DRUGS RELATED TO

COAGULATION
Dong Ngoc Quang
OMFS Postgrad Student
HEPARIN
MECHANISM
Combine with
antithrombin-III
Inactivate many clotting
factors (including
thrombin (II) and VIII
XII)
Encourage the release of
tissue factor pathway
inhibitor (TFPI)
UNFRACTIONATED HEPARIN
Half life 30 mins, unpredictable
Mainly metabolised by endothelial cells,
liver, kidney
Subcutaneous:
Low dose
Bioavailability: 30%
Takes effect after up to 1 hour
NOT for emergency
UNFRACTIONATED HEPARIN
IV route:
Rapid (immediate)
Higher bioavailability
Can be used in emergency
LMWH
Low Molecular Weight Heparin
More predictable dose response
Greater subcutaneous bioavailability
(90%) more effective
Greater effect on Xa than IIa
Same anticoagulant effect as UFH
Reduce the risk of bleeding

Heparin Side Effects
Haemorrhage, increase by alcohol
Osteoporosis (less w/ LMWH)
Thrombocytopenia (life threatening):
caused by Heparin induced antiplatelet
antibodies
Hyperkalemia: inhibition of aldosteron
secretion
Hypersensitivity

aPTT
Activated Partial Thromboplastin Time
Heparin works on intrinsic pathway and is
measured by aPTT
Normal: 25 39 seconds
Prolonged when: using Heparin,
Haemophilia
WARFARIN
Mechanism: inhibits enzymatic reduction
of Vitamin K to its active form
(hydroquinone).Vitamin K is required for
factor II, VII, IX, X, protein C and S
Half life average 40 hours
Crosses the placenta, tiatrogenic
Early stages: defect, Later stages: foetal
haemorrhage
DO NOT use in pregnancy

WARFARIN

Metabolised by cytochrome P450 system,
interacts w/ many drugs
Monitored by Prothrombin time, expressed
in INR.
Dose of warfarin is adjusted to give INR of 2-4
WARFARIN
Adverse effects:
Haemorrhage: bowel and brain.
Treated by Vitamin K or fresh plasma
containing clotting factors
Teratogenicity
Necrosis of soft tissue (buttock, breast): rare
but serious
WARFARIN
Things increase warfarin effects:
Liver disease
High metabolis states
Drugs:
Inhibit synthesis of Vitamin K
Inhibit hepatic metabolism
Inhibit platetlet
Displace warfarin from its binding site on albumin

WARFARIN
Things that decrease warfarin effects:
State: pregnancy, hyperthyrodism
Drugs
Vitamin K, food rich of Vitamin K (broccoli)
Induce hepatic cytochrome P450 enzymes
ASPIRIN
Antiplatelet
Mechanism: permanently inactivate COX
activity of prostaglandin H synthetase
1 and 2 (COX-1, COX-2)
These catalyze the process to convert
Arachidonic acid to PGH
2

PGH
2
is the cursor of PGD
2
, PGE
2
, PGF
2
,
PGI
2
, TA
2

ASPIRIN
Platelet function and mechanisms of antiplatelet therapy. ADP=adenosine diphosphate;
Ecs=endothelial cells; Gi=inhibitory G protein; GP=glycoprotein; PG=prostaglandin; P2=type 2
platelet purinergic receptor; TX=thromboxane; HETE=hydroxyeicosatetraenoic acid;
HPETE=hydroperoxyeicosatetraenoic acid.
Source: Peter, J.M. et al (2005); Aspirin Resistance and
Atherothrombotic Disease, Journal of the American College of
Cardiology, 46(6), p. 987
ASPIRIN
Rapidly absorbed in the stomach and
upper instestine
Inhibition of TXA
2
dependent platelet
function by 1 hour.
Half-life 15 20 mins, inhibitory effect last
for the life span of platelet
ASPIRIN
Doses: use lowest effective dose is the
best strategy
AF:
Effective but < warfarin
DVT:
Effective but better methods of
thrombophylaxis available (LMWH,
rivaroxaban, dabigatran) not
recommended
ASPIRIN
Does not cause a generalized bleeding
abnormality unless used in patients w/
underlying hemostatic defect
Balance between preventing &
haemorrhage depends on absolute
thrombotic vs haemorrhagic risk
GI toxicity: even low dose
NOVEL ANTICOAGULANTS
Focus on the selective inhibition of clotting
factors
Two main factors: Xa and IIa (thrombin)
block both pathways
DABIGATRAN
Rapid absorbtion (onset within 2 hours)
Not metabolized by cytochrome P450
low risk of drug interaction
Bioavailability 6.5%, required high doses
80% excreted via kidney, contraindicated
in patient w/ renal failure
Indication: VTE treatment/prevention,
Stroke prevention in AF
RIVAROXABAN
Factor Xa inhibitor
High bioavailability
Rapid onset
Metabolized by liver, kidney
Can be administered in fixed dose w/o
coagulation monitoring
Minimal drug interactions
Indications: VTE treatment/prevention,
Stroke prevention in AF, ACS
APIXABAN
Factor Xa inhibitor
Bioavailabillity 50%
Excreted mainly in feces, 25% via kidney
Indications: VTE treatment/prevention,
Stroke prevention in AF, ACS

NOVEL ANTICOAGULANTS
Dabigatran extexilate Rivaroxaban Apixaban
Target Thrombin Factor Xa Factor Xa
Prodrug Yes No No
Bioavailability 6.5 >80 >50
Time to peak level
(hours)
2-3 2-4 3
Half-life (hours) 14-17 9 9-14
Renal excretion (%) 80 33 (67% by liver) 25(~70% in feces)
Dosing Once or twice daily Once or twice daily Twice daily
Drug interactions Potent CYP3A4 and P-
glycoprotein inhibitors
Potent CYP3A4 and
P-glycoprotein
inhibitors
Potent CYP3A4 and
P-glycoprotein
inhibitors
Antidode No No No
Properties of dabigatran etexilate, rivaroxaban, and apixaban

Source: Lip. Y. G. et al (2013) Handbook of Oral Anticoagulation. 2
nd
end. Springer
Healthcare. [Online]
Available at: http://www.springerhealthcare.com
THANK YOU