Haemostasis & thrombosis

Question 1

describe the initial stages of thrombosis

-molecular level

Answer 1

Small-scale thrombin production:
Tissue factor (TF)
-TF bearing cells activate factors X & V forming  prothrombinase complex

Prothrombinase complex
-This activates factor II (prothrombin) creating factor IIa (thrombin)

Antithrombin (AT-III)
-AT-III  inactivates fIIa & fXa

Question 2

what are the anticoagulants?

Answer 2

Inhibit factor IIa
Dabigatran (oral) - factor IIa inhibitor

Inhibit factor Xa
Rivaroxaban (oral) - factor Xa inhibitor

Increase activity of AT-III
Heparin (IV, SC) - activates AT-III (fIIa & fXa)
Low-molecular weight heparins (LMWHs, e.g.Dalteparin) - activate AT-III (fXa)

Reduce levels of other factors
Warfarin (oral) - vitamin K antagonist
Vitamin K - required for generation of factors II, VII, IX & X

Question 3

what treatment would you provide?

Presentation
Immobile for 3 weeks after major surgery
Right calf swollen & collateral superficial veins present
Palpation - localised tenderness & pitting oedema

Investigations
Blood pressure = 112/73, Pulse rate = 68 bpm, Respiratory rate = 12 breaths per minute, SpO2 = 98%
Two-level Wells score = 5. Blood taken for D-dimer testing & proximal leg vein scan is arranged

Answer 3

Positive D-dimer test suggests diagnosis of deep-vein thrombosis (DVT)  interim treatment with parenteral anticoagulant.  DALTEPARIN
Ultrasound scan confirms DVT  maintenance treatment with oral anticoagulant  RIVAROXABAN / WARFARIN

Question 4

what are the risk factors for DVT and pulmonary embolism

Answer 4

risk factors- Virchow’s triad

1. Rate of blood flow
   Blood flow slow/stagnating  no replenishment of anticoagulant factors & balance adjusted in favour of coagulation
2. Consistency of blood
   Imbalance between pro-coagulation & anticoagulation factors
3. Blood vessel wall integrity
   Damaged endothelia  blood exposed to pro-coagulation factors

Question 5

acute coronary syndrome

background NSTEMI

Answer 5

Background - NSTEMI
Non-ST elevated myocardial infarction (MI)
‘White’ thrombus  partially occluded coronary artery
Treatment: antiplatelets

Question 6

acute coronary syndrome

background STEMI

Answer 6

Background - STEMI
ST elevated myocardial infarction
‘White’ thrombus  fully occluded coronary artery
Treatment: antiplatelets & thrombolytics

Question 7

acute coronary syndrome caused by?

Answer 7

Caused by:
Damage to endothelium
Atheroma formation
Platelet aggregation

Question 8

thrombosis: amplification stage

- cellular level

Answer 8

AMPLIFICATION STAGE
Cellullar level

Platelet activation & aggregation:
Thrombin
Factor IIa  activates platelets

Activated platelet
Changes shape
Becomes ‘sticky’ and attaches other platelets

Question 9

amplification- platelet activation

-molecular level

Answer 9

Molecular level
Thrombin - binds to protease-activated receptor (PAR) on platelet surface.
PAR activation  rise in intracellular Ca2+
Ca2+ rise  exocytosis of adenosine diphosphate (ADP) from dense granules

1. ADP receptors
   ADP activates P2Y12 receptors  platelet activation/ aggregation
2. Cyclo-oxygenase
   PAR activation  liberates arachidonic acid (AA)
   Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA
3. Glycoprotein IIb/IIIa receptor (GPIIb/IIIa)
   TXA2 activation  expression of GPIIb/IIIa integrin receptor on platelet surface
   GPIIb/IIIa - involved in platelet aggregation

Question 10

how do drugs combat platelet activation- name the drugs:

Answer 10

Prevent platelet activation/ aggregation
Clopidogrel (oral) - ADP (P2Y12) receptor antagonist

Inhibit production of TXA2
Aspirin (oral) - irreversible COX-1 Inhibitor
NB: High doses no more effective BUT more side-effects

Prevent platelet aggregation
Abciximab (IV, SC)
Limited use AND only by specialists

Question 11

presentation and treatment of N STEMI

Answer 11

Presentation: chest pain, SOB
Investigations: ECG, troponin

Question 12

presentation and investigation for DVT and PE

Answer 12

Presentation: swollen leg
Investigations: 2-level Wells score

Question 13

propagation: thrombolytics

cellular levels

Answer 13

Generation of fibrin strands
Activated platelets
Large-scale thrombin production

Thrombin
Factor IIa  binds to fibrinogen and converts to fibrin strands

Question 14

thrombolytics: mechanism

Answer 14

Anticoagulants & anti-platelets - DO NOT remove pre-formed clots

Thrombolytics
Convert plasminogen into plasmin
Plasmin - protease degrades fibrin
Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA)

Question 15

stroke presentation and investigations

Answer 15

Presentation: headache, dizziness & numbness in the face, arms and legs
Investigations: CT scan

Question 16

LO

Coagulation: explain the processes of coagulation, platelet activation and the actions of fibrin

Answer 16

Initial - tissue Factor presentation -> Prothrombinase-mediated formation of factor IIa (thrombin)
Amplification - thrombin (fIIa)-mediated platelet activation -> ADP activates P2Y12 receptor -> COX & GPIIb/IIa
Propagation - thrombin-mediated conversion of fibrinogen -> fibrin strands

Question 17

LO
Thrombosis: explain how a thrombus can form within a vein and identify the drugs used to treat deep vein thrombosis and pulmonary embolism

Answer 17

Thrombus more likely to form in a vein when risk factors affect the following: 1) Rate of blood flow, 2) Consistency of blood, 3) Blood vessel wall integrity (Virchow’s triad).
DVT & PE treatment: Anticoagulants – dalteparin (SC, antithrombin activator), heparin (SC/IV, antithrombin activator), rivaroxaban (oral, fXa inhibitor), warfarin (oral, vitamin K antagonist)

Question 18

Atherosclerosis treatment: identify the drugs used in the prevention and treatment of atherosclerosis and the subsequent rupture of an atherosclerotic plaque

Answer 18

Treatment of atherosclerosis -> antiplatelet drugs*
Antiplatelet drugs fall into 3 main categories:
COX inhibitors (aspirin)
P2Y12 receptor antagonists (clopidogrel)
GPIIb/IIIa receptor antagonists (abciximab)

Subsequent rupture of atherosclerotic plaque**  thrombolytics
Thrombolytic drugs (alteplase)  tissue plasminogen activator

• Antiplatelets used for prophylaxis, not specifically treatment of atherosclerosis
• • Thrombolytics can be used to treat ruptured plaques but mainly indicated for ischaemic stroke