Platelets and Clotting

what is a hematopoetic organ?

Something that produces and develops blood cells

Outline thrombopoiesis (generation of platelets)

• Liver produces Thrombopoieten hormone, which stimulates megakaryoctye production in the bone marrow

• these megakaryocytes become multi nucleated in the bone marrow 

• The megakaryotes undergo cytoplasmic granulation

• Either right after they enter the blood, or before in the bone marrow, fragments break off to form platelets

What does Thrombopoiten hormone do? (TPO)

It stimulates the production of megakaryocytes in the bone marrow, which in turn helps increase the production of platelets

Do platelets have a nucleus?

No they do not

can platelets reproduce or reapir themselves?

No

What do the granules in platelets contain?

Alpha granules:

• coagulation factors

• adhesion molecules

• other pro coagulants

Dense granules

• ADP,ATP, Ca 2+ and seretonin

what are pseudopodia?

They are projections of a cell (of platelets) which can be used for movement and dramatically change their shape

What are the three main steps of the hemostatic response?

1. Vasoconstriction

2. Platelet Agregation/Platelet Plug Formation

3. Blood coagulation cascade

What are the two components of the vasoconstriction response?

1. The local contractile response, whoch involves the neurogenic spasm and myogenic spasm

2. The release of humoral substances seretonin, endothelins and clotting factors

what are myogenic and neurogenic spasms?

neurogenic spasm, a fast and short lived (<60s) contraction caused by pain and nerves impulses

myogenic spasm which is a longer lasting response that is initiated by direct damage to the vessel

What is the role of seretonin in the hemostatic response?

It is released by granules of active platelets and it is a vasoconstrictor (vasoactive substance)

What is the role of endothelins in the hemostatic response?

the are released from the injured endothelin and are vasoactive, vasoconstrictors

function of von willdesbrand factor (vwf)

It is present on collagen fibres of a vessel wall which become exposed after an injury

Glycoproteins on the surface of platelets (thrombocytes) bind with the vwf which causes them to aggregate at the area. 

How does an unstable platelet plug form?

Simply put:

injury to the vessel causes some platelets to become activated, and when they get activated they release the contents of their granules, causing even more platelets to become activated and aggregate at the site of injury.

What is the positive feedback which occurs during the formation of the platelet plug?

• glycoproteins on platelet surface bind vwf and a confirmational change in the platelets causes alpha granules to be released

• this releases fibrinogen and ADP

• the ADP stimnulates activated platelets to release thromboxane A2, which is a potent vasocinstrictor and potentiates aggregation while also activating other platelets

what does thromboxane A2 do? (general)

• helps platelets clump together (aggregation)

• is a vasoconstrictor

• activates other platelets in a positive feedback loop

what is cAMP?

intracellular messenger which inhibits platelet function, partly by removing free cytosolic calcium

How does thromboxane A2 activate platelets?

It binds to receptors which signals a lowering of cAMP on the inside

This low cAMP causes an increase in Ca2+, which triggers the activation 

What happens to the platelet when it is activated?

• shape change→pseudopia

• granule release

• more thromboxane A2 synthesis→positive feedback

What does prostacyclin do?

It is released by endothelial cells and it promotes ATP→cAMP in the platelets, lowering calcium and preventing them from being activated

what are the three main steps of the coagulation cascade?

1. in direct response to the damage, prothrombin activator is formed as a result of a complex cascade of reactions involving many coagulation factors

2. Prothrombin activator catalyzes conversion of prothrombin→thrombin

3. thrombin acts as an enzyme to convert fibrinogen into fibrin fibres that enmesh platelets, blood cells and plasma to form the clot

What is the extrinsic pathway?

• initial response to vascular injury: clots blood that has escaped the vessel into surrounding tissue

what is the intrinsic pathway?

• amplification of the response

• clots blood within the injured vessel (slow)

what are the main players in the extrinsic pathway? Outline the general process

• Tissue factor (TF) exposed

• Plasma factor Vll binds TF → Vlla

• TF-Vlla binds Ca2+ and converts factor X to Xa

• also converts small amount of prothrombin to thrombin, ensuring propagation of the reaction

what are the main players in the intrinsic pathway? Outline the general process

Intrinsic Xase complex acts to convert X to Xa, leading to activation of prothrombinase

What is the point of prothrombinase?

It converts prothrombin (coming from the liver) to thrombin

How does thrombin form a blood clot?

• Fibrinogen is hydrolyzed by thrombin into fibrin monomers

• Fibrin monomers spontaneously polymerize into fibrin polymers

• thrombin converts factor Xlll to Xllla which catalyzes the formation of a cross linked lattice with covalent cross bridging (stable fibrin)

How does fibrinolysis happen?

• tissue plasminogen activator (t-PA) is released from endothelial tissues and binds to fibrin

• t-PA converts clot-bound plasminogen into plasmin to facilitate breakdown of stable fibrin into soluble fragments.