Haemostasis & thrombosis

Question 1

Describe a typical presentation of someone with DVT

Answer 1

• Immobile for long time after major surgery
• Right calf swollen & collateral superficial veins present
• Localised tenderness & pitting oedema

Question 2

In addition to basic observations, state the other specific investigations carried out to diagnose DVT

Answer 2

Two-level Wells score

Blood taken for D-dimer testing (positive = DVT) & proximal leg vein scan is arranged

Question 3

What are the three stages in the cell based theory of coagulation? State which types of drugs target each of the different stages.

Answer 3

Initiation – small-scale production of thrombin – ANTI-COAGULANTS
Amplification – large-scale thrombin production on the surface of platelets – ANTI-PLATELETS
Propagation – thrombin mediated generation of fibrin strands - THROMBOLYTICS

Question 4

Describe the process of initiation.

Answer 4

TF bearing cells activate factor 5 and factor 10 forming the prothrombinase complex (5a + 10a)
The prothrombinase complex converts prothrombin to thrombin

Question 5

What is responsible for the inactivation of factors 2a (thrombin) and 10a?

Answer 5

Antithrombin (AT-III)

Question 6

State some drugs that target the initiation stage of coagulation/anti-coagulants

Answer 6

Dabigatran (NOAC) – factor 2a inhibitor given orally
Rivaroxaban (NOAC) – factor 10a inhibitor given orally
Heparin – potentiates antithrombin given IV/SC
Low Molecular Weight Heparin (e.g. Dalteparin) – activates antithrombin (preferentially targets factor 10a) given IV/SC
Warfarin – vitamin K epoxide reductase inhibitor given orally; inhibits the production of factors 2, 7, 9 and 10

Note that the oral anticoagulants are used as maintenance treatment

Question 7

A patient with DVT may present with chest pain, dyspnoea and tachypnoea. What might this indicate and why? How do you treat?

Answer 7

CTPA confirms pulmonary embolism (PE); the thrombus embolises and travels up into the pulmonary vasculature where it gets stuck.

• Continue with LMWH and heparin
• Maintenance treatment with rivaroxaban/warfarin

Question 8

Describe Virchows triad (risk factors for thrombosis)

Answer 8

1. Blood flow slow/stagnating => no replenishment of anticoagulant factors & balance adjusted in favour of coagulation
2. Imbalance between pro-coagulation & anticoagulation factors
3. Damaged endothelia => blood exposed to pro-coagulation factors

Question 9

What is the difference between red and white thrombi?

Answer 9

Red – forms in veins – rich in fibrin and red blood cells

White – forms in arteries – rich in platelets and macrophages (foam cells)

Question 10

A patient presents with:
- a history of hypertension & hyperlipidaemia
- shortness of breath, sweating, dizziness & chest pain
Upon investigation:
- No changes on ECG & elevated troponin

What would be the diagnosis?

Answer 10

Non-ST elevated Myocardial Infarction (NSTEMI)

Question 11

Briefly describe the difference between an NSTEMI and STEMI, including the drug types you would use for each

Answer 11

NSTEMI:
‘White’ thrombus; partially occluded coronary artery
Treatment: antiplatelets

STEMI:
‘White’ thrombus; fully occluded coronary artery
Treatment: antiplatelets & thrombolytics

Question 12

Explain, in detail, how thrombin causes platelet activation in the propagation stage

Answer 12

• Thrombin binds to PAR (protease-activated receptor; GPCR) on the platelet membrane
• This causes calcium release form internal stores => increased intracellular Ca2+ concentration
• This stimulates ADP exocytosis from dense granules
• The ADP then binds to P2Y12 receptors (ADP receptor) on the same platelet or on neighbouring platelets, which leads to platelet activation/aggregation
• Thrombin binding to the PAR also liberates arachidonic acid
• The arachidonic acid is converted by COX to thromboxane A2
• Thromboxane A2 increases expression of GlpIIb/IIIa (which is involved in platelet aggregation)

Question 13

State three drugs that target the amplification stage of coagulation and explain how they act.

Answer 13

1. Aspirin (oral) = irreversible COX1 inhibitor – it reduces the production of thromboxane by platelets
2. Clopidogrel (oral) = irreversible ADP (P2Y12) receptor antagonist
3. Abciximab (IV/SC) = monoclonal antibodies directed at GlpIIb/IIIa (limited use and only be specialists)

Question 14

What are the indications of these anti-platelet drugs?

Answer 14

Arterial thrombosis:

• Acute coronary syndromes – myocardial infarction (STEMI/NSTEMI)
• Atrial fibrillation – prophylaxis of stroke

Question 15

A patient presents with:

• Severe headache, dizziness & loss of coordination
• Numbness in the face, arms and legs

What is the likely diagnosis?

Answer 15

Ischaemic stroke

Note that a CT scan will eliminate the possibility of haemorrhagic stroke

Question 16

Describe the propagation stage of coagulation.

Answer 16

Large-scale thrombin production;

Thrombin converts fibrinogen to fibrin so fibrin strands are generated

Question 17

Name an important thrombolytic and explain how it acts.

Answer 17

Alteplase (IV) – it is a recombinant tissue plasminogen activator (tPA) i.e. converts plasminogen into plasmin

Plasmin is a protease that degrades fibrin

Question 18

What are the indications of thrombolytics?

Answer 18

• First line treatment for stroke
• STEMI

Note: Anticoagulants & anti-platelets DO NOT remove pre-formed clots and so aren’t used in medical emergencies