Arterial Thrombosis and Haemostasis
Matthew Harper
mth29@cam.ac.uk
Objectives
• To provide an overview of the pharmacology of anti-platelet drugs used to prevent
arterial thrombosis
• To stimulate interest in thrombosis research
• To encourage students to think critically about pharmacology research, disease
models and clinical trials
Outcomes
• At the end of this lecture series, and following you own reading, you should be able
to:
o Describe how platelet are activated during in thrombosis and haemostasis
o Discuss the main pharmacological properties currently-used anti-platelet
drugs, and how this affects their use as anti-thrombotics
o Discuss sources of variation in the effects of these drugs
o Discuss the methodologies used in researching anti-platelet drugs, at the
levels of basic science and of clinical trials
Synopsis
Lecture 1: Platelets in arterial thrombosis – some initial thoughts – arterial thrombosis –
platelet adhesion, activation and aggregation – signalling towards integrin activation
Lecture 2: Aspirin as an anti-thrombotic – Aspirin – TP antagonists – COX-2 inhibitors –
cardiovascular risk of NSAIDs
Lecture 3: P2Y12 inhibitors as anti-thrombotics – role of P2Y12 – clopidogrel – prasugrel –
cangrelor – ticagrelor – P2Y12 inhibitors without aspirin?
Lecture 4: PAR antagonists as anti-thrombotics – PAR signalling – roles of PAR1 and PAR4 –
vorapaxar – PAR4 antagonists – genetic variation in PAR4
Lecture 5: Where next? – coagulation – Factor XIIa – polyphosphates – neutrophil
extracellular traps – final thoughts
Essay Titles:
How do the pharmacological properties of P2Y12 inhibitors affect their use as
antithrombotic drugs? (1 hour)
Is bleeding an inevitable risk of drugs that prevent arterial thrombosis? (1.5 hours)
Can we prevent thrombosis without disrupting homeostasis? (1.5 hours)
How does patient variability alter response to anti-thrombotics? (1.5 hours)
2018 (Paper 3) To what extent have animal models contributed to the development of anti-
platelet drugs?
2018 (Paper 4) Is bleeding an inevitable risk of drugs that prevent arterial thrombosis?
2017 (Paper 4) Discuss the roles of platelet G protein-coupled receptors (GPCRs) in arterial
thrombosis, and whether they make good targets for anti-thrombotic drug therapy.
2017 (Paper 3) Is protease-activated receptor (PAR1) a useful anti-thrombotic drug target?
,2016 (Paper 3) How do the pharmacological properties of different P2Y12 antagonists affect
their use as anti-thrombotics?
2016 (Paper 4) How does rupture of an atherosclerotic plaque lead to arterial thrombosis?
Lecture 1: Platelets in Arterial Thrombosis
Arterial thrombosis:
- Atherothrombotic diseases are responsible for more than ¼ deaths worldwide.
- The pressure within the vascular system is needed to pump the blood throughout
the body but at the same time if vascular integrity is disturbed, the fluid will be
forced out under pressure, in other words bleeding will take place.
- Haemostatic system protects animals from uncontrollable bleeding in case of injury.
- Haemostasis occurs in 2 stages: 1) platelet aggregation (1st haemostatic plug/cell-
based/1ry haemostasis) and 2) coagulation cascade (2nd haemostatic plug/protein-
based/2ry haemostasis). These processes are not completely distinct – platelet
aggregation is affected by coagulation factors and vice versa.
- In general, platelets are the 1st responders to any site of vascular damage. When
platelets detect vascular damage, they adhere to the site of damage, aggregate and
form a plug. Most of the plug forms outside the vessel and prevents blood loss
without protruding into the lumen of the blood vessel and interfering with the blood
flow.
- Atherosclerosis is the main reason for
thrombosis, which unlike haemostasis
takes place mostly in the lumen of the
vessel and interferes with or completely
blocks the blood flow. When
atherosclerotic plaque ruptures, platelets
recognise this event as vascular damage
and aggregate. Moreover, tissue factor
present in the plaque activates
coagulation. Thus, thrombus made up of
plaque fragments, platelet and
coagulated blood is formed.
- Platelet recruitment preferentially occurs
at regions of high shear and disturbed flow, leading to the formation of
predominantly 'white thrombi' over the site of vascular injury, whereas maximal
fibrin generation occurs in regions of low flow, often leading to the development of a
'fibrin-rich thrombus tail', so both anti-platelet aggregations and anti-coagulants are
important.
Acute Coronary Syndrome (ACS):
- Thrombus may block the coronary vessel either partially or completely.
- Even if the blood vessel is only partially blocked, a part of thrombus may detach and
move into a narrow blood vessel blocking it completely, which is called an embolism.
- It may lead to reduced blood flow to cardiac muscle.
- In the absence of blood supply, muscle tissue becomes ischaemic due to a shortage
of oxygen, manifesting as unstable angina (chest pain).
, - In the case of prolonged ischaemia, infarction and muscle necrosis will begin, which
may lead to non-ST segment-elevated myocardial infarction (NSTEMI), in which the
vessels are partly blocked, or ST segment-elevated myocardial infarction (STEMI), in
which coronary arteries are blocked completely.
- NSTEMI usually occurs as a result of atheromatous plaque rupture and is
characterised by stable angina that suddenly worsens, recurring or prolonged angina
at rest or new onset of severe angina. There is a risk of progression to STEMI or
sudden death, particularly in patients who experience pain at rest.
- STEMI usually occurs as a result of atheromatous plaque rupture and leads to
thrombosis and myocardial ischaemia, with irreversible necrosis of the heart muscle,
leading to long-term complications.
Acute Coronary Syndrome Classification
Treatments:
- Relieve the pain
o Nitrates
o Beta blockers
- Reperfuse
o Thrombolytics, e.g. streptokinase
o Percutaneous intervention (=coronary angioplasty), however, increases the
chance of thrombosis if plaque ruptures
o Bypass surgery, i.e. replacing artery with a vein but may involve
complications because the vessel anatomy and physiology is different
- Stop thrombosis
o Antiplatelet agents
o Anticoagulants
When to use an antithrombotic:
- Before
o Prevent a thrombus forming
o This may be in at-risk patient (who hasn’t had a thrombotic event – 1ry
prevention)
- During ACS
o In particular during PCI
- After
, o Prevent formation of new thrombi
o A cardiovascular event increases the likelihood of a following thrombosis
occurring (who already experienced a cardiovascular event – 2ry prevention)
The main challenge for anti-thrombotics is to prevent thrombosis without affecting
haemostasis, thus, not interfering too much with the coagulation cascade not to cause
uncontrollable bleeding.
An ideal anti-thrombotic (Cattaneo, 2010) *non-canonical list of characteristics
- Predictable pharmacodynamic and pharmacokinetic profile (monitoring is
unnecessary, which relieves burden off the healthcare system and decreases the
likelihood of a lethal outcome in case of another cardiovascular event)
- Rapid onset (need to give a drug to work straight away, especially in emergency
setting)
- Rapid offset (availability of an antidote to reverse the adverse effects of the drug, in
the case of anti-thrombotics mostly bleeding)
- No interaction with adjunctive medicines commonly used (high-risk patients usually
have other conditions that need to be managed pharmacologically, e.g. diabetes and
obesity, thus, many drugs need to be given in combination – anti-thrombolytics with
statins etc)
- Potent antithrombotic effect (but without overwhelming bleeding risk)
- Low risk
- Low cost
- Easy administration (oral preferred over parenteral routes of administration)
Platelets
- 20% in diameter of red blood cells, 2-3 um
- Normal platelet count is 150,000-350,000 per ul of blood
- 7-10 day life span
- The platelets are constantly turned over – in humans 100 billion platelets a day are
replaced
- Tiny fraction of blood volume
- Produced in the bone marrow, from megakaryocytes
- As megakaryocytes develop into giant cells, undergo fragmentation, ~1000 platelets
released per megakaryocyte
