Anticoagulants - Pharmacotherapy

2.  The coagulation process that leads to hemostasis involves a complex set of
reactions involving approximately 30 different proteins
 These reactions convert fibrinogen, a soluble protein, to insoluble strands of
fibrin, which, together with platelets, forms a stable thrombus

3. Extrinsic
pathway
Intrinsic
pathway

5.  Direct thrombin inhibitor:
(argatroban, bivalirudin, dabigatran etexilate, desirudin)
 Factor Xa inhibitor:
(apixaban, betrixaban, edoxaban, rivaroxaban, fondaparinux)
** Direct oral anticoagulant ( DOAC):
(apixaban, betrixaban, edoxaban, rivaroxaban, dabigatran
etexilate)
 Vitamin K antagonist:
(warfarin, acenocoumarol)
 Heparin
 LMWH:
(dalteparin, enoxaparin, tinzaparin)

7.  Thrombin (factor lla) : final enzyme in the clotting cascade that
cleaves fibrinogen to fibrin and activates factor V,VIII,XI.
 Direct thrombin inhibitors are able to block the action of both
circulating and clot-bound forms of thrombin because their
site of binding to thrombin is not masked by fibrin ( not
obstructed), they prevent thrombin from cleaving fibrinogen to
fibrin.
 Parenteral DTIs include bivalirudin, argatroban, desirudin
 The only oral DTI available for clinical use is dabigatran

8.  VTE prophylaxis
 VTE treatment
 Atrial fibrillation (AF)
 Acute coronary syndromes (ACS)
 Heparin-induced thrombocytopenia (HIT)

10. Drug Doses Uses Monitoring
Bivalirudin IV bolus 0.75 mg/kg then 1.75 mg/kg/h infusion
(with renal failure use at lower infusion rate
1mg/kg/hr )
PCI, HIT, NSTEMI Upon indication for use:
activated clotting time (ACT)
(aPTT), with a target of 1.5 to
2.5 times the normal range
Argatroban *HIT: initial dose of 2 mcg/kg/min IV continuous
infusion,
*PCI: in pt with HIT or at high risk: bolus
350mcg/kg over 3-5 min then infusion
25mcg/kg/min
PCI, HIT aPTT prior adm.
&after 2h & after any dose
changes. (target 1.5 to 3 times
the initial baseline, not >100 s)
ACT before dosing, 5—10
minutes after bolus adm. & after
any change in infusion rate.
Desirudin 15 mg SC every 12 h, with the first dose
administered 30 minutes before hip arthroplasty
or postoperatively
DVT prophylaxis aPTT

11. Drug Warning C/I side effect Antidote
Bivalirudin Acute stent thrombosis
Bleeding
Hypersensitivity to any component of
formulation.
Major bleeding.
Major blood clotting disorder
Acute gastric or duodenal ulcer
Bacterial endocarditis severe uncontrolled
HTN, diabetic or hemorrhagic
retinopathy.
Using of spinal/epidural anesthesia
Bleeding, hypotensionN
pain, headache, nausea
Argatroban Thrombus formation
Bleeding
Hypersensitivity to any component of
formulation.
Major bleeding
Bleeding
Chest pain
Genitourinary tract
hemorrhage
GI side effect
Desirudin boxed warning: risk
of spinal/epidural hematoma in
patients anticoagulated with
desirudin when neuraxial
anesthesia is used.
Hypersensitivity to any component of
formulation.
Major bleeding
Major blood clotting disorder
Bleeding, deep vain
thrombophlebitis, nausea

12. Dabigatran is the only oral direct thrombin inhibitor available for
clinical use. Additional agents are under development

13. Monitoring Warning C/I S.E antidote:
prior to initiating:
platelet count, (PT),
(aPTT), creatinine if renal
insufficiency
Boxed warning*the risk
of spinal/epidural hemat
oma in patients
undergoing neuraxial
anesthesia or spinal
puncture
*risk of thrombotic
events following
premature
discontinuation
avoidance of dabigatran
in individuals with
creatinine clearance
<15 mL/minute or in
those who are
hemodialysis dependent
dyspepsia, dysmotility,
gastrointestinal reflux,
bleeding
Idarucizumab
Doses: Uses
VTE primary PX: 110mg one to 4 hours after surgery followed by 220mg once daily for 28-
35 days (hip replacement) or 10 days( knee replacement)
* VTE: treatment and secondary PX: 150 mg orally twice daily after 5 to 10 days of parenteral
anticoagulation (CrCl >30 mL/minute).
*Stroke prevention in(AF): 110 mg orally twice daily or 150 mg orally twice daily (CrCl
>30 mL/minute).
the prevention and management of (VTE)
disease, and in stroke prevention in
patients with (AF)

15.  Factor Xa upstream thrombin in clotting cascade at the convergence
point of the intrinsic and extrinsic pathway
 Direct factor Xa inhibitors bind to the active site of factor Xa and
inhibit factor Xa activity without a requirement for cofactors.
 Direct factor Xa inhibitors are able to block the action of both
circulating and clot-bound forms of factor Xa
 whereas indirect factor Xa inhibitors such as heparin and
fondaparinux are only able to inactivate factor Xa in the fluid phase
via antithrombin

16.  they prevent factor Xa from cleaving prothrombin to thrombin. They
bind directly to factor Xa
 No parenteral direct factor Xa inhibitors in clinical use
 Several oral agents are available, including rivaroxaban, apixaban,
edoxaban, betrixaban

17. Drug Dose Uses Monitoring
Rivaroxaban VTE primary PX : 10mg daily , duration depends on surgery type
*Treatment and secondary prevention of VTE: 15 mg BID(with food) for 21
days, followed by 20 mg /D (with food).
*Stroke prevention in (AF): 20 mg once daily with the evening meal (CrCl
>50 mL/min); or 15 mg/d with the evening meal (CrCl ≤50 mL/min).
used in the prevention and
treatment of (VTE) disease, and
in stroke prevention in patients
with atrial fibrillation (AF).
prior to initiating:
CBC, platelet
count, (PT),
(aPTT),(INR)
Apixaban •VTE primary PX: 2.5 mg twice daily, duration depends on surgery
•Treatment and secondary prevention of VTE: 10 mg twice daily for seven
days, followed by 5 mg twice daily. If therapy continues beyond six months,
the dose is reduced to 2.5 mg twice daily
•Stroke prevention in (AF): 5 mg twice daily (CrCl >50 mL/minute); or 2.5 mg
BID for those with any two of the following: age ≥80 years, body weight ≤60
kg, or serum creatinine ≥1.5 mg/dL.
same prior to initiating :
CBC, renal function
Platelet count, PT,
aPTT
Edoxaban VTE: is given after 5 to 10 days of parenteral anticoagulation. Typical dosing
is 30 or 60 mg orally once daily
same Prior to initiation:
CBC, renal function
Betrixaban 160 mg on the first day followed by 80 mg once daily. Doses are given at the
same time each day with food
prevention of VTE in
hospitalized adult medical
patients
Prior to initiation:
renal function

18. Drug Warning C/I S.E Antidote
Rivaroxaban the risk of spinal/epidural hematoma
in patients undergoing neuraxial
anesthesia or spinal puncture and the
risk of thrombotic events following
premature discontinuation
patients with prosthetic heart
valves or during pregnancy
bleeding ,
dizziness,
insomnia anxiety,
depression ,
fatigue, syncope ,
wound secretion,
abdominal pain
Andexanet alfa
Apixaban Same as Rivaroxaban Same Bleeding
increased
gammaglutamyl
trasferase ,
neausea
Andexanet alfa
Edoxaban Same
and reduced efficacy in nonvalvular
atrial fibrillation in patients with a high
CrCl (>95 mL/minute)
Same Bleeding, GI
bleeding,vaginal
hemorrhage
Andexanet alfa
Betrixaban Same as Rivaroxaban Same HTN, headache,
hypokalemia, GI
side effects
Andexanet alfa

20.  Fondaparinux , Heparin, LMWH
 Fondaparinux MOA:
Potentiates the antithrombin effect that inhibit Xa.
Adm.: IV,SC

21. Uses Doses Monitoring Warning C/I Adverse
effects
Antidote
ACS, VTE
treatment &
prophylaxis,
HIT, superfic
ial vein
thrombosis
ACS: SC 2.5
mg/d untill PCI
or
hospitalization
PT, aPTT Spinal/epidur
al
hemtaomas,
thrombocyto
penia,
Bleeding
Hypersensitiv
ity to it,
CrCl<30ml/
min,
bleeding,
bacterial
endocarditis,
antiplatelet
antibody.
Bleeding,
anemia,
hypotension,
insomnia,
wound
secretion.
*Andexanet
alfa

22. *Heparin:
 MOA: accelerate interaction of antithrombin III with both
thrombin and factor Xa.
 Adm.: IV, SC
*LMWH:(enoxaparin,dalterparin,nadroparin,tinzaparin)
 MOA: accelerate interaction of antithrombin with factor
Xa.
 Adm.: SC, IV in acute MI.

24. Uses Doses Monitoring
Anticoagulation ,in PCI, interstitial
cystitis, mechanical prosthetic
valve, STEMI, NSTEMI, VTE
1-STEMI/NSTEMI: Initial bolus of 60 units/kg (maximum: 4,000
units), then 12 units/kg/hour
2-anticoagulation: initial 1000 then 50-70 units/kg q4-6 h.
3-AF: plasma heparin level 0.3-0.7 u/ml
4-PCI: without GPIIb/IIIa inhibitor:70-100 u/kg
With 50-70u/kg
5-thromboprophylaxis:sc 5000u q8-12 h
6-VTE: 80 u/kg IV bolus then 18u/kg/h
therapeutic aPTT
1-aPTT of 1.5 to 2.5 times
Warning C/I S.E Antidote
Bleeding, heparin resistance, hyperkalemia,
hypersensitivity reaction, osteoporosis
if>6month, thrombocytopenia (HIT),
Hypersensitivity to heparin
or any component to the
formulation,
thrombocytopenia, HIT,
uncontrolled active
bleeding
thrombocytopenia (HIT),
chest pain, shock,
vasospasm, chills,
dysethesia, dermal ulcer
protamine sulfate

25. Drug Uses Doses Monitoring
Enoxaparin DVT prophylaxis, DVT,PE treatment, PCI,
NSTEMI, unstable angina, mechanical
prosthetic heart valve to bridge anticoagulant,
Prevention of recurrent VTE in pregnancy.
*Prevention of recurrent VTE in pregnancy: 40mg/d, continue 6weeks
postpartum in high risk women.
*DVT,PE treatment: 1mg/kg/dose Q12
*STEMI: if pt<75year: initial 30mg iv bolus+ plus 1mg/kg sc(max:100mg in
first 2 doses) MD:1mg/kg q 12h. Pt >=75year initial: sc 0.75mg/kg Q12h
(max75mg in 2 first doses) MD: 0.75mg/kg SC q12h
*unstable angina/ NSTEMI: 1mg/kg q12h until PCI or hospitalization.
initial :(PT)
and (aPTT),
anti Xa level
Dalteparin Anticoagulant for hemodialysis and
hemofiltration , DVT treatment and
prophylaxis, PE treatment. mechanical
prosthetic heart valve to bridge anticoagulant,
prevention of recurrent VTE in pregnancy,
unstable angina, or non Q wave MI
*DVT , PE treatment: SC 200 u/kg/d
*prevention of recurrent VTE in pregnancy: SC5000u/d continue for 6month
postpartum
*unstable angina, NSTEMI: SC120u/kg (max 10000u) Q12h for 5-8 days.
initial :(PT)
and (aPTT),
anti Xa level
Nadroparin ACS:Unstable angina,NSTEMI, Anticoagulant
for hemodialysis, DVT treatment,
thromboprophelaxis
*ACS: initial IV:86u/kg bolus(max9500u), MD: after12h 76mg/kg q12h
(max.19000u/d)
*DVT treatment: 86u/kg q12h (max.17100u/d)
initial :(PT)
and (aPTT)
anti Xa level
Tinzaparin DVT,PE treatment ,mechanical prosthetic
heart valve to bridge anticoagulant,
postoperative thromboprophylaxis,
Anticoagulant for hemodialysis,
DVT,PE treatment: SC 175 anti Xa u/kg/d (max. 18000 antiXa u/d) initial :(PT)
and (aPTT)
anti Xa level

26. Drug Warning C/I S.E Antidote
Enoxaparin Spinal/epidural
hematoma.
Bleeding, hyperkalemia,
thrombocytopenia,
Hypersensitivity to enoxaparin or heparin,
history of HIT in the past 100days, active
major bleeding
Anemia, hemorrhage,
peripheral edema,
confusion
1 mg protamine
per 1 mg of
enoxaparin.
Dalteparin same Hypersensitivity to it or heparin, acute
inactive endocarditis, active bleeding,
history of HIT, :pt with unstable angina or
NSTEMI or thromboembulism prophylaxis
undergoing epidural/neuraxial anesthesia.
Hemorrhage,
thrombocytopenia
1 mg protamine
per 100 anti-
factor Xa units of
LMW heparin.
Nadroparin Bleeding, cutaneous
necrosis, hyperkalemia,
thrombocytopenia
Hypersensitivity to it or other LMWH or
heparin, acute inactive endocarditis, active
bleeding, history of HIT
Bleeding, artirial
thrombous,
thromboembolism,
venous thrombosis
1 mg protamine
per 100 anti-
factor Xa units of
LMW heparin.
Tinzaparin Bleeding, hyperkalemia,
thrombocytopenia
Hypersensitivity to it or other LMWH or
heparin, active bleeding, History of HIT,
endocarditis, severe uncontrolled pressure,
Spinal/epidural anesthesia
Increase ALT, hematoma
at injection site, chest
pain
1 mg protamine
per 100 anti-
factor Xa units of
LMW heparin.

27.  Warfarin
 Acenocoumarol
MOA:
inhibit vit K epoxide reductase

29. Drug Uses Doses Monitoring
Warfarin Atrial fibrillation,Acute coronary syndrome,Heart
failure,Prosthetic heart valve,Stroke,Deep vein
thrombosis ,Pulmonary embolism,
Antiphospholipid syndrome
Dose should individualized
Initial dose 2.5-5 mg/d
(PT) ,(INR),
(aPTT), to obtain
a baseline value
for monitoring,
Then PT/ INR
Acenocoumarol Same Dose should individualized
Initial dose 8-12 mg in day1
then 4-8 day on day 2
Usual MD range 1-10 mg/d
PT/INR

30. Drug Warning C/I S.E Antidote
Warfarin Bleeding
Acute kidney injury
Anaphylaxis
Calciphylaxis
Skin necrosis
Atheroemboli
Hypersensitivity to warfarin or any
component of formulation, hemorrhagic,
recent or potential surgery of the eye or
CNS, major regional lumbar block
anesthesia, pericardial effusion, malignant
HTN, bacterial endocarditis, eclampsia,
preeclampsia, pregnancy
Hemorrhage, ,systemic
cholestrol micro-embolism,
chills, alopecia, dermatitis,
pruritus, GI pain ,N/V, bloating,
diarrhea
Vit. K
Acenocoumarol Same Hypersensitivity to acenocoumarol
& same as warfarin
Bleeding ,skin necrosis, priapism Vit. K

33.  LMWH (preferred)
 UFH
 Alternatives: fondaparinux, danaparoid, argatroban

34.  Limited study & information.