Summary This document provides a comprehensive overview of platelet disorders, covering their production, structure, and function, as well as the mechanisms, di
Summary This document provides a comprehensive overview of platelet disorders, covering their production, structure, and function, as well as the mechanisms, diagnosis, and treatment of thrombocytopenia and thrombocytosis. It delves into specific conditions like ITP, TTP, and HUS, distinguishing their key features and management strategies. Qualitative platelet disorders, both inherited and acquired, are also detailed, alongside essential laboratory diagnostics and high-yield facts. Key Points - Platelets are produced in the bone marrow by megakaryocyte fragmentation, with thrombopoietin (TPO) as the major regulator, and they perform adhesion, aggregation, and release functions crucial for hemostasis. - Thrombocytopenia can arise from decreased production, altered distribution (e.g., splenomegaly), or increased destruction, which includes immune-mediated conditions like ITP and consumption disorders such as TTP and HUS. - Thrombotic Thrombocytopenic Purpura (TTP) is characterized by a deficiency of ADAMTS13, leading to the accumulation of ultra-large VWF multimers, causing microangiopathic hemolytic anemia, severe thrombocytopenia, and neurological/renal dysfunction. - Hemolytic Uremic Syndrome (HUS) shares features with TTP but typically affects children, is often triggered by E. coli O157:H7 toxin, and is dominated by severe renal failure with normal ADAMTS13 levels. - Qualitative platelet disorders, exemplified by von Willebrand Disease (vWD), Bernard-Soulier syndrome, and Glanzmann's thrombasthenia, involve normal platelet counts but impaired function due to defects in adhesion, aggregation, or granule release. - Laboratory diagnosis of platelet disorders relies on blood counts, film review for morphology, bleeding time, platelet aggregation studies, and specific assays for VWF, ADAMTS13, or platelet glycoproteins. - Platelet transfusions are generally contraindicated in TTP and HUS as they can exacerbate the thrombotic process, but they are crucial for life-threatening bleeding or for prophylactic measures in other thrombocytopenic conditions. Detailed Notes SECTION 1: PLATELET BASICS Production - Produced in bone marrow by fragmentation of megakaryocyte cytoplasm - Megakaryocyte matures by endomitotic synchronous replication — DNA replicates without nuclear or cytoplasmic division → nucleus enlarges in multiples of two - Early invaginations of plasma membrane form the demarcation membrane → evolves into highly branched network - Each megakaryocyte gives rise to 1,000–5,000 platelets - Platelets released through endothelium of vascular niches of marrow - Stem cell → platelet production: averages 10 days Thrombopoietin (TPO) - Major regulator of platelet formation - 95% produced by the liver - 50% constitutive — plasma level depends on removal by binding to c-MPL receptors on platelets and megakaryocytes - 50% regulated in response to platelet destruction: - Aging platelets lose surface sialic acid → exposes galactose → binds Ashwell-Morell receptor in liver → signals new TPO production - TPO ↑ → ↑ number and maturation rate of megakaryocytes via c-MPL - TPO high in thrombocytopenia from marrow aplasia (no platelets to mop it up) - TPO low in raised platelet counts - Platelet levels start rising 6 days after TPO therapy starts - TPO itself not clinically available → thrombomimetic agents (bind c-MPL) used instead Platelet Structure - Small discoid cells: 3.0 × 0.5 μm Key surface glycoproteins: Glycoprotein Function Defect in --- --- --- GPIa Adhesion to collagen — GPIb Binds VWF → adhesion to subendothelium Bernard-Soulier syndrome GPIIb/IIIa (αIIb/β3) Binds VWF + fibrinogen → aggregation Glanzmann's thrombasthenia Internal structures: Granule Contents --- --- α granules (more common) Clotting factors, VWF, PDGF, fibrinogen Dense granules (less common) ADP, ATP, serotonin, calcium Lysosomes Hydrolytic enzymes - Open canalicular system — plasma membrane invaginates into platelet interior → large reactive surface for coagulation proteins - Membrane phospholipids (Platelet Factor 3) — crucial for: - Tenase complex : IXa + VIIIa + X → Xa - Prothrombinase complex : Xa + Va + prothrombin → thrombin - PDGF (from α granules) → stimulates vascular SMC proliferation → hastens vascular healing Platelet Function Three major functions: Adhesion → Aggregation → Release + Amplification 1. Adhesion: - Platelet adheres to exposed subendothelium via VWF bridge (GPIb receptor) and collagen (GPIa) - VWF = large glycoprotein; multimers of 2–50 dimeric subunits - VWF synthesised by endothelial cells (stored in Weibel-Palade bodies) and megakaryocytes (stored in α granules) - Ultra-large VWF multimers cleaved by ADAMTS13 metalloprotease → smaller multimers 2. Aggregation: - Cross-linking of platelets via active GPIIb/IIIa with fibrinogen bridges - Resting GPIIb/IIIa does NOT bind fibrinogen → activation needed first 3. Release reaction + Amplification: - Activation → release of α and dense granule contents - ADP (from dense granules) → major positive feedback → recruits more platelets - TXA2 (thromboxane A2): - Formed de novo via cytosolic PLA2 activation - ↓ platelet cAMP → initiates release reaction - Potentiates aggregation + causes vasoconstriction - Prostacyclin (PGI2) — from endothelial cells → ↑ cAMP → inhibits aggregation + vasodilation - Nitric oxide (NO) — from endothelial cells, macrophages, platelets → inhibits platelet activation + vasodilation - CD39 (ectonucleotidase/ADPase) — degrades ADP → prevents aggregation on intact endothelium Normal Values Parameter Value --- --- Normal platelet count 150–400 × 10⁹/L Normal platelet lifespan 10 days Platelet size 3.0 × 0.5 μm Splenic sequestration (normal) Up to one third Splenic sequestration (massive splenomegaly) Up to 90% SECTION 2: THROMBOCYTOPENIA Definition: Platelet count 20 × 10⁹/L without symptoms → no treatment needed Acute ITP - Most common in children aged 2–6 years - 75% follow vaccination or infection (chickenpox, infectious mononucleosis) - Mechanism: non-specific immune complex attachment to platelets - Platelet count may drop to 6 months) - Treatment: steroids + IVIg if significant bleeding; platelet count 30 × 10⁹/L → no treatment needed Consumption — TTP Pathogenesis: - Deficiency of ADAMTS13 metalloprotease (cleaves ultra-large VWF multimers at Tyr842-Met843 bond) - Familial TTP — 50 ADAMTS13 mutations reported - Acquired TTP — inhibitory IgG autoantibody against ADAMTS13 (triggered by infection, SLE, drugs, stem cell transplant, cardiac surgery) - Ultra-large VWF multimers accumulate → anchored to endothelial cells → platelets adhere via GPIb → massive platelet aggregation → occlusive platelet thrombi in microvessels → organ ischaemia Clinical features — Classic Pentad: 1. Thrombocytopenia — platelets 80% survive Platelet transfusions CONTRAINDICATED in TTP and HUS — worsen thrombosis Consumption — HUS - Predominantly affects children aged 6 months–4 years - Mimics TTP but renal damage predominates - Caused by E. coli O157:H7 (verotoxin) or Shigella toxin → endothelial cell death in renal microvasculature → platelet thrombi - ADAMTS13 levels NORMAL — key distinction from TTP Clinical features: - Initially: bloody diarrhoea + vomiting - Then: haemolytic anaemia + thrombocytopenia + renal failure - Fever · abdominal pain · schistocytes on film (MAHA) - Neurological complications possible Treatment: - Supportive — renal dialysis if acute renal failure - Control hypertension - Atypical HUS → eculizumab (complement inhibitor) - Usually self-limiting in children; most make full recovery; some have residual kidney problems DIC (brief) - Thrombocytopenia from high rate of platelet consumption in widespread microvascular clotting - Unlike TTP: PT and APTT are prolonged ; D-dimer elevated; fibrinogen low SECTION 3: THROMBOCYTOSIS Definition: Platelet count 450 × 10⁹/L Type Cause Platelet Function --- --- --- Primary (Essential Thrombocythaemia) Myeloproliferative disorder Impaired — high numbers, po