Thrombosis

Question 1

What is thrombosis

Answer 1

Formation of a blood clot within a blood vessel

Question 2

How does haemostasis lead to thrombosis

Answer 2

Coagulation prevents blood loss
Inflammation activate coagulation which promotes inflammation
Coagulation is an inflammatory response

Question 3

Stages of haemostasis

Answer 3

Primary - aggregation of platelets

Secondary - fibrinogen –> fibrin

Question 4

Steps for coagulation

Answer 4

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

Question 5

Describe platelet adherence

Answer 5

• Von Willebrand factor on subendothelial cells activates platelets
• Circulating VWF may bind to exposed subendothelial cells
  Activated endothelial cell express VWF

Question 6

Describe platelet activation

Answer 6

• 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

Question 7

Describe Platelet aggregation

Answer 7

• Fibrinogen acts as a tether, holding platelets together = aggregation
• Fibrinogen is the soluble precursor to fibrin and in the circulation

Question 8

What is platelet substrate for coagulation

Answer 8

• 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

Question 9

Steps for the common pathway for coagulation

Answer 9

1) Factor Xa cleaves prothrombin to form thrombin
2) Thrombin is a protease that cleaves fibrinogen to fibrin

Fibrin fibres into solid clot

Question 10

How does fibrinogen promote blood clotting

Answer 10

Form bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor

Question 11

What does thrombin cleave

Answer 11

Fibrinogen into fibrin

Factors V and VIII to give Va and VIIIa

Question 12

How is a tenase complex formed

Answer 12

VIIIa + IXa = Xa

Question 13

How is a prothrombinase formed

Answer 13

Va + Xa = Thrombin

Question 14

Extrinsic pathway

Answer 14

Begins in the vessel wall

Damaged endothelial cells will release factor III (tissue factor) - greater amount of damage = more released

Question 15

Steps for extrinsic pathway

Answer 15

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

Question 16

Intrinsic pathway

Answer 16

• 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

Question 17

Defects in pathways

Answer 17

Defects in factors of the extrinsic pathway have larger physiological effects than mutations int he enzymes of the intrinsic pathway

Question 18

Arterial thrombosis

Answer 18

Mostly results from atheroma rupture or damage to endothelium
Platelet rich ‘white’ thrombosis - mostly primary
may block downstream arteries

Question 19

Venous thrombosis

Answer 19

Results from stasis or a hyper coagulant state
Platelet poor ‘red’ thrombus - mostly secondary
May move to lungs

Question 20

Virchow’s triad

Answer 20

Stasis, Hyper coagulant state, Endothelial damage

Question 21

Involvement of valves

Answer 21

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

Question 22

What happens in deep vein thrombous

Answer 22

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

Question 23

What are the different fates of a thrombus

Answer 23

Resolution
Embolism
Organised
Recanalised and organised

Question 24

Proximal DVT

Answer 24

Higher risk of pulmonary embolism and post thrombotic syndrome (pain swelling, maybe even ulcers)

Question 25

Distal DVT

Answer 25

Rarely cause pulmonary embolism and post thrombotic syndrome

Question 26

Post thrombotic syndrome

Answer 26

• 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

Question 27

What is tissue plasminogen activator

Answer 27

Serine protease found on endothelial cells

Question 28

What does tissue plasminogen activator do

Answer 28

Catalyses the activation of circulating plasminogen into plasmin

Question 29

What does plasmin do

Answer 29

Catalyses the breakdown of cross linked fibrin clot into fragments called D-dimer

Question 30

What is antithrombin

Answer 30

Small protein molecule made by the liver that circulates in the plasma

Question 31

What is Heparin and what does it do

Answer 31

Is expressed by endothelial cells and binds to the enzyme inhibitor antithrombin II (AT) causing a conformational change that results in AT activation

Question 32

What does activated AT do

Answer 32

Inactivates thrombin, factor Xa, factor VII and other components of the clotting cascade