Platelets

Question 1

What is the structure of a platelet?

Answer 1

NO NUCLEUS
- Can’t synthesise proteins (but can lipids), so need to be packed with everything they need for their life time. The megakaryocyte arms must shuttle all requirements into cell

Small (1-3µm)

Disc shape

Plentiful (150-400 x 109/L)

Contain three types of granules:
- lysosomal granules:
- Contain hydrolytic enzymes
- alpha-granules:
- Most abundant, larger granules, containing diverse proteins
(pro an anti thrombotic molecules and inflammatory) with a
variety of functions
- dense granules:
- Contain small molecular weight prothrombotic molecules eg
ADP, ATP, 5-HT, Ca2+ and serotonin that promote platelet response

Question 2

What are platelet glycoproteins?

Answer 2

Important in platelet adhesion and aggregation

Mediate interactions:
• Platelet to platelet
- Mainly through fibrinogen factors to bind platelets together
• Platelets to subendothelial matrix proteins
• Platelets to plasmic coagulation factors
• Platelets to endothelial cells
- Only activated in disease states

There are four broad classes:

1. Integrins:
   
   • Bind to ECM proteins. Particularly GPIIb-IIIa = fibrinogen receptors.
     Dependent on extracellular calcium, so need physiological
     concentration of calcium outside to bind
   • Adhesion receptors which can interact with; collagen,
     fibronectin, fibrinogen, thrombospondin, VWF - each are at
     different depths within the vessel wall, the depth of the injury
     determines what is exposed
2. Leucine-rich glycoproteins:
   
   • GP1b complex - VWF receptor 
3. Receptors of the immunoglobulin type
   
   • IgG-like domains
4. Selectins:
   
   • In granules, upon activation move to surface to bind to monocytes
     and other inflammatory proteins

Question 3

How to platelets adhere to the vessel surface?

Answer 3

Recruiting more platelets and reinforcing the response

1. Damage to vascular endothelium exposes subendothelial matrix proteins which release TF 3. Kickstarts the coagulation cascade producing thrombin, which acts in the common pathway and activates GP6 receptors causing amplification
2. Initial tethering is through GPIb-VWF interaction (VWF released by endothelium and in plasma). This indirect interaction is very quick
3. This tethering allows platelets to stick but continue to along in the blood flow. This allows more direct and firm reactions to occur
4. Form adhesion is through direct binding of major collagen binding proteins and collagen receptors (a1b2 and GPV)
5. Signalling through GPVI leads to platelet activation - filopodia strands spread in shape and size to achieve pseudopodia and lamellopodia
6. Prothrombotic granules are released which activate and recruit passing platelets = amplification process that reinforces the response
   

Question 4

How are platelets activated?

Answer 4

Signalling through GP6 - series of phosphorylation, increases Ca concentration and release of granule contents and ADP, stimulates surface receptors on platelets. Also causes synthesis of thromboxane (a lipid) through cyclooxgenase. Aspirin blocks the production of cyclooxygenase.

Thrombin in an enzyme that stimulates GP coupled receptors by cleaving the N terminal so that the new terminus is the new agonist/.

Stimulation of top agonists causes Ca2+ release which activates the GPIIb receptor - binds to fibrinogen high allows aggregation of platelets

All platelets converge at his point!! Where adjacent platelets bind to same fibrogeogen, this action signals back to the cell to increase stabilisation. This is stabilisation of this thrombus, causing their surface to become more negative, which creates a procoagulative surface that further intimates the coag cascade, that results in insoluble fibrin formation that covers the thrombin like a web stopping it washiing away.

Question 5

What is platelet aggregation?

Answer 5

Activation of alphaIIb3 results in fibrinogen binding and platelet aggregation

Signalling back into the platelet reinforces the response leading to irreversible fibrinogen binding

Soluble fibrinogen is converted to insoluble fibrin stabilising the thrombus

Question 6

What are common platelet disorders?

Answer 6

Affect haemostasis, but must be significant to affect platelet concentration

Bernard Soulier Syndrome: GPIb deficiency
- cannot bind to VWF and perform initial tethering

Glanzmann Thrombasthenia: aIIb beta 3 (GPIIb-IIIa) deficiency

• this receptor usually performs firm adherence by binding to collagen
• Loss of fibrinogen receptor so platelets can’t aggregate

Grey platelet Syndrome: alpha granule deficiency

- alpha granule proteins have a variety of functions 
- no amplification if response

Hermansky-Pudlak Syndrome: Dense granule deficiency
- Storage pool deficiency - no granules, or are there but cant be
released. Often associated with other effects such as albinism
and pulmonary fibrosis.