Thrombasthenia

CPC 24th November 2002.

Dr. Tariq RoshanDepartment of Hematology.

Case History.

SNS: a 3-year old Malay girl. Presented with

8 months H/O recurrent epistaxis. Failure to thrive.

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

Epistaxis was sometimes associated with gum bleeding

Patient sought medical attention and was admitted to hospital Kota Bharu

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

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

Negative points in the history were Fever Easy bruising Petechiae Skin rashes Joint pain

Family history Father and brother had history of epistaxis during

their childhood which resolved spontaneously

Physical examination

GPE Height and weight below 3rd centile Pallor Cervical lymph nodes were palpable Generalized hypotonia with mild muscle wasting

noted Systemic examination

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’s Haemoglobin was low and total white cell count was normal

FBP showed microcytic hypochromic anemia

Normal platelet count and morphology on light microscopy

Patient ID SNSDate

Special StudiesBoth parents Factor IX was normal.

vWF antigen assay 182%

APTTCont.

INRMixing TestCont.

Plat.BT/CTFactor VIIIFactor IX

HEMOSTASIS

54.2 Sec.33.9 Sec.

1.0739.6 Sec.

32.4 Sec.Corrected

220 x109/LProlonged93.4%38%

Laboratory Investigations 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

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

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

Patient ID SNSDate

Special StudiesBoth parents Factor IX was normal.

vWF antigen assay 182%

APTTCont.

INRMixing TestCont.

Plat.BT/CTFactor VIIIFactor IX

HEMOSTASIS

54.2 Sec.33.9 Sec.

1.0739.6 Sec.

32.4 Sec.Corrected

38%93.4%Prolonged

220 x109/L

HemostasisPrimary vs. Secondary vs.

Tertiary Primary Hemostasis

Platelet Plug formation Dependent on normal platelet number &

function Initial manifestation of clot formation

Secondary Hemostasis Activation of the clotting cascade Deposition & Stabilization of fibrin

Tertiary Hemostasis Dissolution of the fibrin clot Dependent on Plasminogen Activation

Qualitative Defects in Primary Hemostasis Adhesion/Adherence Defects

Glycoprotein (Gp) Ib deficiency Bernard-Soulier syndrome von Willebrand disease

Aggregation defects Afibrinogenemia Release defect Acquired defects

Antibodies to GP IIb-IIIa in NHL and HD

Platelet Function

Adherence Only

Aggregation &Release

Direction of Blood Flow

Platelet Adherence

vWF

vWF

Gp Ib

vWF

Gp Ib

vWF

von Willebrand Disease

Bernard-Soulier Syndrome

Platelet Release Function

DenseGranule

Alpha-granule

Lysosome

ADP

ß-thromboglobulin

Platelet factor 4

Platelet-derived Growth Factor

Fibrinogen

Factor V

Hermansky-Pudlak syndrome

Wiskott-Aldrich syndrome

Gray platelet syndrome

Chédiak-Higashi anomaly

Hydrolase

Platelet Aggregation

IIIaIIbIIIaIIb

IIIaIIb

ADP

ADP

FibrinogenED

DD

Dense Granule

Gp IbvWF

Release Defects

Thrombasthenia

Afibrinogenemia

Platelet Aggregation In-vivo platelet aggregation is

induced by Thrombin mechanisms

Stimulates ADP release Enhances formation of TxA2

Thromboxane A2, mediated through Arachidonic acid release form membrane

phospholipid Cyclo-oxygenase Endoperoxidase

Laboratory Tests for Primary Hemostasis

Function

Platelet count Bleeding time Platelet Aggregation Studies

Luminance method Impedance method

Clot retraction Not available

Expected results: clots should normally be reduced by 50% of their original mass within 1 hour

Flow cytometric studies for Glycoproteins

Platelet Aggregometry%

Tra

nsm

itta

nce

Baseline

Time

Reagent Added

Shape Change

Aggregation Plateau

Time

% T

ran

smit

tan

ce

Secondary Response

Note: With impedancemethod there is increased resistanceof the sample and ATP release

Results of platelet aggregation studies

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

Disorder ADP Epi Thr Ris Col Ara

Bernard-Soulier syndrome Nor Nor Var Var Nor

Chédiak-Higashi anomaly Abn/Var Abn/Var Abn/Var Abn/Var

Glanzmann thrombasthenia Abn Abn Abn Abn

Granule release defects Abn Abn Abn

von Willebrand's disease Abn

Aggregating Agent

Nor

Abn

Flow cytometry for the detection of Gp defeciency

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

Patient was readmitted on 18-11-02 for further investigations to clarify the hepatosplenomegaly

ThrombastheniaSynonyms: Glanzmann thrombasthenia, constitutional thrombopathy, hereditary

hemorrhagic thrombopathy

Background: 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: 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 Platelets adhere to the site of endothelial

injury 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 GP IIb and IIIa have separate genes on

the long arm of chromosome 17 Specific genetic abnormalities of each

GP include 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

Consequently 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

Patients are classified into: type1, type2, or the variant type, depending on the degree of GP IIb-IIIa deficiency, fibrinogen binding, and clot retraction

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 IIb-IIIa with extremely variable fibrinogen binding and clot retraction

Frequency: 300 cases are reported in medical literature 1st case diagnosed in HUSM

Mortality/Morbidity: Death following bleeding approx. 5%

Age: Typically diagnosed during infancy Epistaxis is more severe in children but rare

in adults History

In the neonatal period: mucocutaneous bleeding

In childhood: purpura, epistaxis & gingival bleeding

The bleeding tendency decreases with age

Additional presentations include 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

Other disorders to be considered in the differential diagnosis:

Gray platelet syndrome Hermansky-Pudlak syndrome Chediak-Higashi syndrome ITP DIC Medication-induced platelet inhibition

Prostaglandin synthetase inhibitors (Aspirin, NSAIDS) ADP receptor inhibitors (Clopidogrel, Ticlopidine) Receptor blocking drugs (Dipyridamole) Beta-lactam antibiotics Heparin

Others Alcohol Uremia hyperglobulinemias

Lab investigations: Bleeding time Aggregation studies Platelet count and morphology PT/ APTT Flow cytometric studies

Medical Care Emergency care:

Refractory bleeding requires transfusion of normal platelets

HLA-matched platelets is the treatment of choice

In rare cases, antibodies to Gp IIb-IIIa are detectable

Medical treatment: Antifibrinolytic agents inhibit fibrinolysis via

inhibition of plasminogen activator substances 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

Vasopressin analogs, act like ADH to increase factor VIII levels

Desmopressin (DDAVP); synthetic vasopressin analog

The use of DDAVP not recommended routinely Contraindicated in documented hypersensitivity

Clotting factors Coagulation factor VIIa, recombinant

Other therapies cited in literature IV Igs Repeated plasma pheresis Bone marrow transplant

Conclusion & Take home message 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