L8: Platelets in health and disease Flashcards
Signs of platelet disorders
- Mucocutaneous bleeding
- Purpura
- Petechiae (non-blanching rash)
- Haematoma
Platelets
- More red cells than platelets and less white cells
- Normal range 150-400x10^9/L
- Produced in bone marrow
Megakaryoblast
- First step in platelet development
- Large, little cytoplasm, immature nucleole
Megakaryocyte
- More cytoplasm, granulated, multinucleated
- Located next to BM sinusoidal endothelial cells, filopodia extend into capillaries
- Each megakaryocyte –> 4000 platelets
- Mature megakaryocyte contain 4-64x amount of haploid DNA (mostly 18-32N)
Steps in platelet development
- Megakaryocyte development in adult BM
- Endomitosis to create polyploid nucleus
- Cytoplasmic maturation
- Pre-platelet formation and release
- Pre-platelet to pro-platelet interconversion
- Platelet release
Thrombocytopoiesis
Stem cell -> megakaryoblast -> megakaryocyte -> platelets
Hormones:
- Steel (stem cell) factor
- LIF (leukaemia inhibitory factor)
- IL6 and IL11
- Thrombopoietin (most impt)
Platelet homeostasis
- Maintained at constant level
- 1/3 do not circulate but remain in spleen
- Require 400,000 new platelets/uL blood/day
- Lifespan 7-10 days
- Consumption: senescence (old) and utilisation in haemostasis
Platelet ultrastructure
Complex cytoskeleton
Electron-dense granules: Ca2+, Mg2+, ATP, ADP and serotonin
Alpha-granules: coagulation factors, platelet-derived growth factor, TGF-b, heparin neutralising factor (PF4), thrombospondin
Primary haemostasis
= Process of forming platelet plug at site of vessel injury
- Injury: endothelial injury –> vascular constriction
- Initiation: exposed collagen bound by VWF in blood, VWF binds platelet via platelet receptor GP 1B-IX-V
- Extension:
- Platelet activated -> exposes integrin αIIbβ3 -> proteins link between platelets (e.g. fibrinogen)
- Granules released recruiting more platelets - Stabilisation: using clotting cascade, forming fibrin
Clinical: problems with primary haemostasis
- Congenital lack of VWF = Von Willebrand disease
- Lack of GP-1b on platelets = Bernard-Soulier syndrome
Leads to haemorrhagic diathesis characterised by abnormal platelet adherence
Platelet quiescence
NO, PGI2 released from endothelium
Prevent platelet aggregation
Platelet aggregation
Most platelets do not adhere directly to sub-endothelial structure, but to each other = aggregation
- Adherence to collagen -> prostaglandin synthesis activated -> thromboxane A2 released
- Thromboxane A2 triggers release of platelet granules (coagulation factors , ADP, fibrinogen)
- Leads to aggregation and clotting cascade activation
Thromboxane A2 synthesis and action
Synthesis:
- Within platelets phospholipids generate arachidonic acid (via phospholipase)
- Arachidonic acid -> prostaglandins via cyclo-oxygenase
- Prostaglandins -> thromboxane A2 via thromboxane synthase
Action:
Thromboxane A2 slows conversion of ATP to cAMP –> lower platelet cAMP –> lower Ca2+ –> granule release
Prostacyclin
- Increases platelet cAMP –> increase Ca2+
- Inhibits granule release
- Prevents platelet aggregation on normal endothelium
Aspirin action
Aspirin binds to cyclo-oxygenase irreversibly leading to covalent acetylation
–> reduces thromboxane A2
Enzyme modification permanent
If stopping aspirin, 10% of platelets free of aspirin each day (at 5 days 50% free)
Causes of high platelets
Increased production:
Myeloproliferative neoplasms: polycythemia vera, essential thrombocythemia, primary myelofibrosis
Presentation of thrombocytopenia
- Epistaxis, easy bruising, petechiae, oral blood blisters
- Low platelets in FBC
- If no splenomegaly or hepatomegaly then no underlying malignancy
- Most likely scenario is ITP, sometimes viral trigger and presents acutely
Lab phenomenon: Sometimes EDTA (used in FBC) causes clumping and appears as thrombocytopenia (low platelet count)
Causes of thrombocytopenia
Decreased production:
- Selective decrease in megakaryocytes (viral, drugs)
- General BM failure (aplasia, leukaemia)
Increased destruction:
- ITP
- Other autoimmune e.g. SLE
- Drugs
- DIC
- Viral infection
Other: hypersplenism, massive transfusion
Immune thrombocytopenia - mechanism
- Sensitised platelet has anti-platelet antibodies bound to it
- Macrophages respond to Fc portion of antibody on platelet –> digest platelets
Less platelets, often larger platelets, bone marrow aspirate shows elevated megakaryocytes
Treatment of ITP
- Prednisolone (immune suppression steroid)
- If relapse on prednisolone, splenectomy
- New agents for ITP: thrombopoietin (TPO)-mimetic –> binds to TPO receptor and stimulates platelet production
Hereditary platelet defects
Glanzmann’s thrombasthesthenia: no aIIbB3 (rare)
Secretory defects
Minor receptor defects (more common)
(acquired defects vastly more common)
Testing platelet function
- Platelet function assay (screen)
- Platelet aggregation testing
