long-term sun
exposure
o Vision problems
▪ Reduced vision rapid, involuntary eye
movements, and increased sensitivity to light are
common
▪ Remain stable after early childhood
Chediak-Higashi Syndrome (CHS)
• Rare autosomal recessive disorder characterized by
o Partial oculocutaneous albinism
o frequent pyogenic bacterial infections
o giant lysosomal granules in cells of hematologic and
nonhematologic origin
o platelet dense granule deficiency
o hemorrhage
• Defective cytotoxic T cells and NK cells
• Arises from the mutations in the lysosomal trafficking
regulator or the LYST gene on Chromosome 1
o Protein coded by the gene interacts with protein
including the SNARE complex protein, HRS, and the
signalling proteins
o Participates in the intracellular membrane fusion
reaction and vessel trafficking
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 LECTURE UNIT 11: PLATELET DISORDERS

• Decreased platelet count and a defective platelet o Impaired thrombin-induced calcium ion mobilization
function & increased calcium ions transport reported in some
patients
o Prolonged bleeding time
o Abnormal platelet aggregation studies with any • Heterogenous disorder
aggregating agents used associated with
abnormalities in α-
▪ Abnormal relase of the granule contents with a
granule formation and
decrease ADP and serotonin
maturation
• Defect in parts of Chromosome 1 • Platelets are large with
• During the accelerated phase, thrombocytopenia can discrete gray color
also contribute to a prolonged bleeding time
o Almost the same
o Bleeding episodes vary from mild to moderate but size with RBCs
worsen as platelet count decreases
Quebec Platelet Disorder

• Autosomal dominant disorder

Alpha-Storage Pool Deficiency
Gray Platelet Syndrome
• Platelet α-granules are the storage site for proteins:
o produced by the megakaryocyte
▪ e.g., platelet-derived growth factor,
thrombospondin, and platelet factor 4
o present in the plasma and taken up by plate lets and
transported to α-granules for storage
▪ e.g., albumin, IgG, and fibrinogen
• Inherited in an autosomal recessive fashion
o A mutation in the region of Chromosome 3
involving the gene NBEAL2 that is crucial for the
development of α-granules
• Clinically, it is characterized by:
o Lifelong mild bleeding tendencies
o Prolonged bleeding time
o Moderate thrombocytopenia
o Fibrosis of the bone marrow
o Large gray platelets in wright-stained smear
• Laboratory Findiings
o Variable platelet aggregation responses
▪ ADP and Epinephrine – Normal
▪ Thrombin and collagen – Impaired
• Delayed bleeding and abnormal proteolysis of alpha-
granule proteins
o due to increased amounts of platelet urokinase type
plasminogen activator
• Consequently, stored platelet plasminogen is converted
to plasmin
o Plasmin – play a role in degrading a number of
proteins stored in platelet α-granules
▪ Proteins – Factor V, Von Willebrand factor,
Fibrinogen, Thrombospondin I, and Osteonectin
• There is also a quantitative deficiency in platelet protein
Multimerin I
• Upon platelet activation of Quebec platelet disorder,
urokinase type plasminogen can be released into
forming blood clots and accelerate clot lysis resulting in
a delayed onset of bleeding
• Characterized by:
o Normal to reduced platelet counts
o Proteolytic degradation of soluble and membrane
proteins of alpha granule
o Deficiency of an alpha-granule Factor V binding
protein – multimerin
o Selective defective aggregation with epinephrine
o Platelet Factor-V is degraded along with other
alpha-granule proteins, fibrinogen, vWF,
thrombospondin, osteonectin, fibronectin, and P-
selectin
• Patients suffer from mucocutaneous bleeding which is
often delayed by 12 to 24 hours following injury
o Patients are unresponsive to platelet transfusion but
will respond to fibrinolytic inhibitors.
IV. Defects in Cytoskeletal Regulation
Wiskott-Aldrich Syndrome
• An X-linked inherited
disorder affecting T-
lymphocytes and platelets
• Characterized by
thrombocytopenia,
immunodeficiency, and
eczema

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 LECTURE UNIT 11: PLATELET DISORDERS
• Patients with this syndrome lacks the ability to make
anti-polysaccharide antibodies which results in the
propensity for pneumococcal sepsis
• Platelet abnormalities in Wiskott-Aldrich Syndrome:
o Deficiency in dense granules
o Deficiencies of platelet GP1b, GP IIb/IIIa, and GP Ia
o Platelets are small – feature of diagnostic
improtance
• This syndrome arises from mutation WAS protein of
502 amino acids that binds to several other signaling
proteins
o link between cytoskeleton and signaling pathways
o these proteins are key regulators of the cytoskeletal
assembly
▪ Cdc42 (GTPase)
▪ P47nck (SH3-containing adapter protein)
V. Platelet Coagulant-Protein Interaction - Membrane
Phospholipids Defects
• Platelets play an important role in the blood coagulation
by providing the surface on which several specific key
enzymatic reactions occur
• In resting platelets, asymmetry is seen in the distribution
of some of the phospholipids (e.g., phosphatidylserine &
phosphatidylethanolamine) that are located
predominantly on the inner leaflet
o Phosphatidylcholine has the opposite distribution
• Platelet activation results in the redistribution with
expression of phosphatidylserine on the outer surface
o Mediated by phospholipid scramblase
• The exposure of phosphatidylserine on the outer
surface is an important event in the expression of the
platelet procoagulant activities
Scott Syndrome
• In SCOTT syndrome, platelet contribution to blood
coagulation is impaired but the aggregation and
secretion responses are normal.
• SCOTT Syndrome is a very rare autosomal recessive
disorder
• Laboratory Findings:
o bleeding disorder but they have a normal bleeding
time and platelet aggregation responses
o normal PT and APTT result
o diminished platelet Factor Xa binding sites and
binding of Factors IXa and VIIIa
▪ Associated with decrease surface expression of
phosphatidylserine following platelet activation
Acquired Defects
Myeloproliferative Disorders
• These are chronic myeloproliferative neoplasms which
include:
o Polycythemia vera (PCV)
o Chronic Myelogenous Leukemia (CML)
o Essential thrombocythemia (ET)
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o Chronic Idiopathic Myelofibrosis (Myelofebrosis with
myeloid metaplasia)
• Platelet dysfunction is the common finding in patients
with this disorder
• Increased platelet count but they have a functionally
abnormal platelet
o Platelets are defective in any or all platelet functions
whether it is adhesion, aggregation, release or
contraction
Acute Leukemias and Myelodysplastic Syndromes
• Major cause of bleeding in these conditions is
thrombocytopenia
o However, in patients with normal or elevated platelet
counts, bleeding complications may be associated
with platelet dysfunction
• Acquired platelet defects associated with clinical
bleeding are more common in:
o AML, ALL, Acute myelomonoblastic leukemias,
HCL, myelodysplastic syndromes
▪ Reduced aggregation response to ADP,
epinephrine, and collagen along with a
diminished nucleotide secretion
• Platelets may be morphologically abnormal
o Decreased microtubules
o Reduced number
o Abnormal size of dense granules
o Excessive membranous system
• Megakaryocytes exhibit dysplasia
Dysproteinemias
• Bleeding appears to be related to:
o Platelet dysfunction
o Specific coagulation abnormalities
o Hyperviscosity
o Alterations in blood vessels due to amyloid
deposition
• Qualitative platelet defects also occur in some patients
o Attributed to the coating of platelet by the
paraproteins
Uremia
• Platelet dysfunction and impaired platelet-vessel-wall
interaction
o Major cause of hemostatic defects in uremia
Acquired Storage Pool Disease
• Dense-granule Storage Pool Disease
o Reflects the in vivo release of platelet dense granule
contents due to activation or production of abnormal
platelets by the bone marrow
• Observed in patients with:
o Antiplatelet antibodies
o Systemic Lupus Erythematosus (SLE)
o Chronic Idiopathic Thrombocytopenic Purpura (ITP)
8
 LECTURE UNIT 11: PLATELET DISORDERS

o Hemolytic Uremic Syndrome (HUS) and

Disseminated Intravascular Coagulation (DIC)
o Renal transplant rejection
o Multiple cavernous hemagioma
o Myeloproliferative Disorder (MPD)
o Acute and chronic leukemias
o Severe valvular disease
o Patients undergoing Cardiopulmonary bypass
o Platelet concentrates stored for transfusion
Drugs that Inhibit Platelet Function

• Numerous drugs may affect platelet function and cause:

o Platelet dysfunction
o impaired platelet-vessel-wall interaction
o interefere with platelet factor receptor
o inhibit Prostaglandin pathways
• Nitrofurantoin - interfere with platelet factor receptor
• Theophylline - interfere with platelet
phosphodiesterase activity
• Aspirin - inhibit cyclooxygenase synthesis in platelets
• Penicillin-type antibiotics (Carbenicillin)
• Alcohol (Ethanol)
o Impair the platelet factor III release and reduces
secondary aggregation
o Impair prostaglandin synthesis
o Inhibit thromboxane A2 release
• Nonsteroidal anti-inflammatory agents
(Indomethacin, Ibuprofen, Butazolidin, and Dextran)
o Used as plasma expanders
• Foods – can also inhibit platelet function
o Fish that is rich in omega-3 fatty acids
▪ Result in the replacement of the arachidonic acid
and production of inactive prostaglandin
o Onion
o Garlic
o Ginger
o Cumin
o Turmeric
o Cloves
o Black fungus
o Gingko biloba – inhibit platelet aggregation
• Excessive intake of Vitamin E
o Can cause defects in the prostaglandin synthesis

TOLO. ERESE. DE LEON. LIM. FLORES. IGARI. ANIBAN. PIENCENAVES. CENA. BOLDIOS. SARMEINTO. MACAVINTA. BSMLS 3 9
ADVINCULA. POSIA. GALAGALA. SUBANG. TING. MONTEROSO. DACALOS