Lecture 22- Anticoagulants

Question 1

Haemostasis

Answer 1

• Limits bleeding following injury- adhesion and activation of platelets and fibrin formation
  
  • Haemostatic plug + fibrin mesh= stable bleeding control

Question 2

Thrombosis=

Answer 2

pathological haemostasis – in the absence of bleeding (things have gone wrong)

Question 3

Thromboembolic disease is common

Answer 3

• deep vein thrombosis (DVT) and pulmonary embolism (PE)
• transient ischaemic attacks (TIA), ischaemic stroke - myocardial infarction (MI)
• consequence of atrial fibrillation (AF)

Question 4

Venous and intracardiac thrombosis driven largely by

Answer 4

coagulation cascade and fibrin compared to arterial thrombus - mainly platelet rich

Question 5

the coagulation cascade

Answer 5

Question 6

Anticoagulant drugs

Answer 6

prevent thrombus formation and thrombus growing

• by regulating the coagulation cascade preventing solidification of all blood

Question 7

Coagulation factors are present in blood as

Answer 7

zymogens

Question 8

name an intrinsic inhibitor of the coagulation cascade

Answer 8

antithrombin III (AT-III)

Question 9

key contributors tot he regulation of the coagulation cascade

Answer 9

• Number of intrinsic inhibitors of this pathway including antithrombin III (AT-III)
• Vascular endothelium and its regulation of many mediators also critical for balance in coagulation cascade (and platelet activation)
• Calcium is an important cofactor in many of the coagulation cascade steps (think of chelators used in blood tubes)

Question 10

name some anticoagulants

Answer 10

• Heparins
• Warfarin
• Direct oral anticoagulants (DOACS)

Question 11

heparins are produced naturally in

Answer 11

mast cells and vascular endothelium

Question 12

production of heparins

Answer 12

• Extracted for pharmaceutical use from porcine intestinal mucosa (less so now - bovine lung)

Question 13

types of heparin

Answer 13

• Unfractionated heparins (UFH) are large ~7-30 kDa
• Low molecular weight heparins (LMWH) ~1-6 kDa produced in 1980’s

Question 14

basic MOA of heparins

Answer 14

• Enhance antithrombin III (AT-III) activity - ~ 1000-fold

Question 15

Indications for use of heparins

Answer 15

• Prevention of venous thromboembolism
  
  • perioperative prophylaxis with LMWH - duration and dose is dependant on risk
• During pregnancy used as do not cross placenta – monitored with caution
• Venous Thromboembolism (VTE)–DVT and PE
  
  • initial treatment prior to oral agents (see later slides)
  • Long term in some patient group
  • Cancer related VTE
• Acute Coronary Syndromes (ACS)
  
  • short term - reducing recurrence and or extension of coronary artery thrombosis post STEMI- PCI and non PCI patients
  • NSTEMI

Question 16

Unfractionated heparin (UFH) pharmacokinetics

Answer 16

• ~ 45 polysaccharide unit mixture
  
  • fast onset of action t1/2 30min low dose
  • 2h at higher doses – mixed elimination so is unpredictable
• Typically i.v. bolus and infusion, s.c. for prophylaxis with low bioavailability

Question 17

Unfractionated heparin (UFH) Mode of action

Answer 17

• Binding to antithrombin (ATIII) causing conformational change and increased activity of ATIII
• To catalyse inhibition of thrombin (IIa), heparin needs to simultaneously bind ATIII AND IIa.
• Xa inhibition only needs ATIII binding

Question 18

name some low molecular weight heparins (LMWH)

Answer 18

• dalteparin, enoxaparin, fondaparinux

Question 19

Low molecular weight heparins (LMWH) Pharmacokinetics

Answer 19

• Typically ~ 15 polysaccharides which are absorbed more uniformly (units/kg dosing)
• Almost always s.c. (enoxaparin i.v. in ACS)
• Bioavailability > 90%, longer t1/2 ~ 2+h
• More predictable dose response as does not bind to endothelial cells, plasma proteins and macrophages – it isn’t long enough

Question 20

LMWH MOA

Answer 20

• Do not inactivate thrombin (IIa) – not long enough
• Inhibition of Xa specifically – by enhancing ATIII activity
• Fondaparinux – synthetic pentasaccharide selectively inhibits Xa by binding to ATIII – s.c., t1/2 18h

Question 21

unfractionated heparin vs LMWH

Answer 21

Question 22

when are UFH used

Answer 22

moderate renal impairment and v.fine control

Question 23

when are LMWH used

Answer 23

most situations

Question 24

Adverse drug reaction

Answer 24

• Bruising and bleeding (most common)
  
  • Intracranial
  • Site of injection
  • GI
  • Epistaxis
• Heparin induce thrombocytopenia (HIT)
  
  • Autoimmune response 2-14 days after initiation of heparin
    
    • Antibodies to heparin platelet factor 4 complex produced
    • Depletion of platelets
    • but paradoxically can lead to thrombosis as more platelets activated by damaged endothelium
• Hyperkalaemia- inhibition of aldosterone secretion
• Osteoporosis- rare long-term use, higher risk with UFH and more prevalent in pregnancy (least common)

Question 25

heparin Contraindications

Answer 25

• Clotting disorder
• Renal impairment (LMWH and fondaparinux)

Question 26

heparin drug-drug interactions

Answer 26

• Antithrombotic drugs
• ACEi/ARB
• Spironolactone

Question 27

Heparin monitoring and reversal

Answer 27

• (activated) partial thomboplastin time (aPTT) when using therapeutic i.v. doses of UFH required – dose titrated/adjusted against this value
• LMWH much more predictable in its action so normally requires little monitoring

Question 28

heparin reversal agents:

Answer 28

• Protamine sulphate forms inactive complex with heparin – given i.v. dissociates heparin from ATIII, irreversible binding amount given guided by heparin dose
  
  • Paradoxically can cause bleeding!?
  • Much greater effect with UFH than LMWH, no affect on fondaparinux

Question 29

name the vitamin k antagonist

Answer 29

warfarin

Question 30

warfarin uses

Answer 30

• Venous thromboembolism
• PE
• DVT (and secondary prevention Superficial vein thrombosis)
• Atrial fibrillation with high risk of stroke (use CHA2DS2Vasc)
• Patients who need cardioversion
• Heart valve replacement bio prosthetic and some mechanical
• Generally used in longer term anticoagulation compared to heparins
• Slow onset of action likely to require heparin cover (see later slides) if anticoagulation needed immediately

Question 31

Pharmacokinetics of warfarin

Answer 31

• Good GI absorption and taken orally ~95+% bioavailability
• Functional CYP2C9 polymorphisms contribute to significant inter individual variability
• [Plasma] does not correlate directly with clinical effect
• Warfarin is a racemic mixture of two enantiomers – R and S which have different potency and metabolised differently

Question 32

How is warfarin different to heparin

Answer 32

• Delay in onset of action as circulating active clotting factors present for several days
• Must be cleared and replaced with non-carboxylated forms (inactive clotting factors)
• Half life= 36-48h (some variation)

Question 33

MOA

Answer 33

• Inhibit activation of vitamin K dependant clotting factors (coagulation vitamin)
• Inhibits conversion of vitamin K to active reduced form – competitive inhibition of VKOR
• Hepatic synthesis of clotting factors II, VII, IX and X requires vitamin K as cofactor for activation

Question 34

warfarin adverse drug reaction

Answer 34

• Bleeding- any pt taking warfarin are of clinical interest
  
  • Epistaxis and spontaneous retroperitoneal bleeding

Question 35

warfarin antidote

Answer 35

• Most effective antidote is vitamin K1
  
  • addition of prothrombin complex concentrate i.v. Stop warfarin!

Question 36

warfarin Contraindications

Answer 36

• Pregnancy
  
  • Crosses the placenta
  • Avoided at least in 1^st (teratoegnic) and 3^rd (haemorrhage) trimesters
• Hepatic disease
• Response affected by CYP2C9
• Perioperative anticoagulation needs to be considered – need to consider if and when to pause warfarin specific patient group and local guidelines will dictate
  
  • Bridging therapy with LMWH often required when initiating or temporarily stopping warfarin (surgery, sickness…)

Question 37

drug drug interaction warfarin

Answer 37

Drug-drug reaction (huge number- potentiate anticoagulant effect, but some decrease)

• Vitamin K intake e.g. fluctuating amount of green vegetable e.g. broccoli, cucumber
• Changes to gut bacteria e.g. cephalosporin antibiotic (reduces vitamin K)
• Alcohol
• Inhibition of CYP29C9 e.g. clopidogrel, alcohol, amiodarone
• Displacement of warfarin from plasma albumin by NSAIDS and drugs that decrease GI absorption of vitamin K
  
  • Likely increase INR (more anticoagulated)
• Accelerated warfarin metabolism by inducers e.g. barbiturates, phenytoin, rifampicin, St Johns Wort
  
  • Decrease INR- less anticoagulation

Question 38

Warfarin use and INR

Answer 38

• Monitoring required due to huge variation in patient response
• Keeping diet and lifestyle/medications stable is important
• Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma
• Referred to as international normalised ratio – INR - clotting time against a standard
  
  • Allows for standard corrected value comparable across all laboratories

Question 39

which factor is most sensitive to vitamin K deficiency

Answer 39

• Factor VII most sensitive to vitamin K deficiency so used in prothrombin time - standardised against control plasma

Question 40

aiming for an INR of 2.5

Answer 40

• DVT
• PE
• AF (risk

Question 41

aiming for an INR of 3.0 - 3.5

Answer 41

Recurrent DVT or PE in patients currently receiving anticoagulation

Question 42

people on warfarin carry

Answer 42

Carry Anticoagulant card- risk of internal bleeding e.g. after fall or crash

Question 43

High INR=

Answer 43

more anticoagulated

Question 45

Low INR

Answer 45

less anticoagulated

Question 46

INR stands for

Answer 46

international normalised ratio

Question 47

DOAC

Answer 47

• Direct acting oral anticoagulants (DOAC)
  
  • May see described as NOAC but DOAC internationally preferred

Question 48

name some DOACs

Answer 48

• Direct Xa acting drugs
  
  • Apixaban
  • Edoxaban
  • Rivaroxaban
    
    • Inhibit both free Xa and that bound with ATIII, do not directly effect thrombin (IIa) - hepatic metabolism and excreted partly by kidneys
• Direct IIa acting drug
  
  • Dabigatran
    
    • Selective direct competitive thrombin inhibitor, both circulating and thrombus bound IIa

Question 49

NOAC adminstration

Answer 49

• Oral administration, standard dosing and little to no direct monitoring required
  
  • When would monitoring be beneficial? E.g. where adherence isn’t good

Question 50

DOAC indications

Answer 50

• Different DOACs are indicated in many presentations where vitamin K antagonists (warfarin) used to be the only option
• Antidotes now available
  
  • Andexanet and idarucizumab

Question 51

ADR DOAC

Answer 51

ADR

• Bleeding (lower intracranial bleed risk compared to warfarin)
• Caution and dose adjustment separately in GI bleed risk groups

Question 52

DOAC Contraindications

Answer 52

• Metabolism and elimination by several routes
• X dabigatran contraindicated in low creatinine clearance (<30 mL/min)
• others are at very low creatinine clearance (<15 mL/min)
• Little information on use in pregnancy and breastfeeding – avoid

Question 53

Drug drug interaction

Answer 53

• Less frequent interactions than warfarin but affected by CYP inhibitors and inducers
  
  • [plasma] reduced by carbamazepine, phenytoin and barbiturates
  • [plasma] increased by macrolides