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Thrombasthenia
CPC
24th November 2002.
Dr. Tariq Roshan
Department of Hematology.
Case History.
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SNS: a 3-year old Malay girl.
Presented with
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8 months H/O recurrent epistaxis.
Failure to thrive.
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Problem started at the age of 1 year
The condition became worse over the previous 8
months
The frequency of epistaxis has been once in every 3-4
days
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Epistaxis was sometimes associated with gum
bleeding
Patient sought medical attention and was
admitted to hospital Kota Bharu
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In HKB patient noted to be pale and diagnosed
anemic secondary to chronic blood loss
Patient was transfused and was investigated for the
possible causes of bleeding including those of
bleeding disorders
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No diagnosis was made during that admission.
ENT examination in HKB showed no anatomical abnormalities
8 months later the patient was admitted with the
worsening of her problem to HUSM
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Negative points in the history were
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Fever
Easy bruising
Petechiae
Skin rashes
Joint pain
Family history
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Father and brother had history of epistaxis during their
childhood which resolved spontaneously
Physical examination
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GPE
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Height and weight below 3rd centile
Pallor
Cervical lymph nodes were palpable
Generalized hypotonia with mild muscle wasting noted
Systemic examination
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Examination of CNS, CVS and Respiratory system was
normal
Liver was palpable 5 cm below costal margin and spleen
palpable 8 cm below costal margin
Laboratory Investigations
Patient ID
Date
APTT
Cont.
INR
Mixing Test
Cont.
Plat.
BT/CT
Factor VIII
Factor IX
SNS
54.2 Sec.
33.9 Sec.
1.07
39.6 Sec.
32.4 Sec.
Corrected
220 x109/L
Prolonged
93.4%
38%
Special Studies
Both parents Factor IX was normal.
vWF antigen assay
HEMOSTASIS
182%
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Patient’s Haemoglobin
was low and total
white cell count was
normal
FBP showed microcytic
hypochromic anemia
Normal platelet count
and morphology on
light microscopy
Laboratory Investigations
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contd.
Patient’s RFTs were normal with mild
elevation of ALT & ALP
Blood sugar and urine analysis were also
normal
Patient was screened for TORCHES, all results
were negative
Sputum for AFB was negative
Bone marrow aspiration and trephine biopsy
were normal with no evidence of infiltration
of abnormal cells. Adequate megakaryocytes
Conclusions drawn from the
Haemostasis data
Patient ID
Date
APTT
Cont.
INR
Mixing Test
Cont.
Plat.
BT/CT
Factor VIII
Factor IX
SNS
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54.2 Sec.
33.9 Sec.
1.07
39.6 Sec.
32.4 Sec.
Corrected
220 x109/L
Prolonged
93.4%
38%
Special Studies
Both parents Factor IX was normal.
vWF antigen assay
HEMOSTASIS
182%
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The increased bleeding time and
normal platelet count indicate a
primary hemostasis function
problem
Such data may result from platelet
disorders or vascular function
disorders
Haemophilia can be excluded
considering the clinical
presentation
Low factor IX can be due to
systemic disease or liver problem
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However, in view of normal INR,
liver pathology as a possible cause
of low factor IX, was excluded
Low factor IX can also be seen in
glycogen storage diseases as
Gaucher disease and should be
ruled out by investigation
Hemostasis
Primary vs. Secondary vs. Tertiary
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Primary Hemostasis
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Secondary Hemostasis
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Platelet Plug formation
Dependent on normal platelet number & function
Initial manifestation of clot formation
Activation of the clotting cascade
Deposition & Stabilization of fibrin
Tertiary Hemostasis
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Dissolution of the fibrin clot
Dependent on Plasminogen Activation
Qualitative Defects in Primary
Hemostasis
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Adhesion/Adherence Defects
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Glycoprotein (Gp) Ib deficiency
Bernard-Soulier syndrome
von Willebrand disease
Aggregation defects
Afibrinogenemia
Release defect
Acquired defects
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Antibodies to GP IIb-IIIa in NHL and HD
Platelet Function
Adherence
Only
Aggregation &
Release
Direction of Blood Flow
Platelet Adherence
von Willebrand Disease
vWF
Gp Ib
vWF
Gp Ib
vWF
vWF
Bernard-Soulier
Syndrome
Platelet Release Function
ADP Wiskott-Aldrich syndrome
ß-thromboglobulin
Platelet factor 4
Hermansky-Pudlak
syndrome
DenseGranule
Platelet-derived Growth
Factor
Alpha-granule
Gray platelet syndrome
Fibrinogen
Lysosome
ChédiakHigashi anomaly
Factor V
Hydrolase
Platelet Aggregation
vWF
Gp Ib
Dense Granule
Thrombasthenia
IIb
IIIa
Release Defects
ADP IIb IIIa
D
D
ADP
D
IIb IIIa
E Fibrinogen
Afibrinogenemia
Platelet Aggregation
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In-vivo platelet aggregation is induced
by
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Thrombin mechanisms
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Stimulates ADP release
Enhances formation of TxA2
Thromboxane A2, mediated through
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Arachidonic acid release form membrane
phospholipid
 Cyclo-oxygenase
 Endoperoxidase
Laboratory Tests for Primary
Hemostasis Function
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Platelet count
Bleeding time
Platelet Aggregation Studies
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Luminance method
Impedance method
Clot retraction
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Not available
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Expected results: clots should normally be reduced by 50%
of their original mass within 1 hour
Flow cytometric studies for Glycoproteins
Platelet Aggregometry
% Transmittance
Secondary Response
Aggregation Plateau
Shape Change
Reagent Added
Baseline
Note: With impedance
method there is increased resistance
of the sample and ATP release
Time
Results of platelet aggregation
studies
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No aggregation with arachidonic acid
and ADP
Markedly reduced aggregation with
collagen
Normal aggregation with ristocetin
ATP release with thrombin is normal but
absent with arachidonic acid
Platelet Aggregometry
interpretation
Aggregating Agent
Disorder
ADP
Epi
Thr
Ris
Col
Ara
Bernard-Soulier syndrome
Nor
Nor
Var
Abn
Var
Nor
Chédiak-Higashi anomaly
Abn/Var
Abn/Var
Abn/Var
Abn/Var
Glanzmann thrombasthenia
Abn
Abn
Granule release defects
Abn
Abn
von Willebrand's disease
Abn
Nor
Abn
Abn
Abn
Flow cytometry for the
detection of Gp defeciency
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The study of GP IIb IIIa showed
reduction in PAC-1 which is a finding
consistent with Glanzmann
thrombasthenia
However hepatosplenomegaly is not
explainable by the diagnosis
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Patient was readmitted on 18-11-02 for further
investigations to clarify the hepatosplenomegaly
Thrombasthenia
Synonyms: Glanzmann thrombasthenia, constitutional
thrombopathy, hereditary hemorrhagic thrombopathy
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Background:
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Thrombasthenia was first describe in 1918 by Glanzmann
when he noted purpuric bleeding in patients with normal
platelet counts
Typically, thrombasthenia is diagnosed at an early age
Pathophysiology:
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Autosomal recessive trait
The production and assembly of the platelet membrane
glycoprotein IIb-IIIa is altered, preventing the
aggregation of platelets and subsequent clot formation
Review of platelet function
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Platelets adhere to the site of endothelial injury
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Activate
Aggregate
Secrete & promote further platelet recruitment & aggregation
vWF binds to the exposed collagen and binds
GP Ib-IX-V complex on the surface of platelet,
adhering platelets to the site of injury
Fibrinogen and vWF bind to the GP IIb-IIIa
complex on the activated platelet’s surface,
allowing cross-linking and formation of clot
Specific Deficiency
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GP IIb and IIIa have separate genes on the
long arm of chromosome 17
Specific genetic abnormalities of each GP
include
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Missense mutations
Nonsense mutations
Splice site mutations
Deletions and
Point mutations
Abnormalities in either gene or in the
assembly of the complex result in an
abnormal or deficient receptor
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Consequently
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One or other GP is not formed properly, leaving
the other unpaired in the endoplasmic reticulum,
where it is degraded
Platelet aggregation is rendered deficient or
completely absent
Heterozygotes are asymptomatic
Binding sites for thrombin are preserved in
thrombasthenic platelets
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Patients are classified into: type1, type2, or
the variant type, depending on the degree
of GP IIb-IIIa deficiency, fibrinogen
binding, and clot retraction
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Type 1 : most severe form, less than 5% of normal
GP IIb-IIIa present with absent fibrinogen binding
and clot retraction
Type 2 : 10-20% of GP IIb-IIIa, normal to
moderately deficient clot retraction with fibrinogen
binding
Variant type : 50% of the normal amount of GP IIbIIIa with extremely variable fibrinogen binding and
clot retraction
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Frequency:
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Mortality/Morbidity:
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Death following bleeding approx. 5%
Age:
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300 cases are reported in medical literature
1st case diagnosed in HUSM
Typically diagnosed during infancy
Epistaxis is more severe in children but rare in
adults
History
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In the neonatal period: mucocutaneous bleeding
In childhood: purpura, epistaxis & gingival bleeding
The bleeding tendency decreases with age
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Additional presentations include
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GI bleeding
Excessive bleeding at menarche & following
parturition
Post surgical bleeding
Hemarthrosis and deep hematomas are unusual
The absence of family history should not
delay a workup for thrombasthenia as it is a
recessive trait
Beyond identification of hemorrhage, physical
examination is usually of limited use
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Other disorders to be considered in the differential diagnosis:
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Gray platelet syndrome
Hermansky-Pudlak syndrome
Chediak-Higashi syndrome
ITP
DIC
Medication-induced platelet inhibition
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Others
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Prostaglandin synthetase inhibitors (Aspirin, NSAIDS)
ADP receptor inhibitors (Clopidogrel, Ticlopidine)
Receptor blocking drugs (Dipyridamole)
Beta-lactam antibiotics
Heparin
Alcohol
Uremia
hyperglobulinemias
Lab investigations:
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Bleeding time
Aggregation studies
Platelet count and morphology
PT/ APTT
Flow cytometric studies
Medical Care
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Emergency care:
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Refractory bleeding requires transfusion of normal
platelets
HLA-matched platelets is the treatment of choice
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In rare cases, antibodies to Gp IIb-IIIa are detectable
Medical treatment:
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Antifibrinolytic agents inhibit fibrinolysis via inhibition
of plasminogen activator substances
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Aminocaproic acid; may be useful in controlling bleeding
after dental extraction
Contraindicated in the evidence of active intravascular
clotting process (DIC)
Hematuria is relative contraindication
Co-administration with estrogens may cause increase
clotting factors, leading to hypercoagulable state
Medical treatment contd
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Vasopressin analogs, act like ADH to increase
factor VIII levels
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Desmopressin (DDAVP); synthetic vasopressin analog
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Clotting factors
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The use of DDAVP not recommended routinely
Contraindicated in documented hypersensitivity
Coagulation factor VIIa, recombinant
Other therapies cited in literature
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IV Igs
Repeated plasma pheresis
Bone marrow transplant
Conclusion & Take home
message
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Final diagnosis of our patient was Glanzmann
thrombasthenia
Family studies for platelet function defect are
recommended
However, further investigations are required
to clarify the cause of hepatosplenomegaly
and low factor IX
Refractory haemorrhage in the presence of
normal platelet count and normal coagulation
factors need to be investigated further (Now
in HUSM)
Thank you
&
Selamat Hari Raya