Session 10 Flashcards
- Describe the main factors involved in normal and abnormal haemostasis and refer to Virchows Triad
- Understand the general features of thrombus formation & clotting cascades and recognise the sites at which Anticlotting Agents (ACAs) act.
- Appreciate the Vitamin K antagonist action of warfarin and similar ACAs
- Describe the main therapeutic uses of Warfarin and understand the practical importance of warfarin PKs in titrating doses
- Know the International Normalised Ratio (INR) in monitoring the effect of warfarin on blood clotting time
- Be aware of important ADRs and DDIs with warfarin and their particular importance in affecting therapeutic activity eg risk of intracranial haemorrhage and raised INR >4-5
- Describe with reference to the INR the steps in managing reversal of warfarin action
- Recognise the two major molecular heparin groups and appreciate their: differing PKs; sites and mechanisms of action; therapeutic uses
- Describe administration & monitoring of heparin, thmost serious ADRs and how to reverse heparin by use of protamine.
- Be aware of the mode of action of newer ACAs, specifically selective factor Xa inhibitors and direct thrombin inhibitors
- Understand the mechanism of action and uses of the four different anti-platelet drugs presented in this lecture.
Describe the main factors involved in normal and abnormal haemostasis and refer to Virchows Triad LO
What causes a thrombus? What is Virchows Triad?
Disorders of haemostasis are common
- Normal=?
- Abnormal=?
- Arterial: Color of clot and disease states it causes and drug classes used to treat?
- Venous:
- Other uses:
- Haemostasis
- Thrombosis, Embolism
- White clot: CVA, MI: Antiplatelets and Thrombolysis
- Red clot: DVT, PE: Anti- Coagulation
- Pro thrombotic state, & primary prevention
Understand the general features of thrombus formation and clotting cascades & recognise the sites at which antclotting agents act LO
Understand the general features of thrombus formation and clotting cascades & recognise the sites at which antclotting agents act LO
- Intrinsic pathway means damage to?
- Extrinsic pathway means damage to?
- Blood vessel wall
- Tissue surface
Understand the general features of thrombus formation and clotting cascades & recognise the sites at which antclotting agents act LO
Draw the clogging cascade
Understand the general features of thrombus formation and clotting cascades & recognise the sites at which antclotting agents act LO
Where are the sites at which anticlotting agents act?
Appreciate the Vitamin K antagonist action of warfarin and similar ACAs LO
State the mechanism of action of warfarin.
- Warfarin inhibits production of Vitamin K dependent clotting factors
- Stops conversion of Vit K to activereduced form
- II (Prothrombin), VII, IX, X: Extrinsic Pathway
Appreciate the Vitamin K antagonist action of warfarin and similar ACAs LO
Complete the diagram
Describe the main therapeutic uses of Warfarin and understand the practical importance of warfarin PKs in titrating doses LO
What PKs must we consider when thinking of wafarin?
PKs and Clinical Consequences
Comment on:
- Warfarins absorption
- Onset
- Offset
- Mostly free or protein bound
- How it is metabolised
- Why we don’t give it to pregnant women
- Good GI Absorption: Give orally
- Preferred choice for long term AC (anticoagulation) - Slow onset of action:
- Therefore, needs Heparin cover initially - Slow offset: t1/2 48 hrs but variable!
- Need to stop 3 days before surgery
- Time to synthesize new clotting factors - Heavily Protein Bound
- Caution with drugs that displace it - Hepatic Metabolism: Mixed function Oxidase cytochrome p450 System
- Caution with Liver Disease
- Caution if used with drugs that affect p450 system - Crosses Placenta:
- Do not give in 1st Trimester: Teratogenic
- Do not give in 3rd Trimester: Brain Haem
0 If Female patient on warfarin advise re pregnancy
Know the International Normalised Ratio (INR) in monitoring the effect of warfarin on blood clotting time LO
How do we monitor warfarin?
- Extrinsic Pathway Factors
- Prothrombin Time
(Citrated plasma Clotting Time after adding Calcium and Thromboplastins)
- I.N.R = International Normalised Ratio
(Allows a standard value between labs & corrected for different lab thromboplastins reagents)
Drug Interactions
- What are the effects on anticoagulation by the majority of drugs & the minority?
- Majority increase anticoagulant effect
Some decrease effect
N.B: Perhaps more than with any other drug: INTERACTIONS WITH WARFARIN ARE HIGHLY SIGNIFICANT !!!!
Be aware of important ADRs and DDIs with warfarin and their particular importance in affecting therapeutic activity e.g.. risk of intracranial haemorrhage & raised INR > 4-5 LO
Drugs potentiating (increase the power) Warfarin
3 are Clinically Significant:
Which ones have a lesser effect?
How do they effect the INR?
- Inhibit Hepatic Metabolism
• Amiodarone, Quinolone, Metronidazole, Cimetidine, ingesting alcohol
- Inhibit Platelet function
• Aspirin
- Reduce Vitamin K from gut bacteria
• Cephalosporin Antibiotics
- Albumin Displacement (NSAIDS) & drugs that decrease GI absorption of Vit K have lesser effect
- INR will increase if you start one de novo
Drugs inhibiting Warfarin:
Mechanism
Effect on INR
Antiepileptics (except Na valproate), Rifampicin & St Johns Wort
Most work by inducing hepatic enzymes thereby increasing metabolism of warfarin
INR
Describe the main therapeutic uses of Warfarin and understand the practical importance of warfarin PKs in titrating doses LO
What are the main Uses of Warfarin
Indication (Duration)
INR range: 2.0 - 3.0
DVT (3-6 months)
PE (6 Months)
Atrial fibrillation (Until Risk > Benefit)
INR range: 2.5 - 4.5
Mechanical prosthetic valves (high risk)
Patients with recurrent thromboses on Warfarin
Thrombosis associated with inherited thrombophilia conditions
Be aware of important ADRs & DDIs with warfarin and their particular importance in affecting therapeutic activity e.g. risk of intracranial haemorrhage & raised INR >4-5 LO
Adverse effects? (5)
Be aware of important ADRs & DDIs with warfarin and their particular importance in affecting therapeutic activity e.g. risk of intracranial haemorrhage & raised INR >4-5 LO
What is this graph showing?
Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.
Describe with reference to the INR the steps in managing reversal of warfarin action LO
What can we use to reverse the action of wafarin with reference to INR
Common Sense: Stop Warfarin
Consider
- Bleeding, INR, Indication
- Mechanical Valve call cardiologist for advice
Agents
- *- IV Vit K (pro-coagulant affects re-warfarinisation for 6 weeks)
- Prothrombin Complex Concentrate
- Fresh Frozen Plasma**
Source of Bleeding (OGD, surgery)
Elective Surgery
Describe the main therapeutic uses of Warfarin and understand the practical importance of warfarin PKs in titrating doses LO
Practical Information on starting warfarin
What are the first steps when initiating warfarin in a patient
Initiation
- Indication
- PMH e.g PUD, SAH, Bleeding Disorder
- Medications (interactions)
- Age, Mobility (blood tests and clinics), Falls risk score
- Review blood tests (LFTs, Plt, INR),
- Consider Loading Dose and Heparin cover
- Prescribe (when to start)
Bleeding whilst anticoagulated:
4 categories:
When should we start wafarin in a patient with a PE & DVT
Things to Discuss with Patient:
- Side effects
- Bleeding and when to consult a doctor
- Young and female ? - Interactions
- Other Medication (starting or stopping!)
- Over the Counter drugs
- Alcohol and Cranberry/Grapefruit Juice - INR Monitoring (1-4 weeks)
- Give patient Anticoagulant Card
Management of INCREASE INR (no mechanical valve)
Anticoagulants: Heparin
- Structure
- Mechanism of action
- Glycosaminoglycan – glucose backbone
One of 5 different groups on each glucose, some with sulphate. Produced by mast cells - Both Activate Anti-Thrombin III (ATIII)
Via Unique Pentasaccharide Sequence
Deactivates Factor Xa, IIa, IXa, (probably VIIa, XIa, XIIa)
Draw an image showing where heparin has it’s effects in the clotting cascade
Recognise the two major molecular heparin groups and appreciate their: differing PKs; sites & mechanism of action; therapeutic uses LO
What are the two major heparin groups? How to administer?
- Unfractionated Heparin (intravenous, continuous, occasionally, subcutaneous for prophylaxis) 20 kDa
- Low Molecular Weight Heparins (subcutaneous) 3-4 kDa
Unfractionated Heparin
- Structure?
- Mechanism of action?
- Mix of variable long length heparin chains
- Variable lengths (12-15 kDaltons)
- Mix of variable long length heparin chains
- Unique pentasaccharide sequence which binds to ANTI-THROMBIN III
- This causes conformational change and increased AT III activity
- AT III inactivates thrombin (IIa) and factor Xa: but also V,VII,IX,XI
Heparins and AT III
- To catalyse inhibition of IIa by AT III, heparin needs to bind simultaneously to IIa and AT
III. Unfractionated heparin is large enough for this, but not Low MW Heparin. - Xa inhibition by AT III needs only heparin to bind to AT III, so both Low MW & unfractionated heparin can act here.
Low Molecular Weight Heparins (LMWH)
- Structure
- Comment on their:
a. Absorption
b. Half life - Mechanism of action
- Smaller chains (usually 4-5 kDaltons)
- < 18 saccharide units, usually about 15 units
- Smaller chains (usually 4-5 kDaltons)
- a. Absorbed more uniformly, high bioavailability >90%
B. Long biological half life
More predictable dose response (does not bind to macrophages, endothelial cells, plasma proteins) - Like UH, have unique sequence to bind to ANTI-THROMBIN III
- Unlike UH, they do not inactivate thrombin (IIa)
- Affects Factor Xa specifically. No monitoring required usually.
- Cleared by Kidneys, care in Renal Failure
- Less likely to cause thrombocytopenia
- Like UH, have unique sequence to bind to ANTI-THROMBIN III
Differnce with OCD and psychosis
OCD patients know what there thinking/doing is not normal
do not hold false beliefs
can recognise themselves
Recognise the two major molecular heparin groups and appreciate their: differing PKs; sites & mechanism of action; therapeutic uses
Recognise the two major molecular heparin groups and appreciate their: differing PKs; sites & mechanism of action; therapeutic uses
Uses of heparin
- Prevention of Thrombo-embolism
- Treatment
Prevention of Thrombo-embolism
- Peri-operative: LMWH low dose
- Immobility: CCF, frail or unwell patient
- Used to cover for risk of thrombosis around times of operation in those normally on warfarin but who have stopped it for the surgery, as quick offset time allows its cessation if bleeding
What can heparin be used to treat?
- *DVT/PE and AF**
- Administered prior to warfarin-quick onset to cover patient whilst warfarin loading is achieved
- LMWH often used unless fine control required
- *Acute Coronary Syndromes**
- Reduces recurrence/extension of coronary artery thrombosis
- MI, unstable angina
- *Pregnancy**
- Can be used cautiously in pregnancy in place of warfarin
Describe administration and monitoring of heparin, the most serious ADRs and how to reverse heparin by use of protamine LO
State the ADRs of heparin.
- *Bruising/bleeding Sites**
- Intracranial
- Injection sites
- Gastrointestinal loss
- Epistaxis
- *Thrombocytopenia (HIT)**
- Autoimmune phenomenon (usually 1-2 weeks of Rx)
- May bleed or get serious thromboses
- Heparin and PF4 on platelet surface are immunogenic – immune complexes activate more platelets, release more PF4, forms more IgG and complexes, leads to depletion of platelets, thrombosis
- Platelets <100 (or a 50% reduction)
- Lab assay for these antibodies
- Stop heparin, add hirudin
Osteoporosis
Describe administration and monitoring of heparin, the most serious ADRs and how to reverse heparin by use of ? LO
- What substance is used in the reversal of heparin therapy?
- How does it work?
- Stop Heparin
If actively bleeding, give ?
Monitor APTT if ?
- Protamine sulphate
- Dissociates heparin from anti-thrombin III
Irreversible binding to heparin
Allergy/Anaphylaxis - Protamine
unfractionated
Heparin
UNFRACTIONATED
½ ½
Loading dose, then IV infusion
(remember 5 T
rule- T
approx. 1-2h)
Monitor APTT
LMWH
No monitoring.
Occasionally, may need X
a
assay
Be aware of the mode of action of newer ACAs, specifically selective factor Xa inhibitors & direct thrombin inhibitors LO
Give examples of antiplatelet drugs and their brief mode of action.
- *Aspirin**
- COX-1 inhibition
- *Dipyridamole**
- Phosphodiesterase Inhibitors
- *Clopidogrel**
- ADP antagonists
Glycoprotein IIb / IIIa Inhibitors
What ACAs effect platelet adhesion, activation & aggregation
Mechanism of action of aspirin & Glycoprotein IIb / IIIa Inhibitors
Aspirin inhibits COX1 irreversibly- Covalent acetylation of serine: “hit and run” drug
Gp IIb / IIIa Inhibitors
Abciximab, tirofiban, eptifibatide
Decreases platelet crosslinking by fibrinogen
Mechanism of action of Dipyridamole & Clopidogrel
Clopidogrel, Prasugrel, {Ticagrelor}
- Ticlodipine now out dated due toadverse effects (eg ?)
- Mechanism of action?
- Cardiac Indications:
- Used with?
- bone marrow
- Inhibit ADP Dependent Aggregation
- ACS, PCI (do NOT stop)
- Aspirin
- More serious bleeds but same rate of life threatening
- Not for long term use if possible,
- Eg use for 1 year after NSTEMI
Dipyridamole
- Mechanism of action
- Effect on the body
- Secondary Prevention of ?
- Probably Phosphodiesterase Inhibitor
- Positive Ionotrope and vasodilatory (flushes & headaches)
- Stroke
Glycoprotein IIb/IIIa Receptor Antagonists
- Mechanism of action
- 3 Classes:
- Uses:
- Fibrinogen binds these receptors which causes platelet aggregation
Antagonists block this final pathway - Mab Abciximab
Peptides – eptifibatide, tirofiban - High risk ACS
- Post PCI (Increases bleeding complications but decreases acute thrombosis and re-
stenosis)
- High risk ACS
Warfarin
- Mechanism: inhibits vitamin K dependent clotting factors:
- Initiation:
- Patient counselling
- VII, IX, X + protein C and S
- If using to treat DVT/PE need to cover patient with SC therapeutic dalteparin until INR is therapeutic
- If using for AF then no need for dalteparin cover
- If using to treat DVT/PE need to cover patient with SC therapeutic dalteparin until INR is therapeutic
- Avoid NSAIDs/aspirin – increase bleeding risk
- Warn about effects of alcohol – in high amounts alcohol acts as an enzyme inhibitor
- Lots of drugs interact with warfarin (enzyme Inducers/inhibitors)
- Lots of foods interact with warfarin! Leafy greens (cabbage) & cereals contain Vit K – reduce warfarin effect.
- Avoid NSAIDs/aspirin – increase bleeding risk
Warfarin – reversal?
- If INR raised (3-7) and no bleeding then ?
- If INR is greatly raised (>8) and/or minor bleeding then
- If INR elevated (>10) or major bleeding then ?
- reduce dose and recheck INR
- OMIT warfarin & recheck INR
- 5-10mg IV vitamin K
- Discussion with haematology regarding need for PCC or FFP (beriplex)
- 5-10mg IV vitamin K
Heparin
- Types:
- Mechanism: ?
- PKs?
- ADR:
- Reversal agent - ?
- (1) Low molecular weight heparin – daily subcutaneous injection e.g. Dalteparin
(2) Unfractionated heparin – IV (bolus followed by infusion) - Glycosaminoglycan which binds to (and activates) Anti-Thrombin III which then deactivates Factor Xa. Unfractionated heparin can also bind to IIa (thrombin) and inactivate it.
- Rapid onset and offset, poor GI absorption, variable according to weight
- Bruising/bleeding, thrombocytopenia (autoimmune)
- protamine
DOAC – direct oral anticoagulants
- Direct Factor Xa inhibitors (bind to antithrombin III) Examples: ?
- Direct Thrombin (Factor IIa) inhibitors Example: ?
- Benefits:
- Negatives:
- Rivaroxaban, Apixiban, Fondaparinux
- dabigatran
- decreased risk of intracranial haemorrhage compared to other anticoagulants, no monitoring of therapeutic effect required (INR)
- increased GI bleed risk, not all have a reversal agent if patient is bleeding, need reduced doses in patients with renal failure
