Thrombosis

Question 1

Why does coagulation occur

Answer 1

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

Question 2

Describe the two main phases of coagulation

Answer 2

• Circulating fibrinogen is not activated and so does not form strands
• When there is tissue damage/inflammation there is primary aggregation and activation of platelets - the surface of platelets is an important component enabling the clotting cascade which is needed to make thrombin
• There is also a secondary conversion of fibrinogen into fibrin caused by thrombin - the fibrin forms strands that solidify the agglutinated platelets to prevent blood loss

Question 3

Describe how coagulation and fibrinolysis is balanced

Answer 3

• There is normally a balance between coagulation and fibrinolysis
• Coagulation is always happening to some degree because of tissue damage or inflammation
• Hence anticoagulant/ibrinolytic agents are also present to balance this

Question 4

Describe how anticoagulants prevent thrombosis

Answer 4

• Endothelial cells express various factors inhibiting coagulation
• Nitric Oxide (inhibits platelets)
• Prostaglandin I2 (inhibits platelet activation)
• Antithrombin inhibits clotting when bound to heparan

Question 5

Describe how fibrinolysis reverses thrombosis

Answer 5

The clot is broken down by plasmin which is activated from plasminogen by Tissue Plasminogen Activator (tPA)

Question 6

Briefly describe coagulation

Answer 6

• If endothelial cells become damaged or inflamed, they may favour coagulation, subendothelial cells if disturbed release tissue factor or Von Willebrand factor
• Von Willebrand factor (activates platelets)
• Tissue Factor initiates clotting

Question 7

Describe arterial and venous thrombosis

Answer 7

Arterial thrombosis -
* Mostly result from atheroma rupture or damage to the endothelium (eg. MI, stroke)
* Platelet-rich ‘white’ thrombus - mostly primary
* May block downstream arteries

Venous thrombosis -
* Often results from stasis or a hyper-coagulant state (eg DVT)
* Platelet-poor ‘red’ thrombus - mostly secondary
* May move to lungs

Question 8

Describe Virchow’s Triad

Answer 8

• Stasis - static blood lacks kinetic energy and tends to clot
• Hyper-coagulant state - e.g. infection/sepsis, genetic predisposition or drugs like HRT
• Endothelial damage e.g. from surgery or a cannula

Question 9

Describe the involvement of valves in thrombosis

Answer 9

• Contraction of nearby muscles constrict the veins acting as a pump to return blood to the heart
• Valves in the veins prevents backflow of blood
• The blood tends to eddy currents - blood contacts the valve and so changes direction - increases the risk of stasis
• Damaged valves may not close completely allowing blood to flow in the wrong direction and pool in the legs

Question 10

Describe deep vein thrombosis

Answer 10

• If venous return is blocked, the affected organ becomes congested with fluid
• There is increased pressure so more filtration
• The risk is that the thrombus may become dislodged and make its way back to the heart

Question 11

Describe what the fate of a thrombus may be

Answer 11

• Resolution e.g. thrombolysis
• Embolism e.g. moved to another location and blocks a vessel - more likely to go back to heart in vein and to block another vessel in an artery
• Organised - becomes covered by the endothelium - narrower vessel but blood flow is still possible
• Recanalised and organised - holes made in the thrombus and lined with endothelium to form a new lumen

Question 12

State the difference between proximal and distal deep vein thrombosis

Answer 12

Proximal deep vein thrombosis - higher risk of pulmonary embolism and post thrombotic syndrome

Distal deep vein thrombosis- rarely cause pulmonary embolism and rarely cause post thrombotic syndrome

Question 13

Describe the symptoms of post thrombotic syndrome

Answer 13

• 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 increased tissue permeability
• Pain, swelling, discoloration and ulceration can follow

Question 14

Describe how a venous thrombosis can lead to a pulmonary embolism

Answer 14

• A thrombus in the veins will travel back to the right side of the heart if dislodged (an embolus)
• From the right side of the heart it will then pass into the pulmonary circulation
• A pulmonary embolism is a blockage in a pulmonary artery - can cause a decreased blood flow to a large area of the lungs which will reduce oxygen/carbon dioxide exchange so becomes life threatening

Question 15

Describe what happens when there is tissue damage

Answer 15

• Endothelial cells are elongated cells that extend across many subendothelial cells which are exposed when endothelial cells are damaged
• These exposed subendothelial cells express von willebrand factors - glycoproteins that normally circulate in the blood
• The primary function of von willebrand factors is to bind to other proteins so binds to subendothelial collagen as well as collagen, platelets, and some coagulation proteins (especially VIII)

Question 16

Describe how platelets adhere to the subendothelial collagen

Answer 16

• Damaged endothelium exposes Von Willebrand factor on subendothelial cells which activates platelets
• Circulating Von Willebrand factor may bind to exposed subendothelial cells
• Activated endothelial cells can also express Von Willebrand factor

Question 17

Describe how platelets are activated

Answer 17

• Activated platelets release Thromboxane A2 (TxA2) & 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/IIIa
• Platelets can also be activated by thrombin, collagen and many other mediators

Question 18

Describe platelet aggregation

Answer 18

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

Question 19

Describe what aggregated platelets provide for coagulation

Answer 19

• Once a clump of platelets aggregate they form a negatively charged surface which is required for coagulation
• Exposure of Tissue Factor (TF) expressing cells during injury also allows the complex formation of TF with coagulation factor VII
• Coagulation involves the conversion of fibrinogen to fibrin and then crosslinking of the fibrin clot

Question 20

Describe the common pathway of coagulation

Answer 20

• Clotting cascade produces activated factor ten Xa which is a protease that catalyses the conversion of prothrombin to thrombin
• Thrombin is a protease that cleaves fibrinogen into fibrin - fibrinogen is a large molecule present in plasma - forms insoluble fibrin once cleaved
• Fibrinogen promotes blood clotting by forming bridges between and activating blood platelets by binding to their GPIIb and IIIa surface membrane fibrinogen receptor
• Fibrin forms long polymers which hold activated platelets together in a blood clot
• Once there is enough thrombin present factor thirteen is activated and causes cross linking of fibrin, further stabilising the clot

Question 21

Describe briefly the 2 pathways that precede the common pathway

Answer 21

Extrinsic pathways -
- Begins in the vessel wall
- Damaged endothelial cells release tissue factor - the greater the amount of damage the more is released
- Tissue factor combines with calcium on negatively charged platelet surface and activates factor VII
- The VIIa tissue factor complex can be quickly inactivated by antithrombin in vivo

Intrinsic pathway -
- Begins in the bloodstream
- Activated when blood is exposed to collagen
- Activated when blood is put onto a charged surface such as glass
- Defects in the factors in this pathway have smaller physiological effects than in extrinsic pathway mutations

Question 22

Describe the role of tissue plasminogen activator in fibrinolysis

Answer 22

• Tissue plasminogen activator is a serine protease found on endothelial cells which catalyses the activation of circulating plasminogen into plasmin
• Plasmin catalyses the breakdown of cross linked fibrin clot into fragments called D dimers

Question 23

Describe the importance of antithrombin in anticoagulation

Answer 23

• A small protein molecule made by the liver that circulates in the plasma
• Heparan is expressed by endothelial cells and binds to the enzyme inhibitor antithrombin III causes a conformational change that results in AT activation
• The activated AT then inactivates thrombin, factor Xa, factor VII and other components of the clotting cascade
• Some of these thrombolytic agents such as tissue plasminogen activator and related compounds are used to treat strokes and myocardial infarctions