Blood Coagulation 2

Arterial Thrombosis

What is it usually as a consequence of?

Atherosclerosis

Arterial Thrombosis

Major associated problems

• Heart attack

• Stroke

Arterial Thrombosis

Key aims in prevention

• Remove / reduce modifiable risk factors e.g. smoking, hypertension, diabetes, lack of activity obesity

• Bear in mind unavoidable factors e.g. age, sex, family history

What are Acute Coronary Syndromes?

• A range of acute myocardial ischaemic states

Includes

• Unstable angina

• NSTEMI

• STEMI

What is atherosclerosis?

• Build up of plaque (atheroma) between the arterial intima and basement membrane

• Caused by a chronic inflammatory process » engulfment of cholesterol by macrophages, forms foam cells which form the atheroma

• Lumen becomes narrowed

• Which reduces blood flow

2 types of atherosclerotic plaque

Hard and stable

• Fibrous cap over the atheroma

• Less problematic

Soft and unstable

• Problematic

Why are soft and unstable atherosclerotic plaques problematic?

When exposed to the shear forces within the blood vessel, they are more prone to:

• Being ruptured

• Breaking off

• Exposing the underlying the basement membrane = causes thrombosis within the blood vessel

What happens during a myocardial infarction?

• Rupture of an atheromatous plaque

• Causes development of a thrombus » platelet aggregation, fibrin deposition and activation of inflammatory mediators

• Total occlusion of coronary artery

• Ischaemia (no blood flow)

Thrombolysis

What is Thrombolysis?

• Used in myocardial infarction

• Aims to re-establish coronary blood flow to:

  • Reduces myocardial damage

  • Preserves LV function

Thrombolysis

How soon should Thrombolysis be established?

’Time is muscle’

• Should give as soon as onset of pain is possible

• Ideally within a ‘golden hour’

Thrombolysis

Contraindications

Risk of bleeding so:

• Recent major injury

• Peptic ulcer

• Risk of subarachnoid haemorrhage

• Recent head injury

• Prolonged and vigorous CPR

Thrombolysis

Why does thombolysis increase risk of bleeding?

• Leads to fibrin clot being dissolved

• So reduces blood clotting = increases risk of bleeding

Interventional Cardiology

What is interventional cardiology?

PCI (Percutaneous Coronary Intervention)

Interventional Cardiology

Is it preferred to Thrombolysis in the treatment of myocardial infarction?

YES

• Mechanically improves myocardial perfusion

• So reduces risk of bleeding

Interventional Cardiology

Advantages

• Mechanically improves/restores myocardial perfusion

• Better outcomes than thrombolysis in treatment of MI

• Lacks the haemorrhagic risks of thrombolysis

• Can be used when thrombolysis is contraindicated

• Stents can be inserted to help keep arteries patent

• Antiplatelet drugs are given before, during and after

Ischaemic Stroke

What is ischaemic stroke?

Occlusion of the arteries supplying blood to the brain

Ischaemic Stroke

Approx. 85% of strokes are ischaemic. What are the other 15% classified as?

Haemorrhagic » due to a bleed in the brain

Ischaemic Stroke

Most common type of ischaemic stroke

What drugs are used for the prophylaxis of this type of ischaemic stroke?

Thrombotic stroke

• Thrombosis of a cerebral artery (artery supplying the brain)

• Due to atherosclerosis

Prophylaxis:

• Anti-platelet drugs » to prevent formation of thrombus

Ischaemic Stroke

Less common type of ischaemic stroke

What drugs are used for the prophylaxis of this type of ischaemic stroke?

Embolic stroke

• Thrombus originates in the heart and embolises in the brain = blocks an artery in the brain which reduces blood flow

• Strong association with AF, recent MI and valve dysfunction » where there is a disruption of organised flow of blood through the heart = stagnant blood = formation of thrombus

Prophylaxis:

• Anticoagulant drugs » As problem is due to stagnant blood forming a fibrin-based clot

Ischaemic Stroke

What do the signs and symptoms associated with ischaemic stroke depend on?

• The size of the blocked vessel

• The location of the blocked vessel

Ischaemic Stroke

Where will motor symptoms associated with stroke occur?

On the opposite side of the body to the side of the affected vessel

Ischaemic Stroke

Signs and Symptoms of stroke

Facial weakness: Can the person smile? Has their mouth or eye drooped?

Arm weakness: Can the person raise both of their arms?

Speech problems: Can the person speak clearly and understand you?

Time to call 999: Any of the above signs

Ischaemic Stroke

Which type of ischaemic stroke tends to lead to more severe outcomes and why?

• Embolic stroke

• The size of the artery blocked tends to be larger

Venous Thrombosis

What is venous thrombosis?

• Thrombus which develops in the deep veins e.g. lower leg

• AKA Deep Vein Thrombosis (DVT)

Venous Thrombosis

What is the major concern with venous thrombosis?

Pulmonary embolism

• Risk that thrombus will break off and emobilise

• Carried through the venous circulation to the heart and pulmonary circulation = blocks pulmonary artery with a narrower diameter than the clot

Post-phlebitic syndrome

• Inflammation in blood vessels affected by venous thrombosis

• Painful for patient

Venous Thrombosis

Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) comprise a single clinical entity:

Venous Thromboembolism (VTE)

Venous Thrombosis

What is meant when we say ‘Management of VTE’?

Management of BOTH DVT and PE

Venous Thrombosis

Risk factors of venous thrombosis

• Age

• Immobility

• Recent operation esp in the legs or hips

• Pregnancy

• Oral contraceptive

• HRT

• Cancer and chemotherapy

• Travel

• Family history

• Genetic thrombophilia

Venous Thrombosis

What does Virchow’s Triad show?

• An accumulation of risk factors for venous thrombosis

It describes:

• Issues with the blood vessel

• Issues with the quality of the blood

• Issues with the flow of blood

» If even one factor is disrupted, can cause venous thrombosis

» If more than one factor is disrupted, significantly increases risk

Venous Thrombosis

Risk Factors

Immobility

• Stagnation of venous blood flow

• = Formation of thrombus

Venous Thrombosis

Risk Factors

Recent operation esp in the legs or hips

• Immobility = stagnant blood

• Activation of tissue factor pathway due to surgery = activation of coagulation mechanisms

Venous Thrombosis

Risk Factors

Age

Considered an independent AND a non-independent risk factor:

Independent risk factor:

• Quality of blood vessels and CVS declines with age

Non-independent risk factor:

• Older individuals are more at risk of falls, operations, HRT, cancer etc

Venous Thrombosis

Risk Factors

Pregnancy

• Immobility

• Changes in levels of fibrinogen and other coagulation factors e.g. factor 8 = affects blood and blood flow in Virchow’s Triad

» Whilst there is a risk of venous thrombosis in pregnancy, not a major problem unless patient already has risk factors before pregnancy

Venous Thrombosis

Risk Factors

Travel

Immobility = stagnant blood

Venous Thrombosis

Risk Factors

Genetic thrombophilia

• Genetic factors that affect the ability of the blood to clot

• Affects the blood side of Virchow’s Triad

Venous Thromboembolism

Signs and symptoms of VTE

DVT: pain, swelling and heat in affected limb

PE: acute chest pain, dyspnoea

Venous Thromboembolism

What does the severity of PE depend on?

The size of the vessel affected

Venous Thromboembolism

What is a ‘silent’ PE?

Such a small vessel is affected that patient is unaffected

Venous Thrombolemolism

Treatment of VTE

Anticoagulant drugs » inhibit plasma coagulation

• Heparin

• Warfarin

• DOACs

Thrombolysis or surgical removal of thrombus (thrombectomy) only in severe cases

Warfarin

Overall mechanism of action

• Vitamin K antagonist

• Inhibits synthesis of factors X, IX, VIII and II in the liver » involved in plasma coagulation

  • By preventing the conversion of non-functional factors to functional factors via post-translational modification

  • So they are released into the blood in a non-functional form

Warfarin

How are non-functional coagulation factors converted to functional coagulation factors and how does warfarin inhibit this to have an anticoagulation affect?

• Non-functional coagulation factors are converted into functional coagulation factors by an enzyme called gamma glutamyl carboxylase

• This enzyme carboxylates glutamic acid residues on the non-functional coagulation factors

• Which allows them to bind to calcium and phospholipids when they enter the blood

• Which allows the non-functional factors to be converted to their functional form

• Gamma glutamyl carboxylase carries out its reaction with a paired reaction of the oxidation of vitamin K to vitamin K epoxide

• Vitamin K epoxide reductase recycles the Vitamin K back to its reduced form, so it can take part in the reaction again

• Warfarin inhibits the Vitamin K reductase = indirectly inhibits action of gamma glutamyl carboxylase = prevents conversion of coagulation factors into their functional form

Warfarin

What is warfarin a derivative of?

Synthetic coumarin derivative

• Dicoumarol found in mouldy sweet-clover hay

• Causes a bleeding disorder in cows

Warfarin

How is warfarin given?

As a racemic mixture

• S-warfarin 5x more potent than R-warfarin as an anticoagulant

BUT

• S-warfarin (CYP2C9) metabolised more rapidly than R-warfarin (CYP3A4)

Warfarin

Problems with warfarin

• Many drug and food interactions

• Narrow therapeutic index

• Unwanted bleeding

• Patient must keep diet and vitamin K stable » can affect efficacy of warfarin

• INR monitoring required

Warfarin

Drug interactions

• Drugs that increase warfarin metabolism reduce anticoagulant effect e.g. carbamazepine, primidone, phenytoin, rifamycins

• Drugs that reduce warfarin metabolism increase anticoagulant effect e.g. cimetidine, amiodarone

• Highly albumin bound drugs may increase anticoagulant effect e.g. NSAIDs

• Use of antiplatelets (e.g. aspirin) + warfarin increases risk of bleeding

Warfarin

Warfarin + Anti-epileptic drugs

• Increase warfarin metabolism by inducing liver enzymes

• Reduces anticoagulant effect of warfarin

E.g. carbamazepine, phenytoin

Warfarin

Warfarin only works…

In vivo

Warfarin

How long does it take for anticoagulant effect to be achieved?

• Takes several days for full anticoagulant effect to be achieved and stabilised

• So patient may need to be on another anti-coagulant e.g. heparin that works immediately in the meantime

Warfarin

Why does warfarin take several days to work?

• The coagulation factors involved (2, 7, 9 and 10) will need to be replaced by new non-functional coagulation factors synthesised in the presence of warfarin

• The rate at which each factor is replaced varies = takes several days to stabilise

Warfarin

Antidote in the case of warfarin overdose

Phytomenadione (Vitamin K₁)

» Replenishes Vitamin K in the liver should the effects of warfarin needs to be reversed

Heparin

Where does it come from?

Naturally occurring molecule in the body

Heparin

Structure

• Glycosaminoglycan

• Formed from repeating disaccharide units

• Extensively N and O sulfated = very negatively charged molecule

• Heparin is the most negatively charged molecule that exists in nature

Heparin

Mechanism of action

Potentiates the activity of the body’s main natural anticoagulation inhibitor, antithrombin:

• Antithrombin inhibits the activity of thrombin (factor 2a) and factor 10a

• Antithrombin is a serpin (serine protease inhibitor)

• Heparin binds to antithrombin

• The reactive arginine centre of the antithrombin becomes more accessible to the serine protease, so it is more readily able to inhibit it in factor 2a and 10a

• So heparin accelerates the rate at which antithrombin is able to inhibit coagulation factors

Heparin

Which part of heparin binds to the antithrombin?

Pentasaccharide region (blue)

Heparin

Where is heparin found in the body?

inside mast cells

Heparin

Which 2 preparations of heparin are available?

1. Unfractionated heparin

2. Low molecular weight heparin (LMWH)

Heparin

What is the difference between unfractionated heparin and LMWH?

Unfractionated heparin: heterogeneous mixture of long and short chains of heparin

LMWH: homogenous mixture of low molecular weight chains

Heparin

Advantages of LMWH over unfractionated heparin?

Longer half life = administered less frequently

Heparin

Advantages of unfractionated heparin over LMWH?

More reversible

Heparin

What is fondaparinux and what is its advantage?

• The pentasaccharide sequence of heparin is enough to potentiate the inhibitory action of antithrombin on factor 10a

• Whereas a longer sequence is needed to increase the inhibitors of thrombin (factor 2a) by antithrombin

• Fondaparinux is a synthetic antithrombin binding pentasaccharide

• Able to inhibit factor 10a but has no affect on thrombin (2a)

Heparin

Heparin is an…

Indirect anticoagulant » as exerts activity via antithrombin

Heparin

Heparin works both…

In vivo AND in vitro

(If you add heparin to blood in a test tube, it would not clot, whereas if you added warfarin to blood in a test tube it would still clot)

Heparin

How must heparin be given?

By injection

Heparin

How long does it take to work?

Immediate anticoagulant effect » because all the components it needs to work are already in the blood

Heparin

Disadvantages

• Risk of bleeding

• Serious hypersensitivity reactions

• Physical incompatibility with many drugs

Heparin

Example of hypersensitivity reaction to heparin

• Heparin induced thrombocytopenia

• Occurs on repeated administration of heparin over a number of days

• Antibodies are created against a protein associated with platelets

• Causes destruction of platelets

Heparin

Reversal agent

Protamine

• Effective against unfractionated heparin

• Less effective against LMWHs

Heparin

When is heparin used?

• Prophylaxis against VTE after surgery

• Can be used in pregnancy » warfarin is contraindicated as teratogenic

• Used while warfarin effects become established

Can anticoagulants e.g. warfarin and heparin be used to treat an existing clot/thrombus?

YES

What is hirudin?

• Peptide found in salivary gland of leeches

• Anticoagulant

• Directly inhibits thrombin

• So allows leeches to extract blood

Which drugs were modelled on hirudin?

When are these drugs sued?

Leperudin: no longer marketed

Bivalirubin: peptide, direct thrombin inhibitor

Argatroban: small molecule, direct thrombin inhibitor

• Given via infusion

• Useful alternatives if patient cannot receive heparin