Haemostasis basics

Question 1

describe the 2 primary components of a thrombus.

Answer 1

1. Platelet plug
   - circulating platelets adhere to site of injury and forms a temporary plug
   - aggregation of platelets = primary haemostasis
2. Fibrin clot
   - coagulation factor proteases are assembled and activated in a sequence resulting in the production of thrombin
   - thrombin = essential for production of fibrin –> cross-links to form a stabilised meshwork around the platelet plug = secondary haemostasis

Question 2

State was is meant by thrombocytopenia.

Answer 2

Platelet count < 150 x 10^9 per litre

Question 3

State was is meant by thrombocytosis.

Answer 3

Platelet count > 450 x10^9 per litre

Question 4

What is released from endothelial cells that prevents platelet adhesion?

Answer 4

Nitric oxide and prostacyclin

Question 5

What is released from endothelial cells that causes vasoconstriction?

Answer 5

Endothelin

Question 6

When does the production of nitric oxide and prostacyclin cease?

Answer 6

When endothelium is damaged and/or collagen is exposed

Question 7

What occurs when endothelium is damaged and collagen exposed?

Answer 7

• Von Willebrand factor is released from endothelium and binds to the exposed collagen
• VWF binds to platelet GP1b receptor
• VWF forms a ‘bridge’ between collagen and some platelets
• These platelets then express GP2b/3a receptors –> binds fibrinogen –> binds more platelets –> forms a meshwork (platelet aggregation)
• The binding of platelets activates more platelets - change shape
• Release of ADP, TXA2 and 5-HT
• 5-HT acts on local smooth muscle cells, causes vasoconstriction and minimises blood loss

Question 8

What initiates the coagulation cascade?

Answer 8

exposure of blood to tissue factor

Question 9

Describe the process of the extrinsic pathway. What can be used to test the extrinsic pathway?

Answer 9

• Factor VII is exposed to tissue factor (factor III)
• Factor VII then becomes Factor VIIa
• Factor X – Factor VIIa + Ca2+ –> Factor Xa (tenase complex)
• Prothrombin – Factor Xa + Ca2+ –> Thrombin

Test: Prothrombin time

Question 10

Describe the process of the intrinsic pathway. What can be used to test the intrinsic pathway?

Answer 10

• Factor XII is activated by exposure to collagen + tissue factor (not always needed)
• Factor XII –> XIIa
• XI – XIIa –> XIa
• IX – XIa + Ca2+ –> IXa
• X – IXa + Ca2+ –> Xa

**IXa on its own converts enough prothrombin to thrombin by forming a small amount of Xa –> damaged endothelium is not always required

Test: Activated partial prothrombin time

Question 11

What is the common pathway?

Answer 11

The conversion of prothrombin –> thrombin and the formation of a stable clot

Question 12

How is a stable clot formed?

Answer 12

Prothrombin – Xa + Ca2+ + V –> thrombin
Fibrinogen – Thrombin –> Fibrin
XIII – thrombin –> XIIIa
XIIIa increases cross-linking in fibrin and forms a stable clot

Question 13

What factors are involved in the amplification of thrombin formation?

Answer 13

• Thrombin formed in the extrinsic pathway forms a +ve feedback loop
• Thrombin converts:
  1. V –> Va
  2. VIII –> VIIIa
  3. XI –> XIa
• XIa converts IX –> IXa
• VIIIa and IXa convert X –> Xa (VIIa helps upregulate the production of Xa to a lesser extent)
• Va increases the effectiveness of Xa
• therefore more prothrombin –> thrombin

Question 14

What do bleeding time and International Normalised Ratio (INR) measure?

Answer 14

Bleeding time = platelet plug formation and platelet function
INR = Coagulability of blood

Question 15

What is a normal INR value or healthy patients and patient on blood thinners?

Answer 15

Healthy patient = 0.8-1.2

On blood thinners = ~2-3

Question 16

What is the difference between haemophilia A and haemophilia B?

Answer 16

A = deficiency of factor VIII --> reduced effectiveness of +ve feedback loop
B = deficiency of factor IX

Question 17

What is plasmin? What keeps plasmin in its inactive form?

Answer 17

Usually circulates in the blood in its inactive form (plasminogen)
Stays in inactive form by action of alpha2-antiplasmin
In its active form in removes clots when damaged tissue has healed (fibrinolysis)

Question 18

What is TPA, what is its role?

Answer 18

TPA = tissue plasminogen activator
It is released from normal endothelial cells (when wound has healed)
Converts plasminogen to plasmin (also catalysed by urokinase plasminogen activator, kallikrein and FXIIIa)
Prevents clot from extending into healthy tissue
TPA production is suppressed at site of injury

Question 19

What is D-dimer? Why is it measured, what does it indicated?

Answer 19

It is a product of fibrin breakdown
Measure in patients with suspected thrombotic disorders (such as DVT)
When in low levels this indicates that clot is not present
When in high levels this indicates that a clot is present (increased fibrin breakdown)

Question 20

What does vitamin K do in regards to blood? What is it used as a treatment for?

Answer 20

It allows binding to Ca2+
Required for the full effectiveness of F VII, IX and X
It is used as a treatment for warfarin overdose

Question 21

What can happen if someone has a lack of vitamin K? What are the risk factors for vitamin K deficiency?

Answer 21

Lack of vitamin K = uncontrolled bleeding (increased INR, may result in unstable clots) 
Risk factors for Vit K deficiency:
- liver disease
- poor diet
- poor absorption 
- antibiotics

Question 22

What is the effect of warfarin on coagulation factors and prothrombin time?

Answer 22

Warfarin competes for sites that Vit K binds to and therefore reduces the effectiveness of FVII, IX and X
Increases prothrombin time

Question 23

What is the effect of heparin on coagulation factors?

Answer 23

Inhibits thrombin and factor Xa

Question 24

How do DOACs/NOAcs act? Why are they used over heparin and warfarin? What complciations can occur with these drugs?

Answer 24

Direct thrombin and FXa inhibitors
They have less serious side effects + more predictable anticoagulation activity (therefore less monitoring and dose adjustment)
Used in patients with kidney problems
*There is no antidote for FXa inhibitors –> can become a problem if emergency surgery is required