Thrombosis

Question 1

Why does coagulation occur?

Answer 1

Immunological response
- Prevents blood loss

Question 2

Describe arterial thrombosis.

Answer 2

• Mostly result from an atheroma rupture or damage to the endothelium (eg. MI, stroke)
• Platelet-rich thrombosis - mostly primary haemostasis
• May block downstream arteries - since they become narrower and more likely to be obstructed

Question 3

Describe venous thrombosis

Answer 3

• Often results from stasis or a hyper-coagulant state (eg. DVT)
• Platelet-poor thrombus - mostly secondary haemostasis
• May move to the lungs

Question 4

List some factors/substances that affect the coagulation-fibrinolysis balance. PART 1

Answer 4

• Tissue plasminogen activator: initiates fibrinolysis
• von Willebrand factor: activates platelets - in coagulation
• Tissue factor: initiates clotting - in coagulation

Question 5

List some factors/substances that affect the coagulation-fibrinolysis balance. PART 2

Answer 5

• Antithrombin: inhibits clotting
• Prostaglandin I2: inhibits platelets
• Nitric oxide: inhibits platelets
  INVOLVED IN FIBRINOLYSIS

Question 6

What is Virchow’s Triad?

Answer 6

Describes the three categories that are thought to contribute to thrombosis

Question 7

What are the components of Virchow’s Triad?

Answer 7

• STASIS: static blood lacks kinetic energy and tends to clot
• HYPER-COAGULANT STATE: eg. infection e.g sepsis, hereditary, drugs (eg. HRT)
• ENDOTHELIAL DAMAGE: eg. surgery or cannula

Question 8

How are the valves involves in stasis?

Answer 8

Blood tends to eddy around the valves, increasing the risk of stasis.

Question 9

What are the four possible fates of a thrombus?

Answer 9

• RESOLUTION
• EMBOLISM
• ORGANISED
• RECALANISED AND ORGANISED

Question 10

What occurs during resolution?

Answer 10

Fibrinolytic system destroys the whole clot over time

Question 11

What occurs during embolism?

Answer 11

• Thrombus dislodges and goes to the heart/lungs
• This is life threatening

Question 12

What occurs during organisation?

Answer 12

• Endothelial cells grow over the clot
• Person more prone to having another clot due to the narrower vein

Question 13

What occurs during recalanisation?

Answer 13

• Thrombus is so big that it can’t be grown over
• Can be grown through

Question 14

What is the difference between a proximal DVT and a distal DVT?

Answer 14

With a proximal DVT, there is a higher risk of a pulmonary embolism and post-thrombotic syndrome.
- Rare in distal DVT

MINOR DIFFERENCE: Proximal affects upper leg. Distal affects lower leg.

Question 15

What does a platelet release when it has been activated?

Answer 15

Releases thromboxane A2 and adenosine diphosphate (ADP)
- Both induce receptors for fibrinogen.

Question 16

Describe the common pathway. PART 1

Answer 16

• Factor IXa activates Factor X by proteolysis to create Factor Xa.
• Factor Xa (FXa) cleaves prothrombin to form thrombin (FIIa).
• Thrombin (FIIa) is a protease that cleaves fibrinogen into fibrin.

Question 17

Describe the common pathway. PART 2

Answer 17

• Thrombin cleaves Factors V and VIII to give FVa and FVIIIa. This is known as amplification. It can also activate platelets.
• FVa and FVIIIa together with Ca2+ form the tenase complex and prothrombinase complex
• These complexes assemble on the negatively charged phospholipid surfaces in the activated platelets.

Question 18

What does fibrinogen promote?

Answer 18

• Blood clotting by activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor

Question 19

Describe the prothrombinase complex.

Answer 19

• Negative surface of the activated platelet causes calcium, prothrombin and Factor Xa and Va to bind.
• Components all bind by a particular domain of glutamic acids (GLA); they stabilise the complex. Synthesis is Vitamin K dependent.

Question 20

What can formation of the GLA domain be inhibited by?

Answer 20

Warfarin

Question 21

What is fibrinolysis?

Answer 21

The breakdown of fibrin into fibrinogen
- Reverse of coagulation

Question 22

How does coagulation occur?

Answer 22

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

Question 23

How is coagulation inhibited?

Answer 23

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

Question 24

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

Answer 24

• Blocks venous return causing the leg to become congested with fluid
• Increases capillary pressure so filtration increases. Causes oedema
• Hypoxia may occur as some cells are not supplied with oxygen
• Thrombosis might become dislodged and make its way to the heart

Question 25

What happens during post-thrombotic syndrome? PART 1

Answer 25

- Occurs when a big vein is blocked by a clot - Causes inflammation along with damage to valves from the thrombus - Causes valvular incompetence which combines with persistent venous obstruction to cause small superficial veins to haemorrhage

Question 26

What happens during post-thrombotic syndrome? PART 2

Answer 26

- Increase in tissue permeability leading to oedema (swelling) due to release of inflammation factors - Pain, swelling and ulceration follows

Question 27

What happens when a small venous thrombus reaches the heart? PART 1

Answer 27

- Highly unlikely to be lodged in the heart - Will pass through the right atrium and ventricle into the pulmonary artery and reach the lungs - Pass down the arterioles and may get lodged blocking these arterioles.

Question 28

What happens when a small venous thrombus reaches the heart? PART 1

Answer 28

- Leads to the formation of a slight VQ mismatch - area of the lung that is not perfused but is well ventilated - Cause hypoxia and in severe cases will eventually leads to necrosis or oedema

Question 29

What happens when a large venous thrombus reaches the heart?

Answer 29

- Pass through the right atria and the right ventricle - Enters the pulmonary artery and becomes lodged - Causes embolism that can block both pulmonary arteries

Question 30

How are blood clots formed? PART 1

Answer 30

- Von Willebrand factors bind to and activate platelets. - Activated platelets release Thromboxane A2 and Adenosine Diphosphate (ADP) - Bind to receptors on adjacent platelets and increases expression of the fibrinogen receptor (a glycoprotein complex)

Question 31

How are blood clots formed? PART 2

Answer 31

- Fibrinogen binds to its receptor and 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 32

How can subendothelial cells be exposed?

Answer 32

- Tissue damage - Release of inflammatory factors

Question 33

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

Answer 33

- Allows for the amplification of proteases found - One protease can cleave many molecules which can form many proteases

Question 34

Which is more important, the extrinsic or intrinsic pathway?

Answer 34

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 35

What is the role of tissue plasminogen activator?

Answer 35

- 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

Question 36

What is the role of antithrombin?

Answer 36

- A small protein molecule made by the liver which circulates in the plasma. - Binds to heparan, found on endothelial cells, to form active antithrombin which inhibits clotting by inactivating thrombin and other components

Question 37

How are stroke and myocardial infarctions treated?

Answer 37

Using thrombolytic agents such as tissue plasminogen activator

Question 38

What is primary haemostasis?

Answer 38

Aggregation of platelets

Question 39

What is secondary haemostasis?

Answer 39

Conversion of fibrinogen into fibrin

Question 40

What are the three basic steps of fibrinolysis?

Answer 40

- Aggregation of platelets - Conversion of fibrinogen to fibrin - Thrombin converted from prothrombin

Question 41

What do anticoagulants do?

Answer 41

Prevent thrombosis

Question 42

What happens if the endothelial cells get damaged and the subendothelial cells get exposed?

Answer 42

von Willebrand factors will bind to platelets and start a clot

Question 43

What do antithrombin and hepsrin do?

Answer 43

Inhibit clotting prostaglandins, platelets and nitric oxide

Question 44

What is the extrinsic pathway?

Answer 44

- Tissue factor is a receptor for VIIa which is bound to negatively charged platelet phospholipid surface along with calcium. - VIIa activates Xa and the common pathway starts

Question 45

What is the extrinsic pathway triggered by?

Answer 45

Transcription factors which activates factor VII

Question 46

RECAP: Why do the veins need valves?

Answer 46

Prevent backflow of blood

Question 47

RECAP: What would happen if the veins were to contract?

Answer 47

Venous return occurs

Question 48

Describe the process of platelet adherence.

Answer 48

- Von Willebrand factor on subendothelial cells activates platelets. - Circulating Von Willebrand factor may bind to exposed subendothelial cells - Activated endothelial cells can also express von Willebrand factor

Question 49

Describe the intrinsic pathway.

Answer 49

- Begins in the blood stream. It is basically activated when blood is exposed to collagen (or other damaged surfaces). - Activated when you put blood onto a charged surface such as glass.

Question 50

Why are D-dimers measured clinically?

Answer 50

- Measured to see the level of thrombolysis - Degradation products of thrombuses are D dimers