This document provides an overview of anticoagulants including their mechanisms of action, indications, dosing, and monitoring. It discusses normal hemostasis and coagulation factors. Unfractionated heparin, low molecular weight heparins, and factor Xa inhibitors are described as parenteral anticoagulants. Oral anticoagulants reviewed include warfarin, rivaroxaban, apixaban, and dabigatran. The roles of clinical pharmacists in managing anticoagulation therapy are also mentioned.

1. Anticoagulants
Prepared by
Ph. Sara Saber
Sep 2015

2. Outline
 Normal hemostasis
 Pathophysiology
 Risk factors of antithrombotic
therapy
 Parenteral and oral anticoagulants
 Patient care and monitoring.
 Role of clinical pharmacists in
management of patients on
anticoagulants

3. Hemostasis
 The normal physiological response that
prevents significant blood loss following
vascular injury.
 It is a finely tuned process that serves to
maintain the integrity of the circulatory
system. However, the process can go out of
balance, leading to significant morbidity and
mortality

4. Major constituents of hemostatic
pathways

5. I- Endothelium

6. II-Platelets

7. III- Coagulation Cascade
 The coagulation process that leads to
haemostasis involves a complex set of
protease reactions involving roughly 30
different proteins.
 • The final result of these reactions is to
convert fibrinogen, a soluble protein, to
insoluble strands of fibrin. Together with
platelets, the fibrin strands form a stable
blood clot.

8. Cont

9. Coagulation Factors
Factor Name
I Fibrinogen
II Prothrombin
III Tissue Factor or
thromboplastin
IV Ca++
V Proaccelerin
VII Proconvertin
VIII Antihemophilic A
factor
IX Antihemophilic B
factor or Christmas
factor
Factor Name
X Stuart or Stuart-
Prower factor
XI Plasma thomboplastin
antecedent
XII Hageman factor,
contact factor
XIII Fibrin stabilizing factor
Prekallikrein factor
High-molecular-weight
kininogen

11. What happens when blood vessel
is injured?

12. Abnormal Hemostasis

13. Major disease states associated
with thrombosis
Venous thromboembolism (VTE).
PE.
CAD( Angina ,MI).
Cardioembolic stroke.

14. Virchow’s Triad

15. Antithrombotic Agents MOA

17. Classification

18. A-Unfractionated Heparin C
 A heterogeneous group of straight-chain anionic
mucopolysaccharides, called glycosaminoglycans
 Heparin is usually stored within the secretory granules of mast
cells and released only into the vasculature at sites of tissue
injury.
MOA
 It acts at multiple sites in the normal coagulation system.
 Heparin interacts with antithrombin (heparin cofactor) to
change its conformation and enhance its ability to inhibit
thrombosis by inactivating clotting factor proteases, especially
thrombin (IIa), IXa and Xa by forming equimolar complexes with
them.

19. MOA

20. Dosing
Numerous concentrations
available; extreme caution is
required to avoid medication
error

21. Monitoring
The most widely used test is aPTT with therapeutic
range defined as 1.5-2.5 times the control aPTT value.

22. Over dose
1 mg protamine sulphate
per 100 units of UFH, up to a maximum of 50 mg, given
as slow IV infusion over 10 minutes.

23. II-Low molecular weight heparins
(LMWHs) B
 Produced by either chemical or enzymatic
depolymerization .
 LMWHs are fragments of UFH approximately one third
the molecular weight of UFH.
 Although all the LMWHs share similarities in their
mechanisms of action with UFH, their molecular weight
distributions vary, resulting in differences in their activity
against factor Xa and thrombin, affinity for plasma
proteins, propensity to release tissue factor pathway
inhibitor, and duration of activity.

24. MOA

25. Dosing Dosing
recommendations
may differ
according to
indication
1.5 mg/kg SC once daily or 1 mg/kg
SC twice daily; if CrCl is less than
30 ml/min: 1 mg/kg SC once daily
175 units/kg SC once daily
200 units/kg SC once daily or 100 units /kg
SC twice daily

26. Prophylaxis
Prophylactic dose of
Enoxaparin is
•4omg OD - 30mg BID.
•If crcl less than 30ml/min
30mg OD.

27. Routine monitoring of anticoagulation activity
and dose adjustments are not required in
majority of patients
Monitoring

29. How does HIT occur?
 Heparin injection immune reaction with
body produce antibody against heparin&
also bind to platelet receptor activation of
platelet thrombosis .

30. III-Factor Xa Inhibitors B
Advantages of Factor Xa Inhibitors
It is a synthetic drug so cannot transmit animal pathogens.
•Consistent from batch to batch
•Rapid onset of activity.
•Long half-life , predictable response.
•Do not require routine coagulation monitoring or dose
adjustments.
•They do not affect platelet function and do not react with heparin
platelet factor-4 (PF-4) antibodies seen in patients with HIT.
Fondaparinux - Rivaroxiban - Apixaban.

31. Fondaparinux
Fondaparinux is FDA approved for treatment of
DVT and PE.
Exerts inhibitory activity against factor Xa and
has no effect on thrombin.

32. Dosing

33. IV-Direct Thrombin Inhibitors
 They bind thrombin and prevent interactions
with its substrates.
 They differ in terms of their chemical
structure, molecular weight, and binding to
the thrombin molecule.
 No platelet interaction that can lead to HIT
 They are the drugs of choice for treatment of
VTE in patients with a diagnosis or history of
HIT

34. MOA

35. Antidote
Currently no antidote
In the event of major bleed
- Fresh frozen plasma
- Factor concentrates
- rFactor VIIa

36. Oral Anticoagulants
 Warfarin.
 Rivaroxaban and apixaban.
 Dabigatran.

37. I-Warfarin X
 Warfarin is the anticoagulant of choice when
long-term or extended anticoagulation is
required.
 Warfarin has a narrow therapeutic index
 Many drug interactions
 Many dietary interactions
 Requires frequent dose adjustments,
significant patient and family education and
careful patient monitoring.

38. MOA
Synthesis of non
functional
coagulation
factors
Antagonism of Vitamin K
Vitamin K
Warfarin
6-8 hrs
20-30hrs
24-40 hrs
60-100 hrs
VII
IX
X
II
N.B Warfarin also inhibits the production of the anticoagulant proteins C and S

39. PK
 Warfarin is commercially available as a racemic mixture of R
and S isomers.
 The S isomer is two to five times more potent than the R
isomer.
 Metabolism of warfarin is isomer-specific.
 The CYP 2C9 enzyme metabolizes the S isomer, whereas the
CYP 1A2 and CYP 3A4 enzymes metabolize the R isomer

41. Monitoring Warfarin Therapy
(PT)

42. International Normalized Ratio:
INR
 A mathmatical correction (of the PT ratio) for
differences in the sensitivity of thromboplastin
reagents.
 In normal individuals INR=1.
 Target INR is usually 2-3 except in patients with
mechanical prosthetic valves it is 2.5-3.5 .

43. Factors that may influence bleeding risk
 Concomitant drugs
 Concomitant diseases
 Quality of management
 Age

44. Conversion from Heparin to
Warfarin
 May begin concomitantly with heparin therapy
 Heparin should be continued for a minimum of five
days
 When INR reaches desired therapeutic range,
discontinue heparin

45. Warfarin Overdose Antidote
 Follow the algorithm for the management of
an elevated INR in patients taking warfarin
 Low-dose vitamin K 2.5 mg orally or 0.5 to 1
mg via slow IV or SC injection.
 Fresh whole blood, fresh frozen plasma, or
plasma concentrates of vitamin K–dependent
clotting factors may be helpful in reversing
warfarin effects.

46. Drug Interactions

47. Dietary Interactions

48. Patient Education
•Introduction to the patient about
the drug and the disease.
•How to take warfarin?
•Laboratory tests
•Things that affect warfarin
therapy
•Problems with warfarin therapy
•Preventing clots and bleeding

49. II-New oral anticoagulants
Advantages of New Anticoagulants over Warfarin
Rapid onset of anticoagulant effect, more predicatable
pharmacokinetics,
lower potential for clinically important interactions with food,
lifestyle and other drugs.
There is no requirement for routine monitoring and dose
adjustments as required with warfarin.
The three drugs, dabigatran, rivaroxaban and apixaban resulted
in lower rates of hemorrhagic stroke and intracranial hemorrhage
in phase III clinical trials compared to warfarin. But concerning
gastrointestinal bleeding, only apixaban showed no increase in
gastrointestinal bleeding compared with warfarin.

50. Disadvantages of New
Anticoagulants
 Absence of an antidote in case of serious
bleeding or when an emergency intervention
needs immediate correction of coagulation.
 No means to monitor drug-drug interactions

51. Warfarin is Fighting to Stay Alive
• Excellent efficacy
• Low cost
• Long track record (1954)
• Point-of-care testing

52. Rivaroxaban: C
• Prevention of stroke and systemic embolism in adult
patients with one or more risk factors, such as
congestive, heart failure , hypertension, age ≥ 75 years,
diabetes mellitus.
• DVT prophylaxis after knee replacement therapy, DVT
prophylaxis after hip replacement therapy, prevention of
thromboembolism in atrial fibrillation, and to treat and
reduce the risk of DVT or PE.
• Does not require monitoring for dosage adjustments in
contrast to warfarin

53. Apixaban: B
 To reduce the risk of stroke and systemic
embolism in patients with non-valvular atrial
fibrillation

54. Black Box Warnings: Increased RISK of STROKE & SPINAL/EPIDURAL HEMATOMA
Stroke
Discontinuing rivaroxaban to patients with non-valvular atrial fibrillation increases the
RISK of stroke. If rivaroxiban must be discontinued for a reason other than
pathological bleeding, administration of another anticoagulant should be considered.
SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas have occurred in patients taking rivaroxiban who are
receiving neuraxial anesthesia, or undergoing spinal puncture. Such hematomas may
result in long-term or permanent paralysis.
Black Box Warnings: Increased RISK of STROKE & SPINAL/EPIDURAL HEMATOMA
Stroke
Discontinuing rivaroxaban to patients with non-valvular atrial fibrillation increases the
RISK of stroke. If rivaroxiban must be discontinued for a reason other than
pathological bleeding, administration of another anticoagulant should be considered.
SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas have occurred in patients taking rivaroxiban who are
receiving neuraxial anesthesia, or undergoing spinal puncture. Such hematomas may
result in long-term or permanent paralysis.

55. Dabigatran etexilate C
 Dabigatran etexilate is a new oral direct thrombin
inhibitor and the prodrug of dabigatran.
 Reducing the risk of stroke and serious blood clots in
certain patients with atrial fibrillation.
 Dabigatran is a direct thrombin inhibitor. It works by
preventing the formation of a blood clot.

56. Dose
The recommended dose of Pradaxa is 220 mg once
daily taken as 2 capsules of 110 mg.
Patients with moderate renal impairment (creatinine
clearance (CrCL) 30-50 mL/min) reducing the dose to
75mg twice daily.
It is not recommended in pt with sever renal
impairment (crcl <30mlmin).

57. At initiation of therapy
 Closely monitor patients receiving anticoagulant therapy for signs and
symptoms of bleeding, including epistaxis, hemoptysis, hematuria,
bright red blood per rectum, severe headache, and joint pain.
 If major bleeding occurs, stop therapy immediately and treat the
source of bleeding.
 Closely monitor patients for potential drug-drug and drug-food
interactions and adherence with the prescribed regimen.
 Measure PT/INR at least weekly during initiation of warfarin therapy
and monthly when anticoagulation is stable

58. References
 Chisholm-Buans MA, Wells BG, Schwinghamver TL, et al. Pharmacotherapy
Principles and Practices, 3rd ed, 2013.
 •Norgard NB, DiNicolantonio JJ, , Topping TJ, Wee B. Novel anticoagulants in
atrial fibrillation stroke prevention. Ther Adv Chronic Dis. 2012; 3(3): 123 –136
 •ELIQUIS FDA prescribing information available at www.Drugs.com, last
accessed June 2013
 •Pradaxa FDA prescribing information available at www.Drugs.com, last
accessed June 2013
 Xareleto FDA prescribing information available at www.Drugs.com, last
accessed June 2013.
 •http://healthcare.utah.edu/thrombosis, last accessed June 2013