D R . V I J A Y D I H O R A

Glanzmann Thrombasthenia

Normal Physiology-Production and Numberof Platelet

Platelets are normally made in the bone marrow from progenitor cells known as megakaryocytes.

Normal platelet lifespan is 10 d. Every day, 1/10 of platelet pool is replenished.

Normal platelet count is between 150,000 and 450,000/mm3

Platelet Production

Platelet production is regulated by thrombopoietin(TPO).

Thrombopoietin binds to the surface of megakaryocytes and platelets-- only free TPO stimulates platelet production

Therefore, platelet mass negatively regulates free TPO and further platelet production

Platelet Plug Formation

Adhesion - Platelets stick to injured vessel wall.

Aggregation - Platelets stick to each other via fibrinogen bridges.

Secretion - Platelets release granular contents and potentiate clotting

STRUTURE

Mucopolysacch.

coat

Granules

Dense core

granules

Mucopolysacch. Coat: Glycoprotein content which are important for interaction of platelets with each other or aggregating agents.

- Granules : express the adhesion molecule P-selectinand CD63. these are transfereed to the membran after synthesis

- Dense core : contain ADP and ATP, ionazed calcium ,Histamine and Serotonine

PLATELETS ADHESION

Adhesion of platelet to subendothelial collagen.

Dependent on the VW factor (Von Willebrand part of Fact VIII). Also dependent on glyoproteins.

Thromboxane A2: Potentiase aggregation

and vasoconstrictor.

Aggregation: Release ADP+thromboxane

A2 aggregation. This is followed by more secration secondary aggregation.

platelet mass or plug.

Membrane Phospholipid

Arachidonic acid

Cyclo-oxygenase

Thromboxane synthetase Thromboxane A2

Primary Hemostasis: Platelet adhesion

GPIb

EC

Sub Endo

glycoprotein Ib (GPIb) –platelet receptor for VWF

Primary Hemostasis: Platelet aggregation

EC EC

GPIIbIIIa

Fibrinogen

GPIIbIIIa – platelet receptor for fibrinogen

Classification of platelet disorders

Quantitative disordersProduction

– Reduced

Infiltration (e.g. tumor)

Aplasia (e.g. chemicals)

Congenital (e.g. Wisskot aldrich syn)

– Ineffective

Megaloblastic anemia,

myelodysplasia,

Destruction

– Immune

Autoantibody e.g. ITP

Alloantibody

– HIT

– Consumption

DIC

TTP

Mechanical

Hemodilution

Qualitative disorders• Inherited

– Bernard-Soulier

– Glanzmann’s

– Storage pool disease

(ChediakHigashi, WiscottAldrich, Gray

Platelet Syndrome)

• Acquired

– Drugs (e.g. ASA)

– Uremia, Post-bypass

– Primary marrow disorders; MDS,

Dysproteinemias

Glanzmann Thrombasthenia

Is inherited in an autosomal recessive manner.The genes of both of these proteins are on chromosome 17.Different genetic mutations of either GP IIb or IIIa genes result in a heterogeneity of thrombasthenia phenotype.Carrier detection in GT is important to control the disease in family members.Can be acquired as an autoimmune disorder

PATHOGENESIS

Platelet glycoprotein IIb/IIIa (GP IIb/IIIa)complex is deficient or present butdysfunctional.

Defect in the GP IIb/IIIa complex leads todefective platelet aggregation andsubsequent bleeding.

Aggregation of PLTs occurs in response toristocetin, but not to other agonists such as ADP, thrombin, collagen orepinephrine.

Severity

Glanzmann Thrombasthenia has three categories of severity, depending on the importance of the platelet deficiency in Glycoprotein IIb/IIIa.

• Type 1 (Severe): A level less than 5% of normal

• Type II (Less severe): A level between 5% and 20% of normal

• Type III (Least severe): A variant of Thrombasthenia with levels of more than 50% of normal, but with major abnormalities in the way platelets aggregate

Symptoms

purpura

Menorrhagia

Mucosal bleeding

Brain hemorrhages

epistaxis

gingival bleeding

gastrointestinal bleeding

postpartum bleeding

increased bleeding post-operatively

DIAGNOSIS

Normal PLT count and morphology.

Greatly prolonged bleeding time.

Absence of PLT aggregation in response

to ADP,collagen,epinephrine or thrombin

(Platelet aggregation test)

Flow cytometry (CD 41,CD 61).

Studies of GP IIb/IIIa receptors on the PLT

membrane.

Aggregation of thrombocytes (platelets). Platelet rich human blood plasma (left vial) is a turbid liquid. Upon addition of ADP, platelets are activated and start to aggregate, forming white flakes (right vial)

Treatment

- Dental hygiene lessens gingival bleeding- Avoidance of antiplatelet agents such as aspirin and other anti-

inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, and anticoagulants

- Iron or folate supplementation- Antifibrinolytic drugs such as tranexamic acid or ε-aminocaproic

acid- Desmopressin (DDAVP) does not normalize the bleeding time in

Glanzmann's thrombasthenia but anecdotally improves hemostasis- Hormonal contraceptives to control excessive menstrual bleeding- Platelet transfusions (only if bleeding is severe; risk of

platelet alloimmunization)- Recombinant factor VIIa- Hematopoietic stem cell transplantation (HSCT) for severe

recurrent hemorrhages