Thrombosis Flashcards
What is thrombosis
Formation of a blood clot within a blood vessel
How does haemostasis lead to thrombosis
Coagulation prevents blood loss
Inflammation activate coagulation which promotes inflammation
Coagulation is an inflammatory response
Stages of haemostasis
Primary - aggregation of platelets
Secondary - fibrinogen –> fibrin
Steps for coagulation
1) Aggregation of platelets
2) Fibrinogen converted into fibrin mesh by thrombin which is a protease
3) Thrombin is converted from prothrombin which is the culmination of a cascade of similar activation steps
Describe platelet adherence
- Von Willebrand factor on subendothelial cells activates platelets
- Circulating VWF may bind to exposed subendothelial cells
Activated endothelial cell express VWF
Describe platelet activation
- Activated platelets release Thromboxane A2 (TxA2) and adenosine diphosphate (ADP) which induce receptors for fibrinogen (GPIIb/IIIa).
- These bind to receptors on adjacent platelets and increase expression of the glycoprotein complex GPIIb/Illa
Describe Platelet aggregation
- Fibrinogen acts as a tether, holding platelets together = aggregation
- Fibrinogen is the soluble precursor to fibrin and in the circulation
What is platelet substrate for coagulation
- Once a clump of platelets aggregate, they form a negatively charge surface which is required for coagulation
- Coagulation involved the conversion of fibrinogen to fibrin and then crosslinking of the fibrin clot
Steps for the common pathway for coagulation
1) Factor Xa cleaves prothrombin to form thrombin
2) Thrombin is a protease that cleaves fibrinogen to fibrin
Fibrin fibres into solid clot
How does fibrinogen promote blood clotting
Form bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor
What does thrombin cleave
Fibrinogen into fibrin
Factors V and VIII to give Va and VIIIa
How is a tenase complex formed
VIIIa + IXa = Xa
How is a prothrombinase formed
Va + Xa = Thrombin
Extrinsic pathway
Begins in the vessel wall
Damaged endothelial cells will release factor III (tissue factor) - greater amount of damage = more released
Steps for extrinsic pathway
1) Factor III combines with Ca2+ on negatively charged platelet surface and activates factor VII
2) Once activated, VIIa activates Xa and the common pathway is initated
3) VIIa tissue factor complex can be quickly inactivated by antithrombin III in vivo
Intrinsic pathway
- Begins in the blood stream. Is activated when the blood is exposed to collagen (or other damaged surfaces)
- Activated when blood is put on a charged surface such as glass
Defects in pathways
Defects in factors of the extrinsic pathway have larger physiological effects than mutations int he enzymes of the intrinsic pathway
Arterial thrombosis
Mostly results from atheroma rupture or damage to endothelium
Platelet rich ‘white’ thrombosis - mostly primary
may block downstream arteries
Venous thrombosis
Results from stasis or a hyper coagulant state
Platelet poor ‘red’ thrombus - mostly secondary
May move to lungs
Virchow’s triad
Stasis, Hyper coagulant state, Endothelial damage
Involvement of valves
prevent backflow of blood
Contraction of nearby muscles squashes veins, acting as a pump to return blood to the heart
Blood tends to eddy around valves, increasing risk of stasis
What happens in deep vein thrombous
Venous return is blocked, affected organ becomes congested with fluid
Increased pressure so more filtration
Risk that the thrombosis might become dislodged and make its way back to the heart
What are the different fates of a thrombus
Resolution
Embolism
Organised
Recanalised and organised
Proximal DVT
Higher risk of pulmonary embolism and post thrombotic syndrome (pain swelling, maybe even ulcers)
Distal DVT
Rarely cause pulmonary embolism and post thrombotic syndrome
Post thrombotic syndrome
- Inflammation along with damage to the venous valves from the thrombus itself
- Valvular incompetence combined with persistent venous obstruction inducing a rupture of small superficial veins, subcutaneous haemorrhage and an increase of tissue permeability
- Pain, swelling, discolouration and even ulceration
What is tissue plasminogen activator
Serine protease found on endothelial cells
What does tissue plasminogen activator do
Catalyses the activation of circulating plasminogen into plasmin
What does plasmin do
Catalyses the breakdown of cross linked fibrin clot into fragments called D-dimer
What is antithrombin
Small protein molecule made by the liver that circulates in the plasma
What is Heparin and what does it do
Is expressed by endothelial cells and binds to the enzyme inhibitor antithrombin II (AT) causing a conformational change that results in AT activation
What does activated AT do
Inactivates thrombin, factor Xa, factor VII and other components of the clotting cascade
