13) Thrombosis - haemostasis in the wrong place

Question 1

How does arterial thrombosis occur?

Answer 1

• Mostly result from atheroma rupture or damage to the endothelium
• It is called ‘white’ thrombosis as it is very platelet rich
• It is mainly primary
• It may block arteries down stream if they break off. This is because as we move down the arteries they get narrower increasing the chances of it getting obstructed

Question 2

How does venous thrombosis occur?

Answer 2

• Often from stasis (stoppage of flow) or a hyper-coagulant stage
• It is called ‘red thrombosis’ as it is very platelet poor
• These are mostly secondary
• They may move to the lungs. This is because as we travel along the venous system the vessels get larger/wider
• They can only get caught in narrow veins (such as those found in the lungs)

Question 3

What is fibrinolysis?

Answer 3

• The breakdown of fibrin into fibrinogen to prevent blood clots getting too big and dangerous

Question 4

When does coagulation and fibrinolysis occur?

Answer 4

• There is a constant balance/equilibrium between coagulation and fibrinolysis occurring all the time in our body

Question 5

How does coagulation occur?

Answer 5

• When endothelial cells become damaged/inflamed they favour coagulation
• Subendothelial cells release tissue factors (called Von Willebrand factors)
• Von Willebrand factors activate platelets and tissue factors initiate clotting

Question 6

How is coagulation inhibited?

Answer 6

• Endothelial cells release nitric oxide which inhibit platelets
• They also produce prostaglandin 12 which inhibits platelet activation
• Endothelial cells express heparan and when bound to antithrombin inhibits clotting

Question 7

What is Virchow’s triad?

Answer 7

• It shows that are three states that can cause coagulation

Question 8

What are the three states in Virchow’s triad?

Answer 8

• Stasis: Static blood which lacks kinetic energy causing them to clot
• Hyper-coagulant state: E.g. infection/sepsis and some drugs
• Endothelial damage: E.g. surgery

Question 9

How are valves involved in coagulation?

Answer 9

• Blood tends to eddy (move in a whirlpool) around valves increasing risk of stasis

Question 10

How can standing cause coagulation?

Answer 10

• Whilst standing blood pools towards the legs due to gravity
• This pooling causes blood to be static leading to coagulation

Question 11

What can happen as a result of thrombosis in the leg?

Answer 11

• Thrombosis in the leg which blocks venous return causes the leg to become congested with fluid
• This increases the pressure in the capillaries of the leg causing increased filtration (oedema)
• Furthermore hypoxia may occur as blood flow is stopped so some cells are not supplied with oxygen
• There is a further risk that this thrombosis will become dislodged and make its way to the heart

Question 12

What are the different fates of a thrombus?

Answer 12

• Resolution through thrombolysis (breaks it down completely)
• Embolism (moves to another location and blocks other vessels)
• Organised (becomes covered by endothelium)
• Recanalized and organised (holes form in the thrombus which are lined by endothelium)

Question 13

What are the different types of Deep Vein Thrombosis (DVT)?

Answer 13

• Proximal DVT: Embolism in the large venous vessels. It is a much bigger clot with a higher risk of reaching the heart and lungs (pulmonary embolism). Because of the larger veins there is a higher chance of suffering post-thrombotic syndrome (e.g. pain, swelling, ulcers)
• Distal DVT: Smaller embolisms found in the smaller venous vessels. They rarely cause pulmonary embolism and rarely cause post-thrombotic syndrome

Question 14

What happens during post-thrombotic syndrome?

Answer 14

• Occurs when a big vein is blocked by a clot
• It causes inflammation along with damage to valves from the thrombus
• We also suffer valvular incompetence which combines with persistent venous obstruction to cause small superficial veins to haemorrhage and (due to release of inflammation factors) there is an increase in tissue permeability leading to oedema (swelling)
• Pain, swelling, discolouration and even ulceration follows

Question 15

What happens when a small venous thrombus reaches the heart?

Answer 15

• If a small thrombus reaches the heart from the veins it is highly unlikely to be lodged in the heart (normally resolved if lodged without any problems/symptoms).
• However it will pass through the right atrium and ventricle into the pulmonary artery where it reaches the lungs.
• They pass down the arterioles and they may get lodged blocking these arterioles.
• This leads to the formation of a slight VQ mismatch which is an area of the lung that is not perfused but is well ventilated
• This will eventually cause hypoxia of a small area of the lung and in severe cases will eventually leads to necrosis or even oedema
• Sometimes these may be asymptomatic.

Question 16

What happens when a large venous thrombus reaches the heart?

Answer 16

• The thrombus will make its way through the right atria and the right ventricle
• However as it enters the pulmonary artery it gets lodged causing a “saddle embolism”
• This is a large embolism that can block both pulmonary arteries which can cause rapid death

Question 17

How are blood clots formed?

Answer 17

• First underlying subendothelial cells may be exposed where the Von Willebrand factors are present
• These Von Willebrand factors bind to and activate platelets. (Platelets can also be activated by other mediators)
• Activated platelets release Thromboxane A2 and Adenosine Diphosphate (ADP) which express fibrinogen receptors
• These bind to receptors on adjacent platelets and increases expression of the fibrinogen receptor (a glycoprotein complex)
• Fibrinogen binds to its receptor and acts as a tether which hold the platelets together (called aggregation)
• Once a few platelets aggregate they form a negatively charged clump where the fibrinogen is converted to fibrin and the fibrin clot is crosslinked (called coagulation)

Question 18

How can subendothelial cells be exposed?

Answer 18

• Tissue damage

- Release of inflammatory factors

Question 19

Where can we find Von Willebrand factors?

Answer 19

• Subendothelial cells express large amounts of Von Willebrand factors.
• There may also be Von Willebrand factors that bind to the exposed subendothelial cells
• Activated endothelial cells can also express Von Willebrand factors

Question 20

What is fibrinogen?

Answer 20

• Fibrinogen is a large molecule present in the plasma which is soluble
• When cleaved it forms fibrin which is insoluble

Question 21

Why is the aggregated clump negatively charged?

Answer 21

• This is due to the negatively charged phospholipids and is required for coagulation

Question 22

What is the common pathway of producing cross-linked Fibrin?

Answer 22

• Clotting cascades produce activated factor ten (Xa)
• This is a protease that catalyses the conversion of prothrombin to thrombin
• Thrombin is a protease that cleaves fibrinogen leaving sticky ends for fibrin to polymerize
• They activate platelets by interacting with fibrin receptors and forming bridges between adjacent platelets
• Fibrin forms long polymers which hold activated platelets together in the blood clot
• Once enough thrombin is present factor thirteen is activated causing cross linking of fibrin which further stabilises the clot

Question 23

What is the purpose of having different pathways leading to the common pathway in blood clotting?

Answer 23

• It allows for the amplification of proteases found
• This is because at each step one protease can cleave many molecules which can form many proteases
• These proteases can go on to cleave many more molecules to form many more proteases

Question 24

Which pathway of blood clotting is more important?

Answer 24

• The extrinsic pathway is more important

- It is shown that mutations in the extrinsic pathway have a much bigger effect than mutations of the intrinsic pathway

Question 25

How does fibrinolysis occur?

Answer 25

• Tissue plasminogen activator: A serine protease found on endothelial cells which catalyses the activation of plasminogen (in circulation) to plasmin. Plasmin then catalyses the breakdown of the cross linked fibrin cloth into fragments called D-dimers
• Antithrombin: A small protein molecule made by the liver which circulates in the plasma. It binds to heparan, found on endothelial cells, to form active antithrombin which inhibits clotting by inactivating thrombin and other components

Question 26

How are stroke and myocardial infarctions treated?

Answer 26

• Using thrombolytic agents such as tissue plasminogen activator