Thrombosis

Question 1

What is the main cause of arterial thrombosis?

Answer 1

Atheroma rupture - causing MI or stroke.

Question 2

What is the main cause of venous thrombosis?

Answer 2

Stasis or a hyper-coagulant state.

Question 3

Compare and contrast “white” and “red” thrombi.

Answer 3

White thrombi - platelet-rich, form in arteries.

Red thrombi - platelet-poor, form in veins.

Question 4

Describe the process of primary fibrinolysis (natural clot breakdown).

Answer 4

Plasminogen, the inactive form of plasmin, is produced by the liver. Plasminogen is activated to plasmin by tPA (tissue plasminogen activator). Plasmin cleaves the insoluble fibrin mesh, forming soluble fibrin fragments (including D-dimer).

Question 5

Describe Virchow’s triad.

Answer 5

Virchow’s triad describes the 3 main factors that contribute to thrombosis:

1. Stasis - static blood lacks kinetic energy - tends to clot.
2. Hyper-coagulant state.
3. Endothelial damage - e.g. surgery or cannula.

Question 6

How do venous valves contribute to risk of thrombosis?

Answer 6

Blood tends to accumulate around valves, increasing risk of stasis.

Question 7

What are the 4 broad fates of a thrombus?

Answer 7

1. Resolution - clot is dissolved.
2. Embolism - clot migrates and lodges in vessel.
3. Organised - endothelium built on top of clot.
4. Recanalised and organised - small blood vessels drilled through clot and endothelium built on clot.

Question 8

What endothelial and sub-endothelial mediators inhibit coagulation?

Answer 8

NO - inhibits platelets.
Prostaglandin I2 (PGI2) - inhibits platelets.
Antithrombin (AT) - inhibits clotting.
tPA (tissue plasminogen activator) - “unclots”.

Question 9

Contrast the clinical significance of proximal and distal DVT.

Answer 9

Proximal DVT - higher risk of pulmonary embolism and post-thrombotic syndrome.

Distal DVT - rarely causes pulmonary emboli and post-thrombotic syndrome.

Question 10

Pulmonary embolism leads to what outcomes?

Answer 10

1. May be asymptomatic if embolus is small.

2. May cause rapid death if embolus is large - due to massive V/Q mismatch.

Question 11

In which veins is a DVT classed as distal?

Answer 11

Tibial and small saphenous.

Question 12

Why does DVT not cause heart attacks?

Answer 12

Thrombus in vein travels to right side of heart, not left.

Question 13

What are the 4 main platelet activators?

Answer 13

1. ADP
2. Thromboxane A2
3. Thrombin
4. Collagen

Question 14

Describe the process of primary haemostasis: platelet activation and aggregation.

Answer 14

1. Sub-endothelial cells express vWF (von Willebrand Factor), which activates platelets by forming a bond with them.
2. Activation of platelets by vWF causes translocation of GpIIb/IIIa (a glycoprotein complex) to the platelet surface.
   Aggregation is promoted by ADP, thrombin, TxA2.
3. Activated platelets release the contents of their granules: ADP, serotonin, vWF, TxA2.
4. TxA2, ADP and other mediators induce GpIIb/IIIa to act as receptors for fibrinogen.
5. Fibrinogen acts as a tether, binding platelets together.

Question 15

A negatively charged platelet surface is required for successful coagulation. Explain how this surface is created.

Answer 15

Many activated platelets that are aggregated together express negatively-charged phospholipids on their surfaces.

Question 16

Describe the intrinsic coagulation cascade.

Answer 16

Same as the extrinsic pathway except FXa is activated by FIXa-FVIIIa complexes rather than TF and FXIIa. FXa goes on to activate thrombin, which forms a clot by cleaving soluble fibrinogen into insoluble fibrin.

Question 17

Describe the extrinsic (tissue factor) coagulation cascade.

Answer 17

1. TF activates FVIIa, which activates FXa, which activates thrombin.
2. Thrombin, a protease, cleaves circulating soluble fibrinogen into an insoluble fibrin mesh, which forms a thrombus (clot).
3. Thrombin activates platelets directly. It also activates the endothelial cells, causing them to release more vWF. Thrombin is therefore responsible for amplification.
4. FIXa and FXa bind to platelets with their cofactors, FVIIIa and FVa respectively. This process requires calcium ions.
5. The FXa-FVa-Ca2+ complex stimulates rapid thrombin production - amplification.

Question 18

What is thrombin and how is it activated?

Answer 18

Thrombin is FIIa - its inactive form, prothrombin, is FII. Thrombin is activated when prothrombin is cleaved by the prothrombinase complex: FXa-FVa.

Question 19

How does antithrombin (AT) inhibit clotting?

Answer 19

AT is a serine protease inhibitor that inhibits thrombin itself, along with other coagulation factors, thus preventing the coagulation cascade.