This document discusses treatment with anticoagulation drugs like warfarin and heparin. It provides details on their mechanisms of action, pharmacokinetics, drug interactions, and monitoring. Warfarin is a vitamin K antagonist that inhibits clotting factors. Its effects are delayed and it requires monitoring with an INR test. Heparin works by enhancing antithrombin, indirectly inhibiting thrombin and factor Xa. It has a risk of heparin-induced thrombocytopenia. Both drugs require careful dosing and monitoring due to their narrow therapeutic windows and variability between patients.

1. Treatment with anticoagulation
By Somayyeh Nasiripour Pharm.D
Board of clinical pharmacy
Assistant professor at IUMS

2. • Antithrombotic agent –
include both antiplatelet agents (eg, aspirin,
clopidogrel) as well as anticoagulants.
• ●Anticoagulant –
include a variety of agents that inhibit one or more steps
in the coagulation cascade.
Their mechanisms vary, including direct enzymatic
inhibition, indirect inhibition by binding to antithrombin,
and antagonism of vitamin K-dependent factors by
preventing their synthesis in the liver and/or modification
of their calcium-binding properties

4. Warfarin
racemic mixture of S and R enantiomers
The more potent S form of the drug is metabolized primarily by the CYP2C9
hepatic microsomal enzyme system. This enzyme system is inducible by many
drugs and has a number of genetic variants
Warfarin is strongly protein-bound, primarily to albumin; only the non-protein-
bound fraction is biologically active
Warfarin is rapidly absorbed from the gastrointestinal tract after oral
administration, with a bioavailability of 100%, and its peak absorption is usually
seen within 60 to 90 minutes.
T ½ ….. 44 hr

5. Mechanism of action
through inhibition of the vitamin K-dependent gamma-carboxylation of coagulation factors II,
VII, IX, and X
Warfarin also inhibits the vitamin K-dependent gamma-carboxylation of proteins C and S
Because of these competing effects, vitamin K antagonists, such as warfarin, create a
biochemical paradox by producing an anticoagulant effect due to the inhibition of
procoagulants (factors II, VII, IX, and X) and a potentially thrombogenic effect by
impairing the synthesis of naturally occurring inhibitors of coagulation (proteins C
and S)
The ultimate anticoagulant effect of warfarin is delayed until the normal clotting factors,
especially prothrombin, are cleared from the circulation. The peak effect does not occur until 36
to 72 hours after drug administration (factor II (prothrombin) is t ½ three days)
For this reason, parenteral anticoagulants and warfarin should overlap by four to five days when
warfarin is initiated in patients with acute thrombotic disease

7. INTERACTIONS
Genetic
interaction
s
Drug
Influence
of diet
Influence
of smoking

8. Genetic interactions
Polymorphisms in the genes for enzymes involved in warfarin clearance and the synthesis of
vitamin K-dependent coagulation factors have been associated ( It was estimated from this
study that genetic alterations in CYP2C9 and VKORC1 accounted for 6 to 10 percent and 21 to
25 percent of the variance in warfarin dose, respectively) polymorphisms in these two
enzymes can account for up to 60 percent of interindividual variability in response to
treatment with warfarin
CYP2C9 is involved in the metabolic clearance of warfarin(wild-type CYP2C9*1 and variants
CYP2C9*2 and CYP2C9*3)
The dose was highest in the *1/*1 genotype (5.2 mg/day), intermediate *1/*2 or *1/*3
genotype (4.2 mg/day) and lowest with the *2/*2, *3/*3, or *2/*3 genotypes (3.4 mg/day).
Vitamin K epoxide reductase complex 1 (VKORC1) recycles vitamin K and is required for
gamma carboxylation of vitamin K-dependent coagulation factors.
The dose was highest in those with the non-A/non-A genotype (5.7 mg/day), intermediate in
those with the non-A/A genotype (4.4 mg/day) and lowest in those with the A/A genotype
(3.7 mg/day).
A reduced starting dose may be considered in patients with A haplotypes, in Asian-Americans,
age >65, liver disease, malnourished, or taking a medication that potentiates warfarin

9. drug interactions
Altered platelet function (eg, aspirin, clopidogrel
Gastrointestinal injury (eg, NSAIDs) COX-2 lead to fewer bleeding, NSAID use for >1 month more bleeding
)
Altered vitamin K synthesis in the GI tract (eg, antibiotics)
●Alterations in warfarin metabolism (eg,PPI (esomeprazole), amiodarone, rifampin, simvastatin,
gemfibrozil)
●Interference with vitamin K metabolism (eg, acetaminophen
patients must be warned against taking any new drugs, including herbal products, over-the-counter medications,
and even cutaneous application of large amounts of potentially interfering drugs (eg, topical azoles)
The risk of over-anticoagulation was most strongly increased by amoxicillin, clarithromycin, norfloxacin, and trimethoprim-
sulfamethoxazole, often within the first three days of antibiotic usage.

12. Influence of diet
Profound week-to-week differences in the dietary content of vitamin K are known to alter the
stability of anticoagulation control with warfarin
recommended dietary allowance for vitamin K is in the range of 65 to 80 mcg/day
The effect of increased dietary vitamin K intake can be overcome by a higher warfarin dose . since
there is evidence that a low intake of vitamin K may be associated with a higher risk of unstable
warfarin control , high vitamin K intake reduces the risk of a low INR by lessening the influence of
incidental consumption of vitamin K-rich food on the INR
The patients with unstable warfarin control had a significantly lower intake of dietary vitamin K (29
versus 76 mcg/day).
We suggest that, in patients with unexplained unstable warfarin control, a trial of supplementation
with low-dose oral vitamin K (eg, 100 to 200 mcg orally per day) be instituted, along with close
monitoring of the INR, in order to improve such contro

13. • cause significant
interaction with warfarin
by increasing warfarin
clearance, requiring a 12
percent (95% CI 7-17)
increase in warfarin
dosage compared with
nonsmokers
smoking

15. Initial
lower
dose
poor
nutrition
congestive
failure
CKD
hepatic
impairment
Patients with
certain genetic
polymorphisms
Age
>65
Drug
intraction

16. Warfarin resistance
• inability to prolong PT or INR into the therapeutic range
when the drug is given at normally prescribed doses.
• Patients who need more than 15 mg/day
• Warfarin resistance is different than warfarin failure,
defined as a new thrombotic event despite a therapeutic
prothrombin time and INR.
• This situation is commonly seen in patients with malignant
diseases
• important characteristic of warfarin resistance is that
patients need much smaller doses of vitamin K to reverse
the effect of warfarin

17. CAUSES WARFARIN RESISTANCE
• Pharmacokinetic
resistance
• Pharmacodynamic
resistance
•Poor patient compliance (the most
common
•• High consumption of vitamin K
•• Decreased absorption of warfarin
•• Increased clearance by P450
•• Drug interactions
Acquired Hereditary

18. Genetic factors
Hyperalbuminemia
Hypoalbuminemia
Hyperlipidemia
Diuretics
Pharmacokinetic
resistance Increased affinity
VKOR for vitamin K
Production of clotting
factors that is not
dependent on vitamin
K
Decreased VKOR
sensitivity to warfarin
Pharmacodynamic
resistance

19. Plasma warfarin levels
• therapeutic
total plasma
warfarin level
lies between
0.5 μg/mL and
3.0
• Subtherapeuti
c should raise
suspicion of
intestinal
malabsorptio
or poor
compliance
• Clotting assays of
factors II, VII, IX,
and X may be a
more precise way
to assess the
pharmacodynami
cs of warfarin
• Measured
turnaround
time of 2 to
7 days, as
oppose to
24 hours for
factor II and
X activity

21. Heparin
• an indirect thrombin inhibitor that complexes with antithrombin
(AT, formerly known as AT III), converting this circulating cofactor
from a slow to a rapid inactivator of thrombin, factor Xa, and to a
lesser extent, factors XIIa, XIa, and IXa
• The binding of heparin to the heparin binding site on AT produces a
conformational change in AT, accelerating the inactivating function
of AT 1000- to 4000-fold
• Inactivation of thrombin, but not factor Xa, requires the formation
of a ternary complex in which heparin binds both to AT and to a
binding site on thrombin containing chains at least 18 saccharide
units long; such long units are present in most chains of
unfractionated heparin, are less commonly present in the low
molecular weight (LMW) heparins

22. Heparin mechanism of action
Heparin
Antithrombin III
Thrombin

23. 5/98 MedSlides.com 23
AT
Unfractionated Heparin
Differential inhibitory activity against
factor Xa and IIa activity
Thrombin (IIa)
HF
S C
AT
LMWH
Thrombin (IIa)
HF
S C
By binding to AT, most UH and LMWH can inhibit Xa activity.
Fewer than half the chains of LMWH are of sufficient length to
also bind factor IIa, therefore has decreased anti-IIa activity.

24. 5/98 MedSlides.com 24
Mechanism of Action
• Summary
– Catalyzes ATIII
– Specific for fluid-phase thrombin
– Prolongs aPTT by inactivating thrombin and
blocking Xa generation

25. Limitations
• narrow therapeutic window of adequate anticoagulation without bleeding
• a highly variable dose-response relation requiring laboratory monitoring.
• The variable anticoagulant response is due in part to differences in bioavailability
of subcutaneous heparin and to competitive occupation of binding sites by plasma
proteins (other than AT and coagulation factors), by proteins secreted by platelets
(platelet factor 4), and by endothelial cells
• Some of these heparin-binding proteins are acute phase reactants, thus reducing
the effectiveness of heparin in acutely ill patients.
• Another limitation to the use of heparin is a reduced ability to inactivate thrombin
bound to fibrin as well as factor Xa bound to activated platelets within a thrombus
.As a result, a thrombus may continue to grow during heparin therapy or clotting
may be reactivated after heparin has been discontinued.
• — The presence of a prolonged baseline aPTT makes this test unreliable for
monitoring therapy with unfractionated heparin

26. Heparin-induced thrombocytopenia
(HIT)
• a life-threatening complication of exposure to heparin (ie, unfractionated
heparin, LMWH) that occurs in up to 5%, regardless of the dose, schedule,
or route of administration
• HIT results from an autoantibody directed against platelet factor 4 (PF4) in
complex with heparin
• HIT antibodies activate platelets and can cause catastrophic arterial and
venous thrombosis, with a mortality rate as high as 20 percent, although
with improved recognition and early intervention, mortality rates below 2
percent have been reported.
• definitive laboratory data (ie, immunoassay and/or functional assay for
HIT antibodies) may not be available for several days. Thus, we make a
presumptive diagnosis of HIT based on clinical findings and immediately
available laboratory data.
• The 4 T's score :(, degree of Thrombocytopenia, Timing, Thrombotic
events or sequelae, alternative causes of thrombocytopenia)

27. Calculator: Pretest probability of heparin-induced
thrombocytopenia (4-T's score)
•
•
• Thrombocytopenia
• Platelet count fall >50 percent AND nadir ≥20,000/microL (2 points)
• Platelet count fall 30 to 50 percent OR nadir 10,000 to 19,000/microL (1 point)
• Platelet count fall <30 percent OR nadir <10,000/microL (0 points)
• Timing of platelet count fall
• Clear onset between days 5 and 10 of heparin exposure, OR platelet count fall at ≤1 day if prior heparin exposure within the last 30
days (2 points)
• Consistent with fall in platelet count at 5 to 10 days, but unclear (eg, missing platelet counts), OR onset after day 10, OR fall ≤1 day
with prior heparin exposure within 30 to 100 days (1 point)
• Platelet count fall at <4 days without recent heparin exposure (0 points)
• Thrombosis or other sequelae
• Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous unfractionated heparin bolus (2 points)
• Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or suspected thrombosis that has not been proven
(1 point)
• None (0 points)
• Other causes for thrombocytopenia present
• None apparent (2 points)
• Possible (1 point)
• Definite (0 points)

29. The importance of the HIT diagnosis and its implications (eg, lifetime avoidance of all forms
of heparin) should be emphasized to the patient and all individuals caring for the patient,
and recorded in the medical record.
Sources of heparin include unfractionated heparin, LMW heparin, heparin flushes, heparin-
bonded catheters, and heparin-containing medications (eg, some prothrombin complex
concentrates)
Heparin cessation alone is often not sufficient since patients with HIT remain at risk for subsequent
thrombosis, especially during the period when the HIT antibody continues to activate platelets
immediate anticoagulation with a non-heparin anticoagulant (eg, argatroban, danaparoid, fondaparinux,
bivalirudin) rather than discontinuation of heparin alone, unless there is a strong contraindication (eg,
bleeding, high bleeding risk).

30. We treat patients with renal insufficiency with argatroban at therapeutic doses
since argatroban is metabolized hepatically and does not require dose adjustment in
this setting.
after discontinuation, the aPTT returns to normal within two hours
●We treat patients with hepatic impairment with
fondaparinux at therapeutic doses.
●We treat patients with renal and hepatic impairment with
argatroban or bivalirudin at reduced doses.

31. Platelet count monitoring
– Patients who have received unfractionated heparin in the past 100 days and who are starting
treatment with unfractionated heparin or LMW heparin are at risk for developing accelerated
thrombocytopenia. For these patients, a baseline platelet count and a repeat platelet count within
24 hours is recommended. Subsequent monitoring depends on the clinical setting and heparin
product, as outlined in the following points
– Postoperative patients receiving unfractionated heparin have the greatest risk of HIT, which may
be >1 percent. For these patients, platelet count monitoring every other day from day 4 to day 14
or until heparin is stopped, whichever occurs first, is suggested.
prophylactic dose unfractionated heparin, or LMW heparin following unfractionated heparin –
Medical and obstetrical patients receiving prophylactic dose unfractionated heparin, or
medical/obstetrical patients receiving LMW heparin following treatment with unfractionated
heparin, have a risk of HIT of approximately 0.1 to 1 percent. For these patients, platelet count
monitoring every two to three days from day 4 to day 14 or until heparin is stopped, whichever
occurs first, is suggested.
Medical/obstetrical patients who are receiving only LMW heparin orheparin as vascular catheter
flushes have a risk of HIT of <0.1 percent. For these patients, routine monitoring is not necessary.

32. Prevention of VTE
• usual dose is 5000 U SC two hours
preoperatively BD /TDS
• Enoxaparin : 40 mg / day SC

34. Subcutaneous heparin
• unfractionated heparin (initial dose 333
units/kg SQ followed by a fixed dose of 250
units/kg SQ every 12 hours)
• the use of twice-daily unmonitored
subcutaneous weight-adjusted unfractionated
heparin was as effective and safe as twice-
daily subcutaneous LMW heparin, and less
expensive.

35. Advantages LMW heparins vs heparin
• greater bioavailability than unfractionated heparin when given by subcutaneous injection.
• ●The duration of the anticoagulant effect is greater because of reduced binding to macrophages and
endothelial cells, permitting administration only once or twice daily.
• ●The anticoagulant response (anti-Xa activity) to LMW heparin is highly correlated with body weight,
permitting administration of a fixed dose. However, the dose may have to be adjusted for patients who are
extremely obese or have renal
• ●Laboratory monitoring is not necessary in nonpregnant patients; in fact, there is little correlation
between anti-Xa activity and either bleeding or recurrent thrombosis.
• ●They are much less likely to induce immune-mediated thrombocytopenia (ie, heparin-induced
thrombocytopenia) than unfractionated heparin:
• ●They do not increase osteoclast number and activity as much as unfractionated heparin, and may
therefore produce less bone loss.
• ●LMW heparin can be safely administered in the outpatient setting
• ●In patients with acute VTE, fixed-dose subcutaneous LMW heparin is more effective than adjusted-dose
unfractionated heparin for reducing the incidence of symptomatic recurrent VTE, major hemorrhage, and
all-cause mortality [79].
• ●Home management using LMW heparin is cost effective, and is likely to be preferred by patients and

36. Direct thrombin inhibitor
They bind to thrombin directly, rather than by enhancing the activity of
antithrombin, as is done by heparin.
Parenteral DTIs include bivalirudin ,argatroban ,desirudin
•The only oral DTI available for clinical use is dabigatran etexilate (Pradaxa);
another oral agent, ximelagatran (Exanta), was withdrawn from the market in
2006 due to hepatotoxicity and cardiovascular events

37. Direct factor Xa inhibitor
They bind directly to factor Xa, rather than enhancing the activity of
antithrombin III, as is done by heparin.
•There are no parenteral direct factor Xa inhibitors in clinical use.
•Several oral agents are available, including rivaroxaban ,apixaban and
edoxaban
Of note, the generic names for these agents all end in "Xa-ban" (eg,
rivaroxaban, apixaban, edoxaban).

38. COMPARISON WITH HEPARIN AND WARFARIN
• similar to warfarinAdherence
• All anticoagulants increase bleeding risk
• Overall, the bleeding risks of the target-
specific oral agents are comparable to
warfarin, with a significant decrease in central
nervous system (CNS) bleeding
Bleeding
risk

40. Advantages over heparin and warfarin
• Heparin and warfarin both have a relatively narrow therapeutic window and
more variable dose-response relationship that depends on a variety of factors;
these features lead to a requirement for frequent monitoring of clotting times
to optimize the therapeutic dose range and prevent bleeding [20,21]. Dose may
be affected by differing bioavailability, diet, and acute medical illnesses. In
contrast, the target-specific oral agents are generally used without a
requirement for monitoring of drug levels or coagulation (clotting) times. This
may be an advantage for patients for whom frequent monitoring is a greater
burden. It remains to be determined whether laboratory monitoring of any of
the target-specific oral agents can further improve their efficacy or safety
Laboratory
monitoring
• Warfarin pharmacokinetics is affected by the level of vitamin K intake and
production in the gastrointestinal tract, as well as induction of hepatic
cytochromes. Thus, warfarin effect can be altered by changes in diet,
administration of other medications, gastrointestinal disorders, and reduced
oral intake. Patients with difficulty controlling the prothrombin
time/international normalized ratio (PT/INR) may benefit from a target-specific
oral agent because these agents have less variability in drug effect for a given
dose than vitamin K antagonists. Affected patients may include those with
unavoidable drug-drug interactions (such as frequent need for antibiotics or a
large number of concomitant and variable medications) or unexplained poor
warfarin control. However, it is important to determine that the INR instability
with a vitamin K antagonist is not due to poor compliance, which may be easier
to monitor for vitamin K antagonists than for the target-specific agents.
Pharmacokinetics

41. Settings in which a heparin or vitamin K antagonist may
be preferable
• The direct thrombin inhibitors and direct factor Xa inhibitors are not used
in patients with prosthetic heart valves, due to greater risk of valve
thrombosis, which may be fatal
Prosthetic heart
valves
• Direct thrombin inhibitors and direct factor Xa inhibitors are not used
during pregnancyPregnancy
• Renal insufficiency is a common setting in which heparin or warfarin may
be preferable to the target-specific agentsRenal impairment
Dosing convenience
Gastrointestinal
disease

42. INDICATIONS
Venous thromboembolism prophylaxis –
●Venous thromboembolism management –
●Atrial fibrillation
●Unstable angina, myocardial infarction,
coronary stenting
●Heparin-induced thrombocytopenia

43. Dabigatran(Pradax: 75 mg, 110 mg, 150 mg)
• Dabigatran etexilate (Pradaxa) is an orally administered prodrug that is
converted in the liver to dabigatran,
• The half-life is approximately 12 to 17 hours in individuals with normal
renal function.
• Absorption is unaffected by food
• capsules should only be dispensed and stored in the original bottle or
blister package in which they came, due to the potential for product
breakdown from moisture and resulting loss of potency
• Once the bottle is opened, the pills inside must be used within four
months
• The capsules should not be crushed or opened before administration, as
removal of the capsule shell results in dramatic increases in oral
bioavailability
FDA Study Shows Dabigatran Lowers Risk for Stroke and Death, Increases GI
Bleeding Compared With Warfarin May 2014

44. Dosing (dabigatran)
• Dabigatran is generally given at a fixed dose
without monitoring. Maximum anticoagulant
effects are achieved within two to three hours
of ingestio
Venous thromboembolism (VTE) prophylaxis in surgical patients: 110 mg one to
four hours after surgery, followed by 220 mg once daily for 28 to 35 days (hip
replacement) or 10 days (knee replacement).
●Treatment and secondary prevention of VTE: 150 mg orally twice daily (CrCl >30
mL/min).
●Stroke prevention in atrial fibrillation (AF): 150 mg orally twice daily (CrCl >30
mL/min); or 75 mg orally twice daily (CrCl 15 to 30 mL/min).

45. Laboratory testing and monitoring (dabigatran)
• Laboratory testing prior to initiating dabigatran should include platelet
count, prothrombin time (PT), and activated partial thromboplastin time
(aPTT), to assess and document coagulation status before anticoagulation;
and measurement of serum creatinine, as a baseline and for potential
dose adjustment in the event of renal insufficiency.
• Routine monitoring of coagulation is not required for patients taking
dabigatran, because drug levels are relatively predictable for a given dose.
Settings in which coagulation testing for dabigatran effect may be helpful include the
following:
●Bleeding in a patient receiving dabigatran, or with suspected dabigatran overdose –
●Need for emergent or urgent surgery in a patient receiving dabigatran –