ANTICOAGULATION

MUNIBA NASEEM
CLINICAL PHARMACIST
⦿ OBJECTIVES
▪ Hemostasis
▪ Pathophysiological event of thrombosis
▪ Need of anticoagulants
▪ Properties of an ideal anticoagulant
▪ Classification of anticoagulants. Parenteral vs
Oral
▪ Switching between anticoagulants
▪ Bridging
▪ Anticoagulation clinic
▪ Role of pharmacist
 HEMOSTASIS
⦿ 5 basic mechanisms:
o Vascular spasm
o Platelet adhesion– activation-- aggregation
o Blood coagulation- occurs as a consequence
of 3 mechanism
1. Formation of prothrombin activator (
involves extrinsic and intrinsic pathway)
2. Conversion of prothrombin to thrombin
3. Conversion of fibrinogen to fibrin
⦿ Clot retraction
⦿ Fibrinolysis
 PATHOPHYSIOLOGY OF
COAGULATION SYSTEM
⦿ Thrombus
▪ Arterial thrombi – forms under condition of
high blood flow, composed of platelet
aggregates held together by fibrin strands
▪ Venous thrombi – forms under condition of
low blood flow, composed of red cells +
large amount of fibrin and a very few
platelets
⦿ Embolus – an intravascular clot that floats
within the blood
⦿ Conditions that require anticoagulation

❑ Thrombophilia
▪ APC resistance (factor V leiden)
▪ Protein C and protein S deficiency
▪ Antithrombin III deficiency
▪ APLA (antiphospholipid antibodies)
▪ Elevated levels of factor VIII
▪ Hyperhomocysteinemia
▪ Heriditary dysfibrinogenemia
⦿ DVT
⦿ PE
⦿ Stroke prevention in AF
⦿ Peripheral arterial ischemia/infarct
⦿ Peripheral arterial disease
⦿ CAD/MI
⦿ PCI (stent placement)
⦿ CHF
⦿ Valve replacement
⦿ CV disease/ stroke
⦿ Cancer
⦿ Pregnacy
 WHY ANTICOAGULANTS

❑ Eliminate or reduce the risk of blood clot

❑ Do not actually dissolve the clot
 PROPERTIES OF AN IDEAL
ANTICOAGULANT
⦿ Orally active
⦿ Rapid onset of action
⦿ Minimum food and drug interactions
⦿ Predictable anticoagulant effect
⦿ Safe in patients with hepatic and renal
impairment
⦿ Rapid offset in action
⦿ Antidote
⦿ Less side effects
 PARENTERAL
ANTICOAGULANTS

HEPARIN
USES:
DVT, PE, AF, DIC, also used to maintain
catheter patency, and as an anticoagulant in
blood transfusions, dialysis and laboratory
samples.
DOSES
Prophylactic : 5000 units sc q8-q12h
DVT/PE treatment:
• Bolus 80units/kg followed by continuous
infusion @18 units/kg/hr
• Outpatient: 333 units/kg sc then 250 units/kg
q12h
Acute cardiac/ stroke: bolus 60units/kg (cardiac
only, no bolus for stroke) followed by 12
units/kg/hr
PEDIATRIC
⦿ Infants: IV: Initial loading dose: 75 units/kg over 10
minutes; then initial continuous maintenance
infusion at: 28 units/kg/hour; adjust dose to maintain
an anti-Xa activity of 0.35 to 0.7 units/mL
⦿ Children and Adolescents: IV: Initial loading dose:
75 units/kg over 10 minutes, then initial continuous
maintenance infusion at: 20 units/kg/hour; adjust
dose to maintain an anti-Xa activity of 0.35 to 0.7
units/mL
ADVERSE EFFECTS
❑ Bleeding – protamine sulphate can reverse heparin.
Dose is 1mg/100 units of heparin (max 100 mg).
Protamine binds tightly to heparin, preventing it
from catalyzing the AT-thrombin reaction
❑ Venous limb gangrene
❑ Elevation of liver enzymes
❑ Osteoprosis
❑ Hypoaldosteronism
❑ Hyperkalemia
❑ HIT
⦿ Type I (non immune mediated/HAT)
o Occurs in 10-30 % of patients
o Due to platelet proaggregating effects
o No risk of thrombosis
o Occurs in first 2 days of heparin therapy
o Disappears when heparin is stopped

⦿ Type II (immune mediated/ HIT)

o Occurs in < 5% of patients
o Due to the formation of PF4/heparin complexes
that induce antibody formation
o PF4/heparin complex + antibodies induces platelet
aggregation followed by thrombin generation
o risk of thrombosis
o Occurs in 5-14 days of heparin therapy
MONITORING
❖ APTT is used to monitor therapeutic doses of UFH
❖ Goal APTT is 46-70 (1.5 -2.3 times normal)
LMWH

⦿ Enoxaparin
⦿ Deltaparin
⦿ Tinzaparin
 ENOXAPARIN

DOSING
Prophylaxis: 40mg qd
DVT/PE treatment: 1mg/kg q12h or 1.5mg/kg q24h
Unstable angina/NSTEMI: 1mg/kg q12h
STEMI: <75 yrs- 30mg IV bolus + 1mg/kg q12h
(max100 mg for 1st 2 doses only)
> 75 yrs – 0.75 mg/kg q12h ( max 75 mg for 1st 2
doses only), no bolus
Dosage titration based on anti Xa levels
NEONATAL
⦿ Prophylaxis: 0.75 mg/kg/dose every 12 hours
⦿ treatment: Initial: SubQ: 1.5 mg/kg/dose every 12 hours Premature
neonates: SubQ: 2 mg/kg/dose every 12 hours
⦿ Full-term neonates: SubQ: 1.7 mg/kg/dose every 12 hours
PEDIATRIC:
⦿ Prophylaxis:
o Infants 1 to <2 months: SubQ: 0.75 mg/kg/dose every 12 hours
o Infants ≥2 months, Children, and Adolescents: SubQ: 0.5 mg/kg/dose every
12 hours
⦿ Treatment
⦿ Infants 1 to <2 months: SubQ: 1.5 mg/kg/dose every 12 hours
⦿ Infants ≥2 months, Children, and Adolescents: SubQ: 1 mg/kg/dose every
12 hours
MONITORING
⦿ Baseline platelets, CBC, serum creatinine
⦿ Platelet count every 3-5 days, serum creatinine
twice weekly
⦿ Anti Xa levels 4 hours after sc injection
• Prophylaxis : 0.2-0.4 units/ml
• Twice daily dosing : 0.6-1 units/ml
• Once daily dosing : 1-2 units/ml
Reversal of anticoagulant effect
⦿ Protamine partially reverse ( appx 60%)

⦿ Administer 2 units FFP

RENAL DOSE ADJUSTMENT
⦿ Decrease frequency to once daily i.e 1mg/kg/d
⦿ Prophylaxis: 20-30 mg qd
CONTRAINDICATIONS
o Thrombocytopenia
o Severe renal insufficiency
o Active bleeding
o HIT
o Neuraxial anesthesia/ spinal puncture – epidural or
spinal hematomas may occur that may result in long
term paralysis
⦿ Optimal timing between the administration of
enoxaparin and neuraxial procedure – enoxaprin should
be stopped 12 hours prior to neuraxial procedure and
can be reinitiated 4 hours after the procedure
 DIRECT THROMBIN
INHIBITORS
⦿ UNIVALENT DTIs
argatroban
⦿ BIVALENT DTIs
lepirudin
bivalirudin
desirudin
ADVERSE EFFECTS
⦿ Intracranial bleeding
⦿ Overall risk of bleeding
⦿ Minor hematuria
ORAL ANTICOAGULANTS
WARFARIN

How vitamin K is involved in blood clotting?

⦿ Viitamin K epoxide reductase inhibitor
DOSAGE
⦿ Generally adjusted to INR 2-3; recommennded
testing INR after 2 doses for initial dose
adjustment.
⦿ initial dose is 5- 10 mg
⦿ Adjusted dose ranges from 0.5-30mg in
resistant individuals
PEDIATRIC
⦿ Day 1: Initial loading dose (if baseline INR is 1 to 1.3): 0.2
mg/kg/day once daily; maximum dose: 10 mg/dose
⦿ Days 2 to 4: Additional loading doses are dependent upon
patient's INR:
o INR 1.1 to 1.3: Repeat the initial loading dose
o INR 1.4 to 1.9: Dose is 50% of the initial loading dose
o INR 2 to 3: Dose is 50% of the initial loading dose
o INR 3.1 to 3.5: Dose is 25% of the initial loading dose
o INR >3.5: Hold the drug until INR <3.5, then restart at 50% of previous
dose
⦿ Days ≥5: Maintenance doses are dependent upon patient's
INR
o INR 1.1 to 1.4: Increase dose by 20% of previous dose
o INR 1.5 to 1.9: Increase dose by 10% of previous dose
o INR 2 to 3: No change
o INR 3.1 to 3.5: Decrease dose by 10% of previous dose
o INR >3.5: Hold the drug until INR <3.5, then restart at 20%
less than the previous dose
⦿ Usual maintenance dose: ~0.1 mg/kg/day once daily; range:
0.05 to 0.34 mg/kg/day
Starting nomogram for otherwise healthy patients
Starting nomogram for elderly patients at bleeding
risk
Management of elevated INR
A 75 year old male was discharged 5 days ago with a
bioprosthetic valve in aortic position. He has a history of
type 2 diabetes, chronic AF, and hypertension. Warfarin was
begun on day 1 (10mg qd) and the patient was discharged
on day 7 with a prescription for warfarin 10mg qd with a
follow-up visit in 2 weeks. The INR history of the patient is
as follows:
Day 1 warfarin dose 10mg INR 1.8; day 5 warfarin dose 10
mg INR 2.4; day 7 warfarin dose 10mg INR 3
QUESTIONS

⦿ Is it reasonable to have the patient wait 2 weeks to have the

INR checked?
⦿ What is the ACCP recommendation for a starting dose of
warafrin?
⦿ The recommended therapeutic INR range should be….
⦿ During a follow up appointment, the patient asks for how
long will he take warfarin. What would be the best
response?
ADVERSE EFFECTS
⦿ Bleeding
⦿ Skin necrosis/ venous limb gangrene
⦿ Fetal bleeding and embryopathy

CONTRAINDICATIONS/PRECAUTIONS
⦿ Acute liver dysfunction
⦿ Heart failure
⦿ Acute GI illness
INTERACTIONS:
⦿ Too many.
⦿ Amiodarone require warfarin dose to be reduced
by 50%
⦿ Antiobiotics
⦿ Estrogen supplements
⦿ CYP3A4 inducers/ inhibitors
⦿ Cholestyramine
⦿ sulphamethoxazole
An 80 year old female patient on warfarin for 8 months for
chronic AF, past medical history include type 2 diabetes. On
9/10, metronidazole was prescribed for 10 daysfollowing a
positive C.diff culture. In addition, zestril 10 mgqd was
ordered for blood pressure control.
upon review of the patient’s history you note the following:
day 5/23 warfarin 5mg qd INR 2.4; 6/27 warfarin 5mg qd
INR 2.2; 7/25 5mg qd INR 2.5; 9/12 warfarin 5mg qd INR
2.9
QUESTION
⦿ What has caused the sudden change in the patient’s status?
⦿ Describe your management plan for this patient as per new
dosing guidelines, any intervention for bleeding, and when
you would want to have the patient return for evaluation
⦿ On 9/14 patient calls you at the clinic complaining of
frequent nose bleeds during the past three days, INR is
checked and the result was 4.0.
 NOAC
DIRECT THROMBIN INHIBITORS
DABIGATRAN
DOSING
⦿ NVAF – 150mg bid (75mg for CrCl <30 ) when INR<2, avoid
in patients with sever renal dysfunction
⦿ VTE – 150mg BID, avoid for CrCl <30; treat patient with
parenteral anticoagulant for 5-10 days first
⦿ DVT prophylaxis
o 150mg daily for 28-35 days for HR and 6-10
days for KR
PATIENT COUNSELING
⦿ Coated pallets in a capsule form with a tartaric acid core to
enhance absorption as low pH is required. The acidity may
explain the increased incidence of dyspeptic symptoms and
GI bleeding. Need acidic environment to absorb. Unknown
effect if patient is also taking a PPI.
⦿ Pallets in capsule can not be chewed, crushed, split, or
opened to empty contents
⦿ Once the bottle is opened, the product must be used within
4 months. Storage in original package o protect from
moisture due to desiccant in cap of bottle and keep the bottle
tightly closed.
⦿ Missed dose can be taken with 6 hours.
⦿ Reversal agent – Idarucuzimab
⦿ Removed by hemodialysis
⦿ No monitoring tool. Consider monitoring
hemoglobin to check for hidden bleeding
DRUG INTERACTIONS
⦿ Antacids
⦿ P-gp inducers
 SELECTIVE FACTOR Xa INHIBITORS

• Rivaroxaban
• Apixaban
• endoxaban
 RIVAROXABAN
DOSAGE:
⦿ Prophylaxis – 10mg qd started 6-10hours
post op
⦿ NVAF – 20mg qd, 15mg qd for CrCl 15-50
⦿ VTE/DVT Treatment – 15mg bid for 3
weeks then 20mg qd, avoid use if CrCl <30
⦿ Reversal agent – Andexanet alfa
⦿ FFP or PCC for serious bleeding
ANTIPLATELETS
Aspirin

Clopidogrel
Parasugrel
Ticlopidine
Ticargrelor
DOSAGE
Aspirin
75-81mg qd (general embolic prophylaxis)
ACS – 325mg once
Clopidogrel
ACS – 300mg once, consider 600mg if PCI
Maintenace – 75mg qd
 THROMBOLYTICS
⦿ Promote fibrinolysis or clot destruction by converting
plasminogen to plasmin.
⦿ These agents actually dissolve the fibrin within the
clot
• Alteplase
• Relteplase
• tenectaplase
 SWITCHING BETWEEN
ANTICOAGULANTS
From To Action
Enoxaparin Fondaparinux/ From therapeutic doses: initiate parenteral anticoagulant
heparin when next enoxaparin dose is expected to be given. In
case of high bleeding risk, consider omitting initial
bolus when transitioning to heparin infusion.
Or From prophylactic doses: initiate parenteral
anticoagulant as clinically needed irrespective of time of
Fondaparinux Enoxaparin/ last enoxaparin dose. In case of high bleeding risk,
heparin consider omitting initial bolus when transitioning to
heparin infusion
Enoxaparin/ Rivaroxaban From therapeutic doses: initiate rivaroxaban when next
fondaparinux enoxaparin dose is expected to be given
From prophylactic dose: initiate rivaroxaban as
clinically needed irrespective of last enoxaparin dose
 From To Action
Enoxaparin/ warfarin Overlap therapeutic parenteral anticoagulant dose for
Fondaparinux/ atleast 5 days and until INR is in therapeutic range for
heparin 24 hours
heparin Enoxaparin/ Initiate parenteral anticoagulant/ rivaroxaban within 2
Fondaparinux/ hours after discontinuation of heparin
Rivaroxaban
Rivaroxaban Heparin/ Discontinue rivaroxaban and give the first dose of
enoxaparin/ parenteral anticoagulant at the time when next
fondaparinux rivaroxaban dose is expected to be given
From 10 mg rivaroxaban dose: initiate parenteral
anticoagulant as clinically needed irrespective of time of
last dose of rivaroxaban
Rivaroxaban Warfarin Consider the use of parenteral anticoagulant as a bridge
(continue heparin/LMWH+ warfarin) when next dose of
rivaroxaban is due. Discontinue parenteral anticoagulant
when INR is therapeutic. INR may be affected by
rivaroxaban for 24 hours.
Warfarin Rivaroxaban Discontinue warfarin and start rivaroxaban when INR<
3
 BRIDGING

⦿ Involves the administration of a short-acting

anticoagulant, typically a LMWH or heparin
⦿ Bridging can be used pre op, post op or both
⦿ Thromboebolic risk vs bleeding risk
⦿ Major factors that increase thromboembolic
risk are AF, prosthetic heart valves and
recent stroke or VTE (within past 3 months)
⦿ Higher bleeding risk confers a greater need for
perioperative hemostasis and hence a longer period
of anticoagulation interruption
⦿ High bleeding risk - CABG, kidney biopsy, and
any procedure lasting > 45minutes
⦿ Low bleeding risk - dental extractions, minor
skin surgery, abdomibnal hysterectomy
CASE 1
⦿ 76 year old female with NVAF, hypertension and
prior stroke 3 months ago, receiving warfarin,
requires elective hip relacement with neuraxial
anesthesia: renal function is normal and weight
is 60kg. This patient has a high thromboembolic
risk and a high bleeding risk.
o Stop warfarin five days before the procedure
o Preoperative bridging with enoxaparin 60 mg
bid, start 3 days before surgery (evening dose)
with last dose 12 hours before procedure .
o Resume warfarin within 24 hours after surgery
o Resume LMWH 48 hours post-op
o Continue LMWH till therapeutic INR
CASE 2
A 68 year old female patient with NVAF,
hypertension and CHF receiving rivaroxaban 15
mg QD, requires a dental cleaning and two
dental extraction; CrCl is 35ml/min. the patient
has a high thrombotic risk and a low bleeding
risk
o Do not take rivaroxaban on the day of procedure
(usually 2-3 days before the procedure)
o Use oral transamin mouthwash just before the
procedure and 2-3 times/day after procedure
o Resume rivaroxaban the day after procedure,
after atleast 24 hours have elapsed
⦿ So anticoagulation pharmacist is involved in :
Appropriate drug selection
Dose adjustment
Bridging needed…. Yes/No
Drug interactions
Management of side effects (bleeding, HIT,
HAT)
Thank you