Lecture 10: Platelets in health and disease Flashcards
What is the function of platelets?
- Angiogenesis
- Wound healing
- Inflammation
- Primary haemostasis
What are platelets derrived from?
Megakaryocytes
Write some notes on megakaryocytes:
- Located next to BM sinusoidal endothelial cells
- Filopedia extend into capillaries
- Each megakaryocytes -> 4000 platelets
- Develop multiple nuclei
Describe how platelets are formed from megakaryocytes? What are the essential factors?
- After DNA replication granules and membrane formed
- Platelets inside cytoplasm
Requires:
- Steel factor
- LIF
- IL6 & IL11
- THrombopoietin (TPO) (Lynch pin essential factor)
Whats the life span and consumption of platelets?
Life span: 7-10 days
Consumption: Senescence, Utilisation in heamostasis
Write some notes on the platelet ultrastructure:
(Things that contribute to platelet clotting)
- Submembranous filaments i.e actin (forms filopod structures (important)
2 types of granules (contain growth and clotting factors)
- Electron dense granules
- Specific Alpha granule
Whats the function of electron dense granules? what do they contain?
Key platelet reaction released and activates other platelets
Ca, Mg, ATP, ADP, serotonin
What are the function of platelet alpha granules and what do they contain?
Contain: Coagulation factors (Fibrinogen, factor V, VWF), Platelet derived growth factor, TGF beta, heparin neutralising factor, thrombospondin, etc)
Function:
- Contribute to surface coagulation reactions
- Growth factors
- Heparin reactions
What is primary heamostasis?
Primary heamostasis is the process of forming a platelet plug at the site of vessel injury
Describe an overview of primary heamostasis:
1) Initial phase of the process is vascular constriction
2) Platelets become activated and aggregate at the site of injury, forming a temporary, loose platelet plug.
Describe in more detail primary heamostasis:
1) Platelets in flowing blood - not activated
2) Vessel wall injury
3) This exposes collagen
4) Von willibrand factor binds exposed collagen
5) Activated platelets adhered to vessel wall
6) Activated platelets release factors to recruit more platelets and forma surface for coagulation cascade
7) Platelets cross link via fibrinogen-integrin
The process of platelet related clotting contains a lot of what?
Redundancy
Describe some platelet interactions in clotting:
- Exposed collagen is bound by VWF
- VWF binds factor five complex and thus platelets
- Activated platelets adhere to VWF via Integrins which are exposed following activation.
- Exposed integrins also bind other platelets via fibrinoin cross linking
- Activated platelets also release granules containing platelet agonists
What do healthy endothelial cells normally release?
Factors to stop platelet activation
Describe what happens following vessel wall injury:
Vessel wall injury, releases:
- Tissue factor -> Blood coagulation cascade -> Thrombin -> Fibrin = Contributes to stable heamostatic plug
- Collagen exposure -> Platelet adhesion and activation (releases granules and activates GPiib/iiia)
From granules: - Platelet phospholipid stimulates coagualtion cascade
- Serotonin promotes vasoconstriction
- Thromboxane stimualtes vasoconstriction AND the next step -> Platelet aggregation
= Primary haemostatic plug and together with fibrin = stable heamostatic plug
- Damaged vessel wall -> Vasoconstriction which aids primary heamostatic plug
What does clopidigrol bind?
G-protein coupled receptor on platelets preventing aggregation/degranulation
Describe how healthy endothelium stops platelet activation:
Healthy endothelium produces prostacyclins which increases formation of cAMP from ATP which in turns lowers Ca in platelets preventing degranulation / activation.
Phospholipids in platelets go on to form thomboxane which lowers cAMP formation and increases Ca. (activation) (phospholipids are released from initial platelets that bind exposed collagen)
How does aspirin prevent clotting?
Prevents thromboxane production
Covalent acetylation of cyclo-oxygenase -> Decrease thromboxane A2 (Enzyme mod is permanent)
How do NSAIDS prevent clotting?
Alter adenylate cyclase activity
What is the function of thromboxane A2 in platelet function?
Decreases platelet cAMP -> Release of granules
What is the function of endothelial prostacyclin in platelet function?
Increases Platelet cAMP, inhibits release of granules
Prevents platelet aggregation on normal endothelium
What factors influence platelet levels in patients?
Must know all.
Decrease in production caused by:
- Viral infection
- Drugs
- Bone marrow failure (caused by: Aplastic anaemia, leukaemia, carcinoma, megablastosis)
Increased destruction
- immune thrombocytopenia
- DIC (i.e from meningitis)
Increased production
- Myeloproliferative neoplasms i.e polycythemia vera, essential thrombocytopenia, primary myelofibrosis
What can cause thrombocytopeania?
Decreased production:
- Selective decrease in megakaryocytes; viral or drugs
- General BM failure; aplasia, leukemia etc
Increased destruction
- Immune thrombocytopenia
- Other autoimmune i.e SLE
- Drugs
- DIC
- Viral infection
Other
- Hypersplenism (1/3 platelets sit in spleen)
- Massive transfusion
What happens in immune thrombocytopenia?
AB binds platelets and they are phagocytosed by macrophages
low levels
How can immune thrombocytopenia be treated?
- Prednisone
- Second line splenectomy
New agents: Thrombopoietin (TPO) mimetics
What is now done to testing platelet function?
Platelet function assay and platelet aggregation testing
