Anticoagulant, Antiplatelet and Thrombolytic Therapies NOT DONE

How does a clot form?

vWF binds to GPIb → release ADP

1. ADP binds to P2Y12 receptor → increase Ca2+ → bind to GPIIb/IIIa → platelet plug

2. Ca2+ → increase PLA2 → acts on A.A (via COX-1)→ increased thromboxane A2

3. PDE3 blocks CAMP → incraesed Ca2+

How do ADP receptor inhibitors work? Name some

** anti-platelet

Prevents binding of ADP to P2Y12 receptor → prevents activation of GPIIb/IIIa

eg. Clopidogrel, Prasugrel, Ticagrelor (only reversible), Ticlopidine

How do COX inhibitors work? Name some

** anti-platelet

Irreversible cyclooxygenase inhibitor blocks synthesis of thromboxane A2

low doses inhibits COX-1: anti-thrombotic effects

higher doses inhibits COX-2 as well: anti-inflammatory effects

e.g. Aspirin

explain the intrinsic pathway

• Factor XII (hageman factor) becomes activated after exposure to subendothelial collagen → XIIa

• This causes the activation of Factor XI → XIa

• Factor Xla + calcium activate factor IX → IXa

• Factor IXa + Factor VIlla form a complex (with calcium) to activate Factor X

• The common pathway then begins

explain the common pathway

• Factor V activated by thrombin → Va

• Factor Xa, Va and calcium bind together to form a prothombinase complex.

•  This activates prothrombin into thrombin (factor II → IIa)

• Thrombin cleaves fibrinogen to form fibrin (factor I → Ia)

** Factor XIlla is known as the stabilising factor

explain the extrinsic pathway

• Tissue factor (secreted by endothelial cells after external damage ) comes into contact with Factor VII and activates it → factor VIIa

• Factor VIla goes on to activate Factor X → Xa

• The common pathway then begins

How do GPIIb/IIIa receptor inhibitors work? Name some

** anti-platelet

A monoclonal antibody that acts as a non-competitive inhibitor of GPIIb/IIIa

prevents binding of fibrinogen → prevents cross-linking and aggregation of platelets

eg. Abciximab (i.v)

Explain how Phosphodiesterase inhibitors and name some

** anti-platelet

** anti-platelet Increases CAMP levels in platelets which inhibits calcium release

** Has anti-platelet and vasodilatory effects

eg. Cilostazol, Dipyridamole

Explain how you can inhibit factor X and name some

** anticoagulant

Indirect inhibition of factor X: Heparin(administered parenterally)

Direct inhibition of factor X: direct oral anticoagulants (DOACs)

Name some direct thrombin inhibitors

** anticoagulant

Dabigatran (oral) (reversible)

Argatraban (IV)

Name a vitamin K antagonists and explain how it works

** anticoagulant

Inhibits Vitamin K epoxide reductase

Warfarin (oral)

How do we lyse clots?

Tissue plasminogen activator analogues

Promote conversion of plasminogen to plasmin → fibrinogen to fibrin

eg. Alteplase, Tenecteplase, Urokinase, Streptokinase (all IV)

How do we treat acute coronary syndrome?

300 mg aspirin immediately

Dual therapy (aspirin+ADP receptor inhibitor) after PCI

Heparin (unfractionated) in addition for patients undergoing primary PCI with radial access

Fibrinolysis is only offered to people with acute STEMI presenting within 12 hours of onset of symptoms if primary PCI cannot be delivered within 2hrs

How do we treat atrial fibrillation?

New onset AF→ Heparin

If valvular AF→ transition to warfarin (DOAC not recommended)

If non-valvular AF→ DOAC

** anticoagulation should be offered for stroke prevention to all patients with a CHA2DS2 VASc score of 2 or above

How do we treat pulmonary embolism?

If hemodynamically unstable:

Continuous unfractionated heparin infusion + thrombolytic therapy

If hemodynamically stable: Start on anti-coagulants

• Start with heparin

• Transition to DOAC or warfarin

Adverse side effects of aspirin

Asthma, bronchospasm, dyspnoea (due to increased leukotrienes)

Gastrointestinal irritation (due to reduced PGE2)

Not prescribed to children younger than 16 years of age due to risk of Reye’s syndrome (increased ammonia and lactic acid)

Toxicity can lead to AGMA, respiratory alkalosis

Adverse side effects of ADP receptor inhibitors

Gastrointestinal ulceration

Thrombotic thrombocytopenic purpura (due to autoantibodies against ADAMTS13)

Fever, anaemia, thrombocytopenia, renal failure, neurological symptoms

Adverse side effects of PDE-3 inhibitors

Can cause cerebral vasodilation→ press down on pain receptors→ headaches

Associated with increased mortality in CHF

Adverse side effects of heparin

Heparin induced thrombocytopenia (HIT) (unfractionated heparin):

Heparin bind to platelet factor 4→ immunogenic→ antibodies produced→ binds to platelets→ activate platelet plugs→ thrombus formation→ arterial and venous circulation

Skin necrosis around subcutaneous injection site

What does aPTT test for?

measures how long it takes for blood to clot

tests intrinsic pathway and the common pathway

What does INR test for?

How does warfarin interact with other things?

Warfarin is metabolised by the cytochrome P450 system

If CYP450 is inhibited→ warfarin not metabolised→ Increased effect→ Bleeding

** Should not be used in patients with severe hepatic impairment