6.2 anti-platelets/ anticoagulants/ thrombolytics Flashcards
Give 2 types of arterial thromboembolic events
Stroke (CVA) and MI
Give 2 types of venous thrombo-embolic events
DVT and PE
What is Virchow’s Triad and give the 3 factors involved
3 factors that are critically important in the development of venous thrombosis:
1) Hypercoagulability
2) Endothelial damage
3) Stasis
Give the MoA of Warfarin
Inhibits production of Vitamin K dependent clotting factors (factor II (prothrombin), VII, IX, X)
What is the t1/2 of Warfarin and what is the implication of this for starting and stopping treatment
Long t1/2 = 48 hrs (but variable), hence it has slow onset and offset of action
This means:
- Initial anti-coagulation requires Heparin cover alongside warfarin
- If patient requires surgery we must stop warfarin 5 days prior
Is the anticoagulant effect of Warfarin reversible?
Yes
How is Warfarin administered and what is its protein binding?
Usually orally as it is has good GI absorption and is heavily protein bound (increased potential for DDis)
How is warfarin metabolised and therfore why must care be taken?
Hepatic metabolism by CYP450
Caution with liver disease or drugs that affect p450 system
Does Warfarin cross the placenta and what is the implication of this during pregnancy?
Crosses Placenta:
- do not give in 1st trimester: Teratogenic
- do not give in 3rd Trimester: risk of bleeding at delivery
How do we monitor Warfarin and how can we assess these results?
Prothrombin Time: measures how long it takes blood to clot (extrinsic pathway)
Use INR (international normalized ratio) to assess the standard value between labs (while the PT may vary from lab-lab, INR should be the same)
If a drug which increases anticoagulant effects is given alongside Warfarin what is the risk?
Increase risk bleeding
If a drug which decreases the anticoagulant effect is given alongside Warfarin what is the risk?
risk of thrombosis
Give 2 types of drugs which may increase the effect of Warfarin? (Incl examples)
- Drugs which Inhibit hepatic metabolism
* Eg. Amiodarone, Quinolone, Metronidazole, Cimetidine, ingesting alcohol - Drugs which reduce Vit K from gut bacteria
* Eg. Cephalosporin, Antibiotics
Give 2 drugs/classes which may decrease the effect of Warfarin
Anti-epileptics (except Na valproate)
Rifampicin
How do drugs which decrease effect of Warfarin work?
What would be seen in the INR?
Most work by inducing hepatic enzymes thereby increasing metabolism of warfarin: INR ↓
Give 4 main Indications for Warfarin use
- DVT/PE
- atrial fibrillation
- dilated cardiomyopathy
- mechanical prosthetic valves
What is the ONLY anti-coagulant which can be used on patients with mechanic valves?
Warfarin
Give 4 limitations of warfarin therapy
- Narrow therapeutic window (INR range 2-3)
- Slow onset/offset of action
- Frequent dose adjustments
- Routine coagulation monitoring
+ others on image below
What is the INR range we aim to achieve?
Compare the risks of an INR which is too LOW vs too HIGH
Normal ➞ 2-3
LOW ➞ risk of stroke
HIGH ➞ risk of hemorrhage
Give 3 adverse effects of Warfarin
1) Bleeding/ bruising
2) Teratogenic (if pregnant)
3) Reversal of Therapy
If a patient on Warfarin presents with bleeding and a high INR what must we do?
Warfarin Reversal!
1) stop Warfarin!
2) consider bleeding, INR, Indication
3) If they have a mechanical valve - call cardiologist/ caematologist
4) administer reversal agents
5) find source of bleeding, potential surgery
Give 3 agents which can be used for Warfarin Reversal
1) IV Vit K (pro-coagulant effects for 6 weeks)
2) Prothrombin Complex Concentrate
3) Fresh Frozen Plasma
How is Heparin administered and why?
Parenteral - due to poor GI absorption
Give the onset and bioavailability of Heparin
Rapid onset, variable bioavailability
Heparin is produced by ________ and binds to _________ via unique Pentasaccharide sequence
Binding leads to activation of ________ and inactivation of Factor _____, _____, _____
Mast cells, Anti-Thrombin III, Anti-Thrombin III
IIa (thrombin) , IXa, Xa,
Describe the structure of Heparin
Heparin is a Glycosaminoglycan meaning it has a glucose backbone
What are the 2 main types of Heparin and how does their administration differ?
Unfractionated Heparin (UFH): continuous IV infusion
LMWH: Administered subcutaneously
Revise Coag cascade
UFH has ______ length heparin chains which inhibit activation of _________ and factor _____.
Its effect can be monitored via _______blood test
long, Prothrombin (IIa), Xa, activated partial thromboplastin time (APTT)
In what instance may the administration of UFH change?
Occasionally used subcutaneously for prophylaxis in patients with renal failure unsuitable for LMWH
Compare chain length of UFH and LMWH + the implication of this is on their actions
As UFH has long chain its can inhibit activation of Prothrombin (IIa) and factor Xa (by binding simultaneously)
As LMWH has small chains it only inhibits factor Xa not IIa (it is not long enough to catalyse inhibition of IIa by AT III)
Give 3 benfits of LMWH over UFH?
It has predictable pharmacokinetics, a high bioavailability >90% and a long half life (cleared by kidneys)
Therefore can be given at a fixed one dose daily and monitoring is not usually required
If monitoring of LMWH is required what can we use?
Anti Xa level
(Not APTT because it does not impact directly on thrombin)
Give 4 comparisons between UFH and LMWH
(Hint: AM PM)
1) Administration ➞ UFH = IV, LMWH =subcutaneous
2) MoA ➞ UFH = long chains so inhibits IIa and Xa, LMWH = short chains so only inhibits Xa
3) PK ➞ UFH = unpredictable, LMWH = predictable
4) Monitoring ➞ UFH = APTT, LMWH = anti-Xa
Study comparison of UFH and LMWH
Give 4 uses of Heparin
1) Cover for risk of thrombosis ➞ given if patient, who is usually on Warfarin requires surgery (quick offset time allows its cessation if bleeding)
2) Prophylaxis in patients at high risk of thrombosis ➞ eg. medical Inpatients, post- op patients, Immobility
3) LMWH given prior to warfarin as quick onset covers patient whilst warfarin loading is achieved
4) Pregnancy ➞ can be used in place of warfarin
Give 3 adverse effects of Heparin
1) Bruising/bleeding
2) Osteoporosis ➞ a/w long term use (UFH>LMWH)
3) Thrombocytopenia (HIT)
What is Heparin Induced Thrombocytopenia, how is it diagnosed and how would you treat?
RARE Autoimmune phenomenon (usually after 4-14 days after starting Heparin). Tends to present with thrombosis not bleeding
Diagnosed by Lab assay and clinical probability
Treatment ➞ Stop heparin and give Fondaparinux
How do we do reversal of therapy for Heparin?
1) Stop Heparin
2) If UFH and actively bleeding, give Protamine
3) Monitor APTT if unfractionated
4) Protamine sulphate: dissociates heparin from anti-thrombin III
Give 4 anti-platelet drugs and the target of each
1) Aspirin (COX inhibition affecting platelet activation)
2) Dipyridamole (phosphodiesterase inhibition)
3) Clopidogrel (inhibits ADP dependant platelet aggregation)
4) Glycoprotein IIb / IIIa Inhibitors (inhibits platelet crosslinking and activation)
What is the purpose of Thrombolytics and how do they work?
Used to lyse already formed clots
Work by promoting Fibrinolysis by converting inactive plasminogen to active plasmin (plasmin degrades fibrin clot)
Give 3 uses of Thrombolytics
1) STEMI
2) Massive PE with haemodynamic compromise
3) Strokes (as long as haemorrhage is excluded by CT)
What are the 2 main types of Thrombolytics?
1) Recombinant tissue plasminogen activator e.g. rt-PA
2) Streptokinase
What are ‘novel oral anticoagulants’ (NOAC)
Give 2 targets and examples of each
NOAC: new anticoagulants
1) Direct Thrombin Inhibitor ➞ Dabigatran
2) Direct Factor Xa Inhibitors ➞ Apixaban, Rivaroxaban, Edoxaban
Give 4 advantages of NOAC over Warfarin
1) Rapid onset/offset of action
2) Few drug interactions
3) Predictable pharmacokinetics
4) Wide therapeutic window
5) eliminated need for regular coagulation monitoring and allowed fixed dosing in adults
Give 4 uses/Indications for NOAC
1) Atrial Fibrillation
2) Treatment of DVT/PE
3) Prevention of Recurrent DVT/PE
4) Prevention of DVT/PE post Hip/Knee surgery
