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Topic 2 - Haemostasis and Coagulation
Haemostasis is the process that causes bleeding to stop and keeps the blood within a damaged blood vessel.
This is the first stage of wound healing and is one of the important survival mechanisms as it prevents blood loss following injury, but it must maintain a delicate balance between normal function and prevention of blood loss.
The endothelial cells are very important in maintaining vascular integrity as they are a source of Von
Willebrand factor and Tissue Plasminogen Activator (tPA).
Vasoconstriction - The first line of defence is the immediate constriction of the smooth muscle cells in the blood vessels to reduce blood flow to the area.
Platelets are produced in the bone marrow and occur due to the fragmentation of the megakaryocyte
cytoplasm [1 megakaryocyte = 4000 platelets] in a process known as Endomitotic Synchronous Nuclear
Circulating platelets have a lifespan of 9-10 days and its 150x10 9-400x109/L.
Platelet production is stimulated by Thrombopoietin (TPO, which is produced in the liver.
Its production is also controlled by negative feedback, which regulates the number of circulating platelets.
Glycocalyx - These are glycoproteins that allow the platelet to adhere to surfaces such as the collagen of damaged vessels.
Glycogen - These are the energy reserves in the platelet.
Platelet contractile proteins - This makes the platelet aggregation irreversible.
Dense tubular system - This is the site of prostaglandin and thromboxane A2 synthesis.
Canalicular System - This allows the granules to be released.
There are 2x types of granules involved in platelet aggregation: Electron dense (δ) granulesδ) granules) granules and
Adhesion - Platelets first adhere to the damaged surface.
Secretion (Granule Release) - The platelets then become activated and release their granules into the circulatory system.
Aggregation - Finally the platelets aggregate together to form a thrombus in the region of damage. They do this as the collagen becomes exposed to the blood due to damage done to the epithelium, and the platelets recognise and stick to these collagen fibres.
Von Willebrand factor (vWF) is also released from the granules and this attaches to the damaged collagen,
forming a link between the platelet and the collagen, allowing adhesion via one of the glycoproteins, such as
GP1b, vWF isn't always required for adhesion.
Once bound to the collagen, the platelets secrete ADP and Thromboxane A2, which increases the degree of aggregation, and the platelets swell due to the presence of ADP, and this is further reinforced through positive feedback, and the platelet plug is formed.
Coagulation Factors - These are co-granulesfactors, serine proteinases and coagulation-granulesrelated-granulesproteins. Many of these are known by their factor number (δ) granuleseg: Factor I = Fibronogen).
1) In the first stage of the coagulation cascade Tissue Factor (TF) is normally located on leukocytes and the exposure of the subendothelium after vessel damage brings them into contact with the Tissue Factor, and this causes it to bind to Factor VII, causing its activation into FVIIa, and forming the TF-VIIa complex.
2) Initiation - The TF-VIIa complex then binds to Factor-X, forming the 'extrinsic tenase complex', activating FX
to FXa. FXa then cleaves Prothrombin to generate trace amounts of Thrombin, but as its co-factor FV is not available due to its down regulation by Tissue Factor Pathway Inhibitor (TFPI) only a very small amount is produced, and this is insufficient to initiate significant fibrin formation.
3) Amplification - As there is only a small amount of Thrombin produced in the first phase it then enters the amplification phase. This trace amount is able to activate the co-factors FV (acts with FXa) and Co-factor VIII
(acts with FIXa), as well as the platelets.
4) Propogation - The shutdown of FX activation by Tissue Factor Pathway Inhibitor (TFPI) means that an alternate route for Thrombin generation is sought. The 'Intrinsic Tenase Complex' utilises FIXa, which was only produced in small amounts earlier. FIXa utilises FVIIa as its co-factor (produced in amplification phase).
FIXa binds to the surface of the platelet and associates with its co-factor. FIXa also associates with FX,
producing much more FXa (90% more produced here). Now FXa, finally produced in enough amounts,
associates with its co-factor FVa (generated during the amplification stage) and is secreted from the alpha granules in platelets to its substrate Prothrombin, forming the Prothrombinase Complex', which catalyses
Prothrombin to produce Thrombin. Enough Thrombin is now produced for the activation of Fibrinogen, to form a Fibrin Polymer, as well as FXIII for positive feedback, ultimately resulting in a stable fibrin clot.
Inhibitors of Coagulation
Tissue Factor Pathway Inhibitor (TFPI) - Inhibits Factor VIIa and Factor Xa. This is the first inhibitor to act and its accumulation occurs due to platelet activation, as it is found in the plasma and the platelets.
Antithrombin III - Inhibits Factor Xa and Thrombin. This is synthesised in the liver and endothelium.
Protein C and Protein S - Protein S inactivates Factors Va and VIIIa. (Protein C enhances these actions, it also enhances Fibrinolysis by activating tPA). These are Vitamin K dependent proteins made in the liver.
Fibrinolysis is the removal of the Blood Clot.
Tissue Plasminogen Activator (δ) granulestPA) activates Plasminogen conversion into Plasmin.
Plasmin degrades the Fibrin, and generates soluble fragments called Fibrin Degradation Products (δ) granulesFDPs).
To help this from happening excessively Streptokinase can reduce this system and affects fibrinolysis,
reducing the level of breakdown.
PAI-granules2 (δ) granulesPlasminogen Activator Inhibitor) can also inhibit this system, preventing it from occurring to reduce the breakdown of the clot.
α2-granulesantiplasmin inhibits Plasmin, reducing the amount of Fibrin broken down.
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