1.

05 QUALITATIVE &
QUANTITATIVE PLATELET
DISORDERS HEMATOLOGY 2
Professor Kerfelcel Retoriano
A.Y 2022-2023

OUTLINE
• Quantitative Platelet Disorders
A. Decreased or Impaired
Platelet Production
B. Decreased Megakaryocytes in
the Bone Marrow
C. Increased Platelet Destruction
or Platelet Utilization
D. Disorders Related to
Distribution or Dilution
• Qualitative Platelet Disorders
A. Platelet Adhesion Disorders
B. Platelet Aggregation Disorders
C. Platelet Secretion or Releases
Reactions Disorders
D. Defect in Thromboxane A2
Generation
E. Prolonged Aspirin Therapy
• Vascular Disorders
A. Hereditary Purpuras
B. Acquired Purpuras

QUANTITATIVE PLATELET DISORDERS

Disorder Description
• Platelet count <100,000 mcL
• Due to:
o Decreased platelet production
o Inc. platelet destruction/ sequestration (spleen)
o Abnormal platelet distribution
o Dilution of the platelet (multiple transfusion)
• Symptoms: petichiae (<3mm, purpura (1cm), ecchymoses
(>3cm)
Platelet Estimate Report platelet estimate as:
0 – 49,000/uL Marked decrease
50,000 – 99,000/uL Moderate decrease
100,000 – 149,000/uL Slight decrease
Thrombocytopenia
150,000 – 199,000/uL Low normal
200,000 – 400,000/uL Normal
401,000 – 599,000/uL Slight increase
600,000 – 800,000/uL Moderate increase
Above 800,000/uL Marked increase

• Megakaryocyte Hypoplasia
o Congenital Hypoplasia – May-Hegglin anomaly, WAS,
Bernard-Soulier syndrome, fanconi anemia, TAR
o Neonatal Hypoplasia – due to ionizing radiation, drugs
like chloramphenicol, tranquilizers, etc
o Acquired Hypoplasia
• Ineffective Thrombopoiesis – megaloblastic anemias
Reactive Thrombocytosis
Thrombocytosis • Moderate increase in the platelet. Associated with recovery
after splenectomy, major surgery and acute blood loss.
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1.5 QUALITATIVE & QUANTITATIVE PLATELET DISORDERS

• Increases in count is short lasting

• Platelet count: <5000,000/uL
• Ex: splenectomy or underlying disorders
• Splenectomy – 1/3 of platelets released into the circulation

Clinical Manifestations of Platelet Disorders

Easy bruising Petechiae – tiny hemorrhages
Gingival Bleeding Ecchymosis – large hematomas
Epistaxis Rarely, deep tissue bleeding like:
hemarthoses – joint bleeding

Primary or Autonomous Thrombocytosis

• Marked increase in the platelet count, which generally persist.
• Associated with thrombotic and/or hemorrhagic complications.
• There is markedly and persistent elevation in the platelet
count which usually exceeds 1 million/μL.
• A typical finding in Polycythemia Vera, Chronic Myelocytic
Leukemia, MMM, and Essential Thrombocythemia

Decreased or Impaired Platelet Production

Congenital Hypoplasia
• Lack of adequate bone marrow megakaryocytes
• TAR (thrombocytopenia w/ absent radii) – renal, cardiac, and skeletal
malformation
• In the newborn, intrauterine exposure to drugs (thiazides) and viral infection
(rubella)
Fanconi’s Syndrome • Pancytopenia and bone marrow hypoplasia
• Rare autosomal dominant disorder
• Large platelet (20um)
May-Hegglin • Presence of Dohle Bodies in neutrophils
Anomaly • Lab findings: prolonged bleeding time
• ↑ in size but normal platelet morphology
• Mutation: MYH9 gene – codes for no-muscle myosin heavy
chain
• Autosomal dominant disorder
Sebastian Syndrome • Characterized by large platelets, thrombocytopenia and
granulocytic inclusions
Fechtner Syndrome • Same with Sebastian + deafness, cataracts and nephritis
• Large platelets, deafness, ocular problems, glomerular
Epstein Syndrome
nephritis
• Rare autosomal recessive disorder
• Characterized by neonatal thrombocytopenia
• Congenital absence or extreme hypoplasia of radial bones of
TAR Syndrome
the forehead w/ absent, short or malformed ulnae and other
orthopedic abnormalities
 Impaired DNA repair disorder

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1.5 QUALITATIVE & QUANTITATIVE PLATELET DISORDERS

 Exposure to radiation
 Also known as Radiation sensitivity Syndrome
• Autosomal recessive disorder
• Platelet count <20,000/mcL
• With petichiae, bleeding & physical anomalies
Congenital  Reflects bone marrow failure
Amegakaryocytic  Mutation: C-mlp gene – complete loss of thrombopoietin
Thrombocytopenia receptor function (reduces megakaryocyte progenitors & high
thrombopoietin levels)
 Karyotyping – method used to determine or screen mutation
in the short and long arm chromosome.
• Normal platelet function
• Normal number & morphology of megakaryocytes
Autosomal Dominant
• Clinical findings: mild thrombocytopenia, small platelets,
and X-linked
macrothrombocytopenia w/ severe bleedings
thrombocytopenia
 Mutation: WASP (Wiskott-Aldrich Syndrome Protein) or GATA-
1

Neonatal Hypoplasia
• Caused by: toxoplasma, CMV (TORCH), HIV infection and in utero exposure to
drugs (chlorothiazide diuretics, oral hypoglycemic tolbutamide)
▪ Toxoplasma
▪ Rubella
▪ Cytomegalovirus – most infectious agent that lowers platelet; inhibits
megakaryocytes and its precursors
▪ Herpes
▪ Syphilis
• Lab findings: thrombocytopenia, small platelets

Acquired Hypoplasia
• Results of chemicals, drugs, radiations, chemotherapy, or infectious agents
• Use of methotrexate, busulfan, cytosine arabinoside, cyclophosphamide, cisplatin
and zidovudine
o Ingestion of ethanol (months to years)
o Interferon therapy
o Large doses of estrogen or estrogenic drugs /(diethylstilbestrol)
o Antibiotics (chloramphenicol, tranquilizer, anticonvulsant)
 Interferon – inhibits cell differentiation and proliferation in the bone marrow
Decreased Megakaryocytes in the Bone Marrow
• Infiltration of the bone marrow by malignant cells.
o Generally, results in decreased number of megakaryocytes due to marrow
replacement or inhibitors of thrombopoiesis (toxins) produced by abnormal
cells.

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1.5 QUALITATIVE & QUANTITATIVE PLATELET DISORDERS

o Seen in metastatic cancer, myeloma, lymphoma, myelofibrosis, leukemia, and

granulomatous diseases.

Increased Platelet Destruction or Platelet Utilization

Immune • Occurs in the absence of any disease associated with
Thrombocytopenic decreased platelets or toxin exposure
Purpura (ITP) • Acute ITP – due to destruction of immune complexes or foreign
antigens adsorbed by platelets during infection.
• Chronic ITP – due to antibody coated platelets by the spleen
and liver. Platelet associated IgG levels are elevated.
• Recurrent ITP – found in patients who do not experience
permanent remission following corticosteroid therapy or
splenectomy.
• Neonatal ITP – found in newborns of women with ITP. Due to
transplacental passage of antiplatelet antibodies
Drug induced • Caused by heparin, quinidine, diuretics, heavy metals, digitoxin,
immunologic and sulfa-antibiotics to name a few.
thrombocytopenia
Post Transfusion • Occurs 7-10 days after transfusion.
Purpura (PTP) • Results from sensitization of individuals negative for the platelet
Ag
Increased Platelet • Thrombotic Thrombocytopenic Purpura – platelet thrombi in
Consumption capillaries & arterioles throughout the body
• Hemolytic Uremic Syndrome – intravascular clotting is
confined to the kidney.
Non-Immunologic • Found in DIC, some bacterial, rickettsial, viral, or malarial
Thrombocytopenia (increased platelet consumption)
• Increased Platelet Sequestration
o Splenomegaly
o Increased splenic pooling results to essentially normal
platelets but the transit time is prolonged
• Dilution of the Platelet Count
o Occurs in multiply transfused patients
o Stored blood contains nonviable dysfunctional platelets

Disorders Related to Distribution or Dilution

• Abnormal platelet sequestration as in “big spleen syndromes” or splenomegaly
• Massive blood transfusions (dilutional loss of platelets)

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1.5 QUALITATIVE & QUANTITATIVE PLATELET DISORDERS

QUALITATIVE PLATELET DISORDER

• Defect in platelet function
• Platelet count usually normal and rarely decreased
• Platelets are defective in function, but platelet count normal

Clinical Findings Laboratory Findings

• Excessive bruising • Abnormal platelet function tests – platelet
• Superficial bleeding like petechiae adhesiveness test, platelet aggregation
• Ecchymoses test, clot retraction time
• Epistaxis • Abnormally capillary fragility test – usually
• Gingival bleeding normal platelet count, others occasionally
• Rarely deep tissue bleeding like low
hemarthroses • Bleeding time is usually prolonged
• Hematomas

Platelet Adhesion Disorders

Bernard-Soulier Syndrome
• Also known as Giant Platelet Syndrome
• An inherited autosomal recessive disorder in which the GPIb/IX complex is
missing from the platelet surface.
• Platelets on smear range from 5 to 8 μm up to 20 μm. (Giant Platelets)
• Platelet adhesiveness test is abnormal, the aggregation test with Ristocetin is
abnormal but normal with other agents like ADP, collagen, epinephrine
• GPIb – factor IX complex deficiency
• Bigger diameter of platelets (≥ 20μm)
• Rare autosomal recessive coagulopathy (bleeding disorder) that causes a
deficiency of glycoprotein Ib (GPIb), the receptor for von Willebrand factor.
• Prolonged bleeding time, thrombocytopenia, increased megakaryocytes
• Decreased platelet survival
• Bruises, Epistaxis, Gum (gingival bleeding)

Von Willebrand Disease (vWD)

• Is the name given to assemble of systematic bleeding disorders caused by either a
quantitative or structural abnormality of vWF that diminishes platelet adhesion.
The hereditary type is an autosomal dominant trait.
• Type 1 vWD – most common form of von Willebrand disease characterized by
reduced levels of VIII:C, vWR:Ag, vWR:Co
• Type 2 vWD – characterized by reduced level of vWR:Ag
• Type 3 vWD – characterized by reduced vWR:Ag, vWR:RCo, and variable VIII:C

Type vWR-Ag vWR:RCo VIII:C

I ↓ ↓ ↓
II ↓ - -
III ↓ ↓ ↓
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• Acquired von Willebrand Disease – associated with:

o Autoimmune disorder
o Lymphoproliferative disorders
o Myeloproliferative disorders
o Pesticide exposure → Aplastic anemia
▪ Condition where BM does not produce sufficient cells.
o Hemolytic Uremic Syndrome
o Polycythemia Vera
▪ Leads to abnormal increased in the number of blood cells (↑RBCs)

Platelet Aggregation Disorders

Glanzmann’s thrombasthenia
• An inherited autosomal recessive disorder caused by a deficiency
• In platelet membrane GPIIb/IIIa complex
• Menorrhagia
• GPIIb/IIIa deficiency • Easy bruising
• Autosomal recessive (both parents carry the gene) • Apistaxis
• Gingival bleeding
• Clot retraction is absent or decreased • Gastrointestinal bleeding
• Laboratory findings: • Increased bleeding post-operatively
o Markedly prolonged bleeding time
o Abnormal aggregation test with all agents like restocetin, ADP, etc. with
normal platelet count morphology.
• Aggregating agents:
o ADP Platelet Factor 3 (PF3)
• most important for aggregation
o Epinephrine
• thromboplastic platelet factor
o Collagen • necessary for generation of plasma
o Ristocetin thromboplastin

Thrombopathia
• ADP deficiency and abnormal platelet aggregate

Thrombocytopathy
• Platelet Factor 3 deficiency
• Abnormal platelet function particularly intravascular hemolysis.

Disease EAC Ristocetin

Glanzmann’s Thrombasthenia Abn N
von Willebrand Disease N Abn
Bernard-Soulier Syndrome N Abn

Platelet Secretion or Releases Reactions Disorders

Storage Pool • Electron dense granule or delta granules deficiencies

Disease o Hermansky-Pudlak Syndrome (HPS)
o Wiskott-Aldrich Syndrome (WAS)
o Chediak-Higashi Syndrome (CHS)
o Thrombocytopenia-Absent Radii (TAR) Syndrome (with
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1.5 QUALITATIVE & QUANTITATIVE PLATELET DISORDERS

congenital absence of radial bones)

o Griscelli syndrome
• Alpha granules Deficiency
o Gray platelet syndrome
o Quebec platelet disorder-caused by degradation of many of
many alpha granule proteins. Abnormal proteolysis of α-
granule due to platelet urokinase-type plasminogen activator
• Primary granules Deficiency – hemmeler anomaly
Thromboxane • Hereditary absence or abnormalities of the components of the
Pathway Disorders thromboxane pathway-called aspirin like defects.
• Acquired defects due to inhibitors of the prostaglandin pathway
• Aspirin-like defects
o Characterize by normal platelet but defective release
o Deficiency in cyclo-oxygenase or thromboxane synthetase
Transcription Factor Mutation
RUNX1/CBFA2 • Associated with predisposition to acute
myeloid leukemia
• Impaired aggregation, secretion and
granule deficiency
GATA-1 • Major transcription factor regulating both
thrombopoiesis and megakaryopoiesis
Deficiency in • Hemmeler Anomaly
Primary Granules
from Granulocytes

Defect in Thromboxane A2 Generation

• Arachidonic acid converted by cyclooxygenase to become TXA2 (1)
Vasoconstriction (2) stimulate platelet secretion
• Deficiency in enzymes
o Phospholipase
o Thromboxane Synthetase
o Cyclohexogenase

Prolonged Aspirin Therapy

• Aspirin → anti-platelet drug – inhibits cyclooxygenase (increased bleeding time)
• Monitored via Bleeding Time:
o Platelet evaluation/activity and vascular integrity.
o Does not test pro clotting factors

VASCULAR DISORDERS
• The pathophysiology of disorders of the blood vessels and their supporting tissue
remains obscure.
• Laboratory studies of platelets and blood coagulation usually yield normal results.
The diagnosis is often based on medical history and is made by ruling out other
sources of bleeding disorders.

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• The usual clinical sign is the tendency to bruise easily or to bleed spontaneously,
esp. from mucosal surfaces.
• Bleeding time is usually prolonged and positive with capillary fragility test.
• Laboratory findings:
o Bleeding time – increased
o Capillary fragility test – increased
o Clotting time – usually normal values unless proclotting factors are involved

Hereditary Purpuras
• Failure to synthesize elastin and collagen

Hereditary Vascular Disease

Hereditary Hemorrhagic
Telangiectasia
Hemangioma –
Thrombocytopenia Syndrome
Ehlers-Danlos Syndrome
Marfan Syndrome
Osteogenesis imperfecta
Pseudoxanthoma elasticum
• Also known as Rendu-Weber-Osler-Syndrome
• Spider web-like lesions, pox lesions
• Localized dilation of the walls of the small blood
vessels of the skin and mucous membranes.
Also known as Kasabach Merrit Syndrome
Inherited as autosomal dominant disorders characterized
by increased vascular fragility.

Acquired Purpuras

Acquired Vascular Disease

1. Allergic Purpura or Anaphylactoid Purpura – skin rash and edema due to certain
foods, drugs, cold temperature, insect bites, vaccination
2. Henoch-Schonlein Purpura – transient joint pain, nephritis, abdominal pain, purpuric
skin lesions due to immune complexes formation.
3. Senile Purpura – common in elderly due to lack of collagen support for small blood
vessels loss of fat and elastic fibers.
4. Scurvy – deficiency of Vitamin C results to poor intracellular development of tissues.
5. Purpura Simplex – simple vascular purpura observed in women of childbearing age.
6. Infectious Purpura
7. Drug-induced Purpura – associated with Aspirin, Coumadin, Diuretics, Barbiturates, and
Sulfonamides.
8. Purpuras associated with paraproteinemias and amyloidosis
9. Idiopathic Purpuras

• Fragile blood vessels

• Menstruation
Devil’s Pinches
• Purpura simplex
• Deficiency of vitamin C – for intracellular development of tissues.
• Causes defects in the synthesis of collagen and hyaluronic acid – a
Scurvy
component of the intercellular cement substance found between
endothelial cells.
Senile Purpura • Old ecchymotic spots/petechiae
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• Disease of the old people

• Loss of skin elasticity → deficiency of elastin and collagen
Drug-induced • Due to prolonged steroid therapy
Purpura
• Common among children (after viral infection)
• Immunologic damage to endothelium
• Common Laboratory Findings:
o Platelet count, Platelet function tests, Coagulation studies =
Henoch-
NORMAL
Schoenlein
o Bleeding time, Tourniquet test = ABNORMAL
Purpura
• Small-vessel vasculitis in which complexes of immunoglobulin A (IgA)
and complement component 3 (C3) are deposited on arterioles,
capillaries, and venules
• Purpura, Arthritis, Abdominal pain

PRACTICE QUESTIONS
• Which of the following instruments can be used to evaluate platelet function?
o A. platelet aggregometer Platelet aggregometer Verify Now
o B. Verify Now – uses whole blood – measure patient response to multiple
– has the ability to measure dense anti-platelet drugs (aspirin, glycoprotein
o C. PFA-100 granules IIb/IIIa inhibitors
o D. All of the above – uses luminescent markers PFA-100 – used in screening bleeding
citrated whole blood time; citrated whole blood

• Which of the following platelet aggregating agents demonstrates a monophasic aggregation

curve when used in optimal concentration
o A. Thrombin Collagen – most commonly used agent that
o B. Collagen demonstrates a single-wave response
o C. Adenosine diphosphate (ADP) (monophasic preceded by a lag time)
o D. Epinephrine

• Normal platelet adhesion depends upon:

o A. Fibrinogen
o B. Glycoprotein Ib
o C. Glycoprotein IIb, IIIa complex
o D. Calcium

• Which of the following test results is normal in a patient with Classic von Willebrand’s
disease?
vWD – inherited, increase
o A. Bleeding time
BT, prolonged APTT,
o B. Activated partial thromboplastin time decrease factor VII: vWF,
o C. Platelet count platelet aggregation is
o D. Factor VIII:C and von Willbrand’s factor (vWF) levels normal

• Thrombocytopenia may be associated with:

o A. Postsplenectomy
o B. Hypersplenism
o C. acute blood loss
o D. Increased proliferation of pluripotential stem cells

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