Hematology 2 Lecture Notes

Qualitative Platelet Disorders

- Platelets are functionally abnormal,
thrombocytopathy.
Can be classified into:
1. Inherited
2. Acquired
1. Inherited Qualitative Platelet Disorders
Platelet defects associated:
1.1. Adhesion Defect
1.2. Aggregation Defect
1.3. Release/Secretory Defect
1.1. Adhesion Defect
- Refers to the abnormality of the platelets in
sticking on to any surface, except for the surface of
other platelets.
- This abnormality could be due to the lacking and
or altered platelet-membrane glycoproteins or the
vWF, which are both required in adhesion
specifically in smaller vessels.
- GP Ib-IX and vWF are required in adhesion in
smaller vessels.
- GP Ib-V-IX Complex are the platelet receptors to
vWF.
Conditions associated:
1.1.1. Bernard-Soulier Syndrome
1.1.2. Platelet-Type (Pseudo) Von Willebrands
Disease
1.1.1. Bernard-Soulier Syndrome
- An inherited autosomal recessive disorder usually
involved in consanguinity.
- The severity of the hemorrhagic problem usually
are first observed in infancy or early childhood and
tend to decrease with age.
- The severity of bleeding is usually greater than
would be expected from the degree of
thrombocytopenia.
- The defect is identified as a point mutation in
codon 129 of the GP-Ib gene.
- Adhesion receptor GP Ib-V-IX is lacking on the
platelet membrane which is necessary for the
binding of platelets to vWF.
- Mild to moderate thrombocytopenia is a frequent
but inconsistent finding.
- Some heterozygotes demonstrate
thrombocytopenia and large platelets but have no
symptoms.
- Platelet anisocytosis on a blood film is marked.
- Majority of the platelets are large (2.5-8m in
diameter) with some of them being as big as
lymphocytes.
- The MPV of the giant platelets is about 12.5fL
compared to 6 9fL normal platelets.

- Other than size, the appearance of the large

platelets is generally normal, although occasionally
there is a central clustering of granules referred to
as pseudonucleus.
- The granular contents and the amount of the vWF
in these platelets are higher than in normal
platelets.
- Platelet life span is shortened from the normal 10
days to 4.1 days.
- Bleeding time in excess of 20 minutes is common.
- Clot retraction and platelet factor 3 (PF3)
availability is normal.
- Platelet retention by glass bean columns is
decreased.
- Ristocetin platelet agglutination studies are
normal, and the addition of normal plasma, which
contains vWF, does not correct the abnormal
response.
- Both plasma and platelet factor VIII antigen levels
are normal to increased.
- Platelet aggregation studies using ADP,
epinephrine, and arachidonic acid produce normal
results, but the results of aggregation studies with
collagen and thrombin are variable.
1.1.2. Platelet-Type (Pseudo) Von Willebrands
Disease
- Is a form of thrombocytopathy that resembles
type Iib vWD.
- An autosomal-dominant bleeding disorder due to
the single point mutation that results in a single
amino acid substitution at either residue 233 or
239 of GP Ib.
- Characterized abnormally enhanced binding of
the vWF to the GP Ib-V-IX platelet membrane
receptor.
- Patients present mild bleeding typical of
thrombocytopenia.
- In severe cases in which factor VIII coagulation
levels are decreased, deep wound bleeding and
hemarthrosis can develop.
- Bleeding time is prolonged.
- Decreased in vWF and factor VIII coagulant
activity is quite variable, resulting in variable PTT
results.
- Ristocetin platelet aggregation studies using
patients own platelets show a hypersensitivity to
aggregation typical of type IIb vWD.
- Ristocetin aggregation is decreased when the
patients plasma plus normal platelets are used.
1.2. Aggregation Defect
- Refers to the abnormality of the platelets to stick
on to one another.
- Deficiency could be in platelet bound membrane
glycoproteins such as GP IIb and GP IIIa and or

Primary Hemostatic Disorders Platelet Qualitative Disorders

Hematology 2 Lecture Notes

fibrinogen, which are necessary in normal
aggregation.
1.2.1.Glanzmanns Thrombasthenia
- An autosomal recessive disorder, associated with
consanguinity which affects the two sexes equally.
- Only homozygotes have clinically recognizable
hemorrhagic disorder.
- Appears to occur most frequently among Iraqi,
Jews, Jordanian, Arabs, Indians, and French
gypsies.
- A number of point mutations have been
demonstrated to cause this disorder.
- A defect in GP IIb-IIIa complex
Can be divided into type I and type II.
- Type I is more severe due to lacking platelet
GP IIb-IIIa complex as well as intraplatelet
fibrinogen.
- Clot retraction is absent.
- Type II has the GP IIb-IIIa complex but only
15% of normal and also subnormal levels of
fibrinogen is observed.
- Hemorrhagic symptoms of epistaxis, bruising,
bleeding from mucous membranes,
gastrointestinal bleeding, menorrhagia are typical
of platelet dysfunction.
- Ecchymosis are seen at birth or early life, but the
severity of the hemorrhagic complications tends to
decrease with age.
- In some individuals, bleeding is severe in enough
to necessitate blood transfusions.
- Platelets are normal in number, size, and
morphology and have a normal life span.
- They do not support clot retraction adequately,
and PF3 availability is deficient.
- The bleeding time is markedly prolonged.
- When placed on a wettable surface such as glass
slide, the platelet fails to spread from pseudopods;
consequently, they will not form clumps on blood
films from capillary blood as normal platelets do.
- Platelets do not aggregate with ADP, epinephrine,
collagen or thrombin but will agglutinate on the
addition of ristocetin.
- The ability of platelet in granular content
secretion is not impaired.
- Platelet retention in a glass bead column that
requires both adhesion and aggregation is reduced
markedly in most cases.
- Adhesion to vascular subendothelium is usually
normal, an adhesion defect associated with GT is
being demonstrated.
- With few exceptions, the lack of clot retraction in
the presence of normal platelet count is diagnostic
of GT.
- The platelet GP IIb-IIIa content is about 50% of
normal in patients who are heterozygous for GT.

However these persons have normal clot

retraction, aggregation studies and bleeding time.
- Type I GT platelets lack the platelet-specific
alloantigen HPA-1a (P1A1, Zwa).
- Higher possibility of alloantibody formation must
be considered before platelet transfusion due to
the 98% availability of the HPA-1a antigen in most
of the population.
- Hormonal treatment is used in menorrhagia and
iron supplement for the chronic bleeding induced
anemia.
1.3. Release Defect
- Maybe secondary to a lack of or granules.
- Maybe secondary also to deficient quantity of
stored ADP within the granules, in which case, the
condition is classified as a storage pool disease.
- A second type of release defect is characterized
by impaired secretion in normal granule content,
which is sometimes referred to as aspirin-like
defect.
Can be divided into two mechanisms:
1.3.1. Storage Pool Defects
1.3.2. Granule-Release Defects
1.3.1. Storage Pool Defects
- Involves in the defective or decreased granules,
granules, or both.
- granule deficiencies are much more common
and are more likely to be associated with severe
bleeding that are that of granule deficiencies.
- Normal ratio is 800 granules is to 1 granule.
Disease associated:
1.3.1.1. Gray Platelet Syndrome
1.3.1.2. Wiskott-Aldrich Syndrome
1.3.1.3. Hermansky-Pudlack Syndrome
1.3.1.4. Chdiak-Higashi Anomaly
1.3.1.1. Gray Platelet Syndrome
- granules are lacking.
- In Wrights stained smear, the platelets are larger
than normal and gray or blue-gray in color, in
contrast to the lavender-purple granular
appearance of normal platelets.
- Tests for the constituents of granule are
abnormal
- Decrease in PF3 and normal test for granule
contents are observed.
- The Dense tubular system is abnormal in this
syndrome and maybe associated with abnormal
release and variable aggregation findings.
Alpha Granule Constituents:
1. Fibrinogen
2. Platelet Factor 4
3. Beta-thromboglobulin

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Hematology 2 Lecture Notes

Delta Granule Constituents:
1. Storage form of serotonin
2. ADP
3. ATP
Dense Tubular System contains
1. Stored calcium
2. Cyclooxigenase
- A rare syndrome and appears to be autosomaldominant.
- A lifelong history of mild bleeding, easy bruising,
moderate thrombocytopenia, and abnormal
platelet morphology is characteristic.
- Platelet aggregations induced by ADP,
epinephrine, and arachidonic acid are usually
normal.
1.3.1.2. Wiskott-Aldrich Syndrome
- An immunodeficiency disorder characterized by
small platelets and the triad of thrombocytopenia,
recurrent infections, and eczema.
- It is X-linked, and affected boys rarely survive
childhood because of high risk of hemorrhage and
infection.
- Female carriers are normal.
- The genetic defect has been mapped to the
proximal portion of the short arm of the X
chromosome (Xp11)
- The profound thrombocytopenia has been
attributed to both rapid platelet turnover and
ineffective production.
- Platelets are small measuring about 2/3 of the
normal size, with significantly reduced MPV, and
they have abnormal cellular membranes because
of the lack of a surface protein.
- Splenectomy has been effective in increasing the
size and the number of circulating platelets.
- Increased PA Ig levels have been observed to
patient but PA Ig levels have subsided after
splenectomy and returns to normal.
- Bone marrow transplantation may alleviate the
symptoms.
- Infection, hemorrhage, and lymphoreticular
malignancies are common causes of death.
1.3.1.3. Hermansky-Pudlack Syndrome
- Characterized by a triad of tyrosinase-positive
oculocutaneous alibinism, accumulation of ceroidlike pigment in macrophages, and a bleeding
tendency associated with abnormal platelet
function.
- This is an extremely rare autosomal recessive
condition associated with striking lack of the
granules.
- granules are normal in number.

1.3.1.4Chdiak-Higashi anomaly
- Characterized by albinism, recurrent infections,
hemorrhagic tendencies, and giant lysosomes in all
granule-containing cells.
- Thrombocytopenia does no occur, the
prolongation of the bleeding time exceeds what
would be expected based on platelet counts.
- The ratio of ATP to ADP in these platelets is
consistent with granule deficiency.
- The platelet response to ADP, epinephrine,
collagen, arachidonic acid, and the calcium
ionophore A231987, although variable usually is
deficient.
- Typically, it is secondary wave of aggregation that
is normal or absent.
1.3.2. Granule-Release Defect
- Clinical picture is the same with storage pool
defect, except that the stored contents of the
and granules are normal.
Conditions associated:
1.3.2.1. Deficiencies of Platelet Prostaglandin
Enzymes
1.3.2.2. Cyclooxigenase Deficiency
1.3.2.1. Deficiencies of Platelet Prostaglandin
Enzymes
- Includes defects in cyclooxygenase and abnormal
thromboxane A2 activity.
- Abnormal platelet aggregation curve obtained by
the addition of arachidonic acid to platelets
deficient in cyclooxygenase is corrected by the
addition of prostaglandin G2.
1.3.2.2. Cyclooxigenase Deficiency
- Patient may present with mild bleeding disorder
- Treatment usually consists of avoiding antiplatelet drugs and controlling menorrhagia with
hormonal therapy.
- Thrombin will cause platelet release by way of a
mechanism other than prostaglandin.
2. Acquired Qualitative platelet disorders
Agents
2.1 Drugs
2.2 Diet
2.3 Diseases
2.1 Drugs
- Aspirin, penicillins, and alcohol are the most
frequently reported cause of clinical bleeding
problems.
- Aspirin and alcohol have a synergistic effect in
increasing the bleeding time.

Primary Hemostatic Disorders Platelet Qualitative Disorders

Hematology 2 Lecture Notes

- Patients taking aspirin have an abnormal
secondary aggregation, this abnormality lasts until
the life of the platelet.
- Carbenicillin is the most potent among the
penicillin group.
- Other drugs similarly affect platelets are the
NSAIDs like ibuprofen, indomethacin, butazolidine.
- Aspirins Mechanism of action is the inhibition of
cyclooxygenase activity by irreversible acetylation
of the enzymes active site.
- Prolonged exposure to alcohol, in addition to
thrombocytopenia, impairs PF3 release and
reduces secondary aggregation.
- Direct impairment of prostaglandin synthesis by
ethanol is one of the mechanisms.
- Thromboxane A2 has been reported to be
inhibited in alcoholic patients.
- During abstinence all the effects return to normal.
- The reduced platelet count and impaired platelet
function may contribute to increased incidence of
gastrointestinal hemorrhage associated with
excessive alcohol intake.
- Patients given significant amount of intravenous
dextran and plasma expanders exhibit reduced
platelet function.
- Dextran is used as a prophylaxis against deep vein
thrombosis during surgery due to its anti-platelet
activity.
2.2. Diet
- Increased fish diet have significant decreased
platelet function, as demonstrated by aggregation
studies.
- It is believed that the C19 or C21 chain fatty acids
or eicopentoic acids (omega-3 fatty acids) present
in fish oils result in the replacement of arachidonic
acid and production of inactive prostaglandin.
- Onions, garlic, and related plants contain an
extractable substance capable of inhibiting platelet
aggregation.
- Deficiency of vitamin B12 or folate may lead to a
qualitative platelet defect, as well as to
thrombocytopenia.
- Large amounts of vitamin E also affect platelet
lipids through peroxidation, with resulting defects
in prostaglandin synthesis.

2.3.1. Myeloproliferative Disorders

- Malignant myeloproliferative disorders frequently
are associated with large, hypogranular platelets
that can be defective in any or all functions.
- These abnormalities reflect a fundamental defect
in megakaryocyte maturation.
- A decrease in epinephrine-induced aggregation
defect.
- A decrease in the GP Ib-IX receptor.
2.3.2. Uremia
- Increased BUN level associated with qualitative
platelet defects that can be corrected with dialysis.
- Decreased adhesion, aggregation, and defective
release have been associated.
- These defects are believed to be a result of high
concentrations of metabolites of urea such as
guanidosuccinic acid and phenolic acids that inhibit
platelet aggregation.
- Some patient would exhibit factor VIII/vWF
complexes defect
2.3.3. Disseminated Intravascular Coagulation
- Prematurely activated platelets may release
granules, causing acquired platelet storage pool
disease.
- The fibrinogen degradation products that
circulate in DIC are believed to interact with
platelet membranes and inhibit adhesion and
aggregation.
2.3.4. Immunoglobulin Production
- Antibodies binding to platelet accelerate platelet
destruction and inhibits platelet functions.
- The reduced platelet aggregation using collagen,
ADP and epinephrine seen in SLE and immune
thrombocytopenic purpura has been associated
with increased level of immunoglobulin.
- Specific antibodies such as anti-HPA-1a which
binds to GP IIIa, can bind to membrane receptors
and inhibit platelet function.

2.3. Diseases
Conditions involved:
2.3.1. Myeloproliferative Disorders
2.3.2. Uremia
2.3.3. Disseminated Intravascular Coagulation
2.3.4. Immunoglobulin Production

Primary Hemostatic Disorders Platelet Qualitative Disorders