Thrombosis: Haemostasis in the wrong place Flashcards
Describe the primary and secondary processes of haemostasis
Primary - Aggregation of platelets and RBCs along with circulating fibrinogen
Secondary - Conversion of fibrinogen into fibrin, which forms a strong mesh
How is a mesh formed from the fibrinogen
Thrombin protease cleaves off a section of the fibrinogen molecule to make fibrin, forming the mesh.
Thrombin is converted from prothrombin in a similar way
How does the endothelium of the capillary limit coagulation
Releases nitric oxide and prostaglandin, which are vasodilators and also inhibit platelet activation, preventing aggregation
Endothelial cells also bind tissue plasminogen activator, which catalyses a reaction that leads to fibrinolysis, undoing clots
Endothelium expresses heparan, which tethers a molecule called antithrombin, inhibiting thrombin and other coagulation enzymes, so acts as an anticoagulant.
How may the endothelium favour coagulation
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Describe arterial thrombosis
Platelet rich, arises from damage to endothelium. Found in stroke or MI, resulting from rupture of atherosclertoic plaque
Describe venous thrombosis
Blood pools/static results in venous thrombosis. Mostly secondary thrombosis
Describe Virchow’s triad
Stasis of blood - If blood lacks kinetic energy, more chance of clotting
Hyper-coagulant state - Some genetic isoform of coagulation proteins that makes it more active can be inherited. Infections can make a hyper-coagulant state
Endothelial damage - This is the way we want our body to respond to coagulation. If a vessel is cut or damaged, we need coagulation to prevent blood loss, seal the wound from infection and to act as a pro-inflammatory mediator.
How do valves prevent pooling of blood
Valves prevent backflow of blood, and help its movement to the heart by muscle contractions in the legs. These provide an obstruction, blood can eddy around, increasing risk of stasis and coagulation.
Varicose veins (incompetent valves), blood can backflow down the vein, increasing pooling of blood in the lower legs
How is oedema formed in the legs
Venous thrombosis, back pressure upstream of the blockage increases hydraulic pressure and creates oedema, as fluid is squeezed out of capillaries leading to swelling.
Describe the 4 fates of a thrombus
Thrombolysis - Cleared entirely
Embolism - Dislodged, makes it ways up to the heart, travels through right atrum and ventricle before blocking a vessel in the lung (pulmonary)
Organised thrombus - Endothelium grows over it
Recanalised and organised - Small blood vessels built through clot
How are proximal and distal DVT different
Proximal DVT (above knee) large vessels, closer to heart, large DVT very dangerous
Distal DVT (below kneww), wedge and resolve, small unlikely to cause embolism, more likely to be organised
Describe what happens in embolism
Embolus travels back to the right side of the heart, enters the pulmonary circulation, the vessels narrow, so the embolus is lodged
A large embolus could block a significant pulmonary artery, causing ischaemia. A very large thrombus could form a saddle embolism, blocking both pulmonary arteries, causing death.
A small embolus would cause minimal damage.
What is ischaemia
Restriction of blood flow and therefore oxygen in a larger area of the lung
What is Von Willebrand factor
Glycoprotein that normally circulates in the blood. Blood vessels are lined with a monolayer of endothelial cells, and Von Willebrand factor does not usually interact with these cells.
Von Willebrand factor’s primary function is binding to other proteins e.g. subendothelial cells, collagen, platelets and some coagulation proteins
What is platelet adherence
Initiator of thrombosis, von Willberand factor binds to subendothelial cells and activates platelets.
Endothelial cells release von Willberand factor if damaged or inflamed, promoting coagulation.
What is platelet activation
Activated platelets release Thromboxane A2 (TxA2) and adenosine diphosphate (ADP)
These bind to receptors on the platelets, and increase expression of the glycoprotein complex, GPIIb/IIIa on the cell membrane of platelets, which is a fibrinogen receptor.
TxA2 and ADP activates adjacent platelets, and so more fibrinogen receptor is expressed, more platelet activation and aggregation
Describe platelet aggregation
Activated fibrinogen receptor complexes can bind the circulating inactive form of fibrinogen, which can act as a tether holding the platelets together. The fibrinogen is not active, and is not the fibrin in clotting.
What is platelet substrate for coagulation
Clump of platelets tetherred by fibrinogen, provides a critical mass of negatively charged phospholipid surfaces, required to initiate the coagulation cascade
Describe the common pathway of clotting cascades
Prothrombin cleaved to thrombin (IIa) by factor ten Xa, thrombin (IIa) cleaves fibrinogen into fibrin, fibrinogen promotes blood clotting by activating blood platelets through binding to their GPIIb/IIIa surface membrane fibrinogen receptor. Fibrin form long polymers which hold activated platelets together in a blood clot.
Factor thirteen (XIII) activates, causes cross linking of fibrin, stabilising the clot.
Describe the extrinsic pathway
Begins in the vessel wall, damaged endothelial cells released tissue factor VIIa. Tissue factor combines with calcium on negatively charged platelet surface, activating factor VII
Describe intrinsic pathway
Begins in bloodstream, activates when blood exposed to collagen. Activated when blood is put onto a charged surface such as glass.
Describe tissue plasminogen activator action
Clot broken down by plasmin, which is activated from plasminogen by tPA found on endometrial cells. Cross linked fibrin breaks down into fragments called D-dimers, which can be used to diagnose a blood clot.
Describe antithrombin action
Inhibits enzymes in the coagulation vascade, particularly inhibits thrombin.
