Case 20- Clotting Flashcards
Clotting process
- Vasoconstriction- vascular spasm
- Primary haemostasis- adhesions of platelets to the injury site forming a weak platelet plug
- Secondary haemostasis- coagulation cascade to produce a fibrin network stabilising platelets and trapping red and white cells to make a stable clot
- Clot retraction and repair of endothelial linning
- Fibrinolysis
Vasoconstriction
The endothelium releases NO so the platelets are not prematurely activated and don’t adhere to the endothelium or each other. NO retains vasodilation, damage to the endothelium disrupts NO release, causing activation of the smooth muscle and vasoconstriction.
Primary haemostasis
Damage exposes the subendothelial collagen activating platelets. Platelets are shed from Megakaryocytes. Platelets have no nuclei and when activated they form pseudopodia finger like projections. Normally 2/3 of platelets are in the circulation and 1/3 are in the spleen. The activated platelets bind to each other and the damaged area to form a platelet plug.
Steps of primary haemostasis
- ADP is released from damaged endothelial cells and binds to P2Y 12 receptors on platelets activating them.
- Granules are released from platelets which attract more platelets to the area (can be ADP)
- Exposed collagen has vWF which binds to the GP1b receptor on the platelet, attaching the platelet to the damaged collagen and activating them
- Collagen binds directly to the GPVI receptor on the platelet promoting activation
- Activated platelets use the enzyme COX-1 to convert arachidonic acid to Thromboxane A2 (TXA2) which attracts more platelets to the area
- The GP IIb/IIa receptor on platelets binds platelets to each other and they are anchored together by the molecule Fibrinogen between the two receptors
- A platelet plug is formed to stop bleeding. Receptor activation attracts more platelets
- In small injuries the primary platelet plug is enough to stop bleeding. In bigger cuts it needs to be stabilised by Fibrin which makes it stronger and long lasting
Molecules involved in clot formation
Other molecules involved in clot formation= Thrombin, Epinephrine, Prostaglandin E2, Serotonin • ADP – P2Y12 • vWF – GP1b • TXA2 – TXA2 receptor • Fibrinogen – GP IIb/IIIa
Drugs which inhibit blood clotting
ClopidoGREL, PrasuGREL, TicaGRELor inhibit the P2Y12 receptor
Aspirin binds to COX-1 to stop the formation of TXA2
Tirofiban binds to GP IIb/IIIa receptors stopping a myocardial infarction
Common pathway in secondary haemostasis
Based on the coagulation cascade. Fibrinogen converts to Fibrin
• Factor 1 (Fibrinogen) is activated to Factor 1a (Fibrin) by the enzyme Factor IIA (Thrombin) which is the activated form of Factor II (Prothrombin)
Secondary haemostasis
1) The intrinsic and extrinsic sides of the coagulation cascade converge to form factor Xa and Va which converts Prothrombin to Thrombin, they are assisted by Ca+2 and Phospholipids.
2) The intrinsic pathway is triggered by endothelial damage and is also known as the contact activation pathway.
3) The Tissue Factor Pathway (Extrinsic pathway) is triggered when Tissue Factor enters the blood system.
4) The Prothrombinase complex is made up of phospholipids, Ca+2, activated Va and Xa.
5) The common system is from factor Xa and Va downwards.
6) The coagulation cascade amplifies the signal so enough fibrin is made to form a clot
Extrinsic pathway
When the tissue is damaged tissue factor is in contact with the blood, indicating damage has occurred. Tissue factor causes the conversion of VII to VIIa. VIIa converts factor X to factor Xa in the common pathway.
Intrinsic pathway
1) Triggered by Endothelial damage/collagen which is negatively changed and converts factor XII to factor XIIa (twelve)
2) Factor XIIa converts to XI to factor XIa (eleven)
3) Factor XIa and Ca+2 convert factor IX to factor IXa (nine)
4) With phospholipid and Ca+2 factor IXa converts factor X to active factor Xa, (ten) it is also helped with activated VIIIa from factor VIII which is normally bound to vWF. Thrombin helps to release VIII from vWF (eight)
Trick for remembering intrinsic pathway
In the intrinsic pathway the last letter of the previous factor is the first letter of the next factor.
TwelvE -> EleveN -> NinE -> EighT-> Ten
A thrombin burst
Lots of Thrombin is produced and helps activate the Prothrombinase complex, release vWF from VIII and activates XLa and converts XIII to XIIIa which stabilises Ia Fibrin by cross-linking the fibres.
The factors in the extrinsic and intrinsic pathway
The factor(s) in the extrinsic pathway are: Factor VII (7) (plus calcium) -> common pathway (10…) The factor(s) in the intrinsic pathway are: Twelve, eleven, nine, eight (plus calcium for some steps) -> common pathway (10…) Factor IV is just the name for Ca+2
The factors in the common pathway are
- Ten and five plus calcium and phospholipid (prothrombinase complex)
- Prothrombin (II) -> Thrombin (IIa)
- Fibrinogen (I) -> Fibrin (1a)
- XIII
Clot retraction
The contraction and twisting of the fibrin mesh in order to shrink the blood clot bringing the edges of the blood vessel wall together allowing repair of the damage. Fibroblasts and epithelium help repair the new vessel lining.
Fibrinolysis
1) Helps break down the cross linked fibrin mesh
2) The Tissue Plasminogen Activator (tPA) and Urokinase converts Plasminogen into Plasmin. Plasmin cuts up the Fibrin into FDP’s i.e. D dimer
3) Clots are in equilibrium between being made and being broken down
4) Drugs which activate Plasmin can be used to break down clots
Natural anti and pro-coagulation factors
Natural anti-coagulation= Natural anticoagulants (Protein C and S, antithrombin, Thrombolysis
Natural pro-coagulation= Platelets, Von Willebrand factors, Coagulation factors
Virchow’s triad
3 factors which contribute to the formation of a venous thrombosis:
• Venous stasis- people who are immobilised increases this
• Hypercoagulability- increased by inflammation, cancer, oestrogen, pregnancy, smoking and inherited thrombophilia
• Endothelial injury- cellulitis/phlebitis, injury, indwelling catheter
