Thrombocytopathies Overview

Thrombocytopathies

• Platelets adhere to subendothelial matrix, activate, release granules, and aggregate.
• Disorders occur in adhesion, activation, secretion, and aggregation.
• Bleeding diathesis, prolonged bleeding time, and normal platelet count are common symptoms
• Light transmission aggregometry is used to monitor platelet activation and identify defects.
• Accurate diagnosis can be difficult due to overlap with healthy responses. 40% of patients may misdiagnosed by light transmission aggregometry

Disorders of Platelet Adhesion

• Platelet receptors interact with subendothelial elements (collagen, fibronectin).
• Key receptors include GPIB-IX and a2-B1 (GPIa-IIa).
• Other receptors for collagen include GPIV and GPVI.
• Bernard-Soulier Syndrome (BSS) is an inherited disorder.
• Characterized by giant platelets, mild/moderate thrombocytopenia, and prolonged bleeding time.
• Caused by abnormalities in the GP Ib-IX-V receptor complex.
• Bleeding may be severe and fatal. Cutaneous, muscular, and visceral bleedings. Epistaxis and menorrhagia.
• Platelet counts range from low to near normal.
• Over 80% of platelets are larger than 2.5 µm (often up to 8.0µm).
• Normal number of bone marrow megakaryocytes.
• Absent platelet agglutination to ristocetin(with VWF), normal aggregation, ATP secretion, and thromboxane B₂ formation to aggregating agents.
• Delayed response to thrombin.
• Defective binding with VWF reduces platelet adhesion to vascular injuries.
• Reduced ability to form hemostatic plugs.
• Variable GP Ib-IX-V complex levels seen, some patients with near-normal amounts (variant type of BSS), indistinguishable from classical BSS.
• Clinical and functional abnormalities, though different glycoprotein content.

Disorders of Platelet Signalling Transduction

• Activated platelets release intracellular messengers.
• Modulate platelet responses (calcium mobilization, protein phosphorylation)
• Several signalling mechanisms involved.
• Platelet signalling disorders are heterogeneous abnormalities in secretion and signal transduction.
• Congenital defects in platelet signalling are a major group of inherited thrombocytopathies.
• Many platelet receptors are coupled to G-proteins.
• P2Y1 and Thromboxane A2 receptors and Thrombin act via Gaq.
• Prostaglandin receptors are activated.
• P2Y12 inhibits adenylate cyclase through Gs and Gi2.
• Hydrolysis of phosphoinositide leads to inositol triphosphate (calcium release), diacylglycerol (protein kinase C activation)
• Defects in phospholipase C activation, calcium mobilization, and protein phosphorylation are seen in some patients
• Deficiency in platelet Gaq, Gs hyperfunction, and reduced expression of phospholipase C-β2 have been reported.
• Platelet phospholipase A2 mobilizes arachidonic acid.
• Arachidonic acid forms thromboxane A2 (powerful platelet aggregating agent).
• Defect in arachidonic acid (mobilization and thromboxane A2 production ) can cause abnormal aggregation and secretion.
• Normal thromboxane A2 response to arachidonic acid, but with abnormal aggregation and secretion to other stimuli.
• Deficiency in cyclooxygenase may result in slightly prolonged bleeding time and impaired platelet aggregation.

Disorders of Platelet Aggregation

• Platelet aggregation is the interaction of activated platelets.
• Factors inducing platelet aggregation are classified as primary and secondary.
• Primary agents (ADP, epinephrine, thrombin) directly induce aggregation independently of intraplatelet ADP release or prostaglandin production.
• Secondary agents induce aggregation through ADP release and/or prostaglandin synthesis.
• Disordered platelet aggregation can result from defects in primary, Glanzmann's thrombasthenia, selective ADP/epinephrine receptor impairments, secondary aggregation (storage pool disease, selective thromboxane/collagen receptor impairment).

Glanzmann's Thrombasthenia (GT)

• Bleeding diathesis with prolonged bleeding time, normal platelet count.
• Absent platelet aggregation to ADP, collagen, arachidonic acid, and thrombin.
• Normal ristocetin-induced agglutination and VWF.
• Impaired clot retraction.
• One of the less common congenital bleeding disorders (prevalence ~1/1,000,000).
• Inherited as an autosomal recessive trait.
• Clinical features include spontaneous bruising, mucosal membrane bleeding, subcutaneous hematomas, petechiae, rarely intra-articular bleeding (hemarthroses).

Platelet ADP Receptor Defects

• Defects in platelet ADP receptors (P2Y1 and P2Y12) can lead to a bleeding diathesis.
• P2Y1 receptor is involved in shape change and transient aggregation.
• P2Y12 stabilizes aggregates through aIIbß3 activation.
• P2Y12 receptor defect is inherited as an autosomal recessive trait.

Specific Platelet Receptor Defects

• Can lead to bleeding.
• Include epinephrine and thromboxane receptors.
• May see easy bruising with specific receptor defects.

Storage Pool Disease (SPD)

• More frequent than primary aggregation disorders.
• Abnormalities in dense and a-granule content.
• 8-SPD (low dense granules only), αδ-SPD (both dense & α-granules deficient), α-SPD (α-granules deficient).
• Associated with other rare syndromes (Wiskott-Aldrich, thrombocytopenia with absent radii).
• Clinical features: easy bruising, mucocutaneous hemorrhages, haematuria, epistaxis.
• Often absent or reduced ADP and epinephrine-induced secondary aggregation.
• Usually inherited as autosomal dominant. Recessive inheritance can accompany other abnormalities.
• Often associated with Hermansky-Pudlak and Chédiak-Higashi syndromes.

Hermansky-Pudlak Syndrome (HPS)

• Rare, autosomal recessive disorder.
• Oculocutaneous albinism, absence of platelet dense granules, infiltration of ceroid-pigmented reticuloendothelial cells in lung/colon.
• Abnormal formation of intracellular vesicles.

Chediak-Higashi Syndrome (CHS)

• Extremely rare, autosomal recessive disorder.
• Variable oculocutaneous albinism, poor resistance to infections.
• Often fatal during infancy or early childhood.

Quebec Platelet Disorder

• Rare, autosomal dominant disease with abnormal a-granule protein proteolysis.
• Increased urokinase plasminogen activator (prolonged bleeding
• Intraplatelet plasmin degrades stored a-granule proteins
• Enhanced risk of bleeding symptoms

Treatment

• General measures for avoiding bleeding, supportive treatments for controlling haemorrhage, individualised therapeutic approaches
• Educate patients to avoid trauma
• Regular dental care
• Avoid drugs that impair platelet functions (e.g., aspirin).
• Oral contraceptives can prevent menorrhagia; local (firm) measures for mild bleeding.
• Antifibrinolytic agents (tranexamic acid). Recombinant activated factor VII (rFVIIa). Desmopressin.

This quiz examines thrombocytopathies, focusing on disorders of platelet adhesion, activation, secretion, and aggregation. You'll explore key receptors involved, symptoms, and the challenges in diagnostic accuracy. Delve into conditions like Bernard-Soulier Syndrome and understand their implications on bleeding disorders.