This document provides an overview of the coagulation cascade and anticoagulants. It begins with an introduction to hemostasis and the coagulation cascade. It then describes the intrinsic and extrinsic pathways and interactions between them. Mechanisms of blood coagulation and factors involved are explained. Monitoring tests for hemostatic function like PT, APTT and INR are also outlined. Finally, the mechanisms, pharmacology, uses, and adverse effects of heparin and low molecular weight heparins are summarized.

1. COAGULATION CASCADE &
ANTICOAGULANTS
GUIDED BY
DR. D.K SOREN
ASSO. PROFESSOR
DEPT. OF ANESTHESIOLOGY
PRESENTED BY
DR. SIDDHANTA CHOUDHURY
2ND YR PG
DEPT. OF ANESTHESIOLOGY

2. INTRODUCTION
• The concept of a coagulation cascade describes the biochemical
interactions of the coagulation factors.
• Hemostasis requires both platelet and fibrin plug formation at the site
of vessel injury and that the procoagulant substances activated in this
process remain at the site of injury.
• This control of blood coagulation is accomplished as the procoagulant
reactions only exist on specific cell surfaces to keep coagulation from
spreading throughout the vascular system
• The classic coagulation cascade was proposed in 1964 by Macfarlane
and Davie & Ratnoff.

3. HEMOSTASIS
• It is the process of forming clots in the wall of
damaged blood vessels & preventing blood loss while
maintaining blood in a fluid state with in the vascular
system.
• Spontaneous arrest of bleeding by physiological
processes.

4. HEMOSTASIS
Hemostasis involves 4 main steps:
1. Vasoconstriction
2. Formation of platelet plug
3. Blood coagulation
4. Eventual growth of fibrous tissue into the blood clot to
close the hole in the vessel permanently.

6. FORMATION OF PLATELET PLUG

7. BLOOD COAGULATION
• The clot begins to develop in 15 to 20 seconds if the trauma to the vascular
wall has been severe and in 1 to 2 minutes if the trauma has been minor.
• The clotting mechanism involves a cascade of reactions in which clotting
factors are activated.
• Most of them are plasma proteins synthesized by the liver (vitamin K is
needed for the synthesis of factor II, VII, IX and X).
• They are always present in the plasma in an inactive form.
• When activated they act as proteolytic enzymes which activate other
inactive enzymes.
• Several of these steps require Ca++ and platelet phospholipid.

9. MECHAMISM OF BLOOD COAGULATION
•Clotting takes place in three essential steps:
1. In response to rupture of the vessel or damage to the
blood itself, a complex cascade of chemical reactions
occurs in the blood involving more than a dozen blood
coagulation factors. The net result is formation of a
complex of activated substances collectively called
prothrombin activator.
2. The prothrombin activator catalyzes conversion of
prothrombin into thrombin.
3. The thrombin acts as an enzyme to convert fibrinogen
into fibrin fibers that enmesh platelets, blood cells, and
plasma to form the clot.

11. INITIATION OF COAGULATION
• The mechanisms of coagulation are set into play by
(1) trauma to the vascular wall and adjacent tissues
(2) trauma to the blood
(3) contact of the blood with damaged endothelial cells or with
collagen and other tissue elements outside the blood vessel.
• In each instance, this leads to the formation of prothrombin
activator, which then causes prothrombin conversion to
thrombin and all the subsequent clotting steps.

12. • Prothrombin activator is generally considered to be formed in
two ways, although, in reality, the two ways interact constantly
with each other:
(1) by the extrinsic pathway that begins with trauma to the vascular
wall and surrounding tissues and
(2) by the intrinsic pathway that begins in the blood.
• In both the extrinsic and the intrinsic pathways, a series of
different plasma proteins called blood-clotting factors plays a
major role. Most of these proteins are inactive forms of
proteolytic enzymes.
• When converted to the active forms, their enzymatic actions
cause the successive, cascading reactions of the clotting
process.

13. THE EXTRINSIC PATHWAY

14. THE INTRINSIC PATHWAY

15. INTERACTION BETWEEN THE EXTRINSIC
AND INTRINSIC PATHWAYS

17. WHY BLOOD DOES NOT CLOT IN CIRCULATION ?
• Endothelial surface factor
-smoothness
-layer of glycocalyx
-Negatively charged
• Velocity of circulation
• Natural anticoagulants
• Activation of Fibrinolytic system
• Liver removes activated clotting factors

18. HEMOSTATIC FUNCTION TESTS
• Bleeding time
• Clotting time
• Prothrombin time
• Activated Partial Thromboplastin time
• International Normalized Ratio

19. BLEEDING TIME (B.T)
Definition ;
- time interval between the skin puncture and
spontaneous , unassisted stoppage of bleeding.
Method ; “Duke’s method”
Other methods ; “ivy” Bleeding time
Normal bleeding time ; 1 – 5 min.

20. CLOTTING TIME ( C.T )
Definition ;
- time interval between entry of blood into glass capillary tube,
or a syringe, and formation of fibrin threads.
Method ; Wright’s capillary glass tube
Other Methods ; Duke’s Drop method, Lee and White test-
tube method
Normal Clotting Time ; 3 – 6 min.

21. PROTHROMBIN TIME (P.T)
• Normal P.T ; 15 – 20 sec.
• Clinical Significance ; bleeding tendency occurs below 20% (Normal
plasma prothrombin = 30- 40 mg/dl)
• Low prothrombin suggest Vit. K def. and liver and biliary diseases.
• Prolonged suggests deficiency of factor II, V, VII, and X.
• Tests the functional ability of extrinsic and common pathways

22. ACTIVATED PARTIAL THROMBOPLASTIN TIME
(APTT)
• Measures the overall speed at which blood clots by means of intrinsic and
common coagulation pathways.
• In order to activate the intrinsic pathway of coagulation, an activator (such
as silica, celite, kaolin, ellagic acid) is added during testing.
• Ranges from 30-50 sec.
• Requires the presence of the following coagulation factors: I, II, V, VIII, IX, X,
XI and XII. Notably, deficiencies in factors VII or XIII will not be detected.

23. INR
• INR (international normalized ratio) stands for a way of standardizing
the results of prothrombin time tests.
• Normal is 0.9 – 1.3 but therapeutic values ranges from 2.0 – 4.0

24. ANTICOAGULANTS

25. HISTORY
• Heparin was discovered in 1915 by
McLean
• Warfarin has been the drug of choice for
the prevention and treatment of arterial
and venous thrombotic disorders for
more than 60 years
• It was initially marketed as a pesticide
against rats and mice, and is still popular
for this purpose

26. CLASSIFICATION OF ANTICOAGULANTS

27. Anticoagulants
Direct Thrombin Inhibitors
Hirudin – Lepirudin
Bivalirudin
Argatroban
Melagatran
Ximelagatran (oral)
Dabigatran (oral)
Indirect Thrombin
Inhibitors
Heparin
LMWH – Enoxaparin,
dalteparin
Fondaparinaux
Rivaroxiban (1st oral factor
Xa inhibitor)

28. HEPARIN

29. •It is a sulfated polysaccharide
•Heparin is isolated from mammalian tissues rich in
mast cells.
•Most commercial heparin is derived from porcine
intestinal mucosa and is a polymer of alternating
d-glucuronic acid and N-acetyl-d-glucosamine
residues.

30. Mechanism of Action
• Heparin acts as an anticoagulant by activating antithrombin III and
accelerating the rate at which antithrombin inhibits clotting enzymes,
particularly thrombin and factor Xa.
• Antithrombin, the obligatory plasma cofactor for heparin, is a
member of the serine protease inhibitor (serpin) superfamily.
• Synthesized in the liver and circulating in plasma, antithrombin acts as
a suicide substrate for its target enzymes.

31. Mechanism of Action

32. PHARMACOLOGY
• Heparin must be given parenterally. It is usually administered SC or by
continuous IV infusion. IV route is most often employed.
• In the circulation, heparin binds to the endothelium and to plasma
proteins other than antithrombin. This explains its dose-dependent
clearance.
• Clearance is mainly extrarenal; heparin binds to macrophages, which
internalize and depolymerize the long heparin chains and secrete
shorter chains back into the circulation.
• The plasma half-life of heparin ranges from 30 to 60 min with bolus IV
doses of 25 and 100 units/kg, respectively.

33. • Once heparin enters the circulation, it binds to plasma proteins other than
antithrombin
• Some of the heparin binding proteins found in plasma are acute phase
reactants whose levels are elevated in ill patients.
• Others, such as high-molecular weight multimers of VWF, are released
from activated platelets or endothelial cells. Activated platelets also release
platelet factor 4 (PF4), a highly cationic protein that binds heparin with
high affinity.
• The large amounts of PF4 found in the vicinity of platelet-rich arterial
thrombi can neutralize the anticoagulant activity of heparin. This
phenomenon may attenuate heparin’s capacity to suppress thrombus
growth.
• Because the levels of heparin-binding proteins in plasma vary from person
to person, the anticoagulant response to fixed or weight-adjusted doses of
heparin is unpredictable. Consequently, coagulation monitoring is essential
to ensure that a therapeutic response is obtained.

35. Prophylaxis
•5000 units SC q8-12hr, OR
•7500 units SC q12hr
Treatment
•80 units/kg IV bolus, THEN continuous infusion of 18 units/kg/hr, OR
•5000 units IV bolus, THEN continuous infusion of 1300 units/hr, OR
•250 units/kg (alternatively, 17,500 units) SC, THEN 250 units/kg q12hr
Heparin needs to be continued for at least 5 days and until the INR is 2 for
at least 24 hours
DEEP VEIN THROMBOSIS/ PULMONARY EMBOLISM
USES

36. Acute Coronary Syndromes
PCI
•Without GPIIb/IIIa inhibitor: Initial IV bolus of 70-100 units/kg (target ACT 250-300 sec)
•With GPIIb/IIIa inhibitor: Initial IV bolus of 50-70 units/kg (target ACT >200 sec)
STEMI
•Patient on fibrinolytics: IV bolus of 60 units/kg (max: 4000 units), THEN 12 units/kg/hr (max
1000 units/hr) as continuous IV infusion
•Dose should be adjusted to maintain aPTT of 50-70 sec
Unstable Angina/NSTEMI
•Initial IV bolus of 60-70 units/kg (max: 5000 units), THEN initial IV infusion of 12-15
units/kg/hr (max: 1000 units/hr)
•Dose should be adjusted to maintain aPTT of 50-70 sec

37. Anticoagulation
Intermittent IV injection
•8000-10,000 units IV initially, THEN 50-70 units/kg (5000-
10,000 units) q4-6hr
Continuous IV infusion
•5000 units IV injection, followed by continuous IV infusion of
20,000-40,000 units/24 hr
Catheter Patency
Prevention of clot formation within venous and arterial
catheters
Use 100 units/mL; instill enough volume to fill lumen of
catheter

38. MONITORING THE ANTICOAGULANT EFFECT
• Heparin therapy can be monitored using the activated partial thromboplastin
time (aPTT) or anti-factor Xa level.
• Therapeutic heparin levels are achieved with a two- to threefold prolongation of
the aPTT.
• Anti-factor Xa levels also can be used to monitor heparin therapy. With this test,
therapeutic heparin levels range from 0.3 to 0.7 units/mL.
• Up to 25% of heparin-treated patients with venous thromboembolism require
>35,000 units/d to achieve a therapeutic aPTT. These patients are considered
heparin resistant.
• It is useful to measure anti-factor Xa levels in heparin-resistant patients because
many will have a therapeutic anti-factor Xa level despite a sub therapeutic aPTT.
• This dissociation in test results occurs because elevated plasma levels of
fibrinogen and factor VIII, both of which are acute-phase proteins, shorten the
aPTT but have no effect on anti-factor Xa levels. Heparin therapy in patients who
exhibit this phenomenon is best monitored using anti-factor Xa levels instead of
the aPTT.

39. Contraindications
Severe thrombocytopenia
Uncontrolled, active bleeding (except DIC)
Conditions in which coagulation tests cannot be performed at appropriate
intervals
Cautions
Any risk factor for hemorrhage (eg, subacute bacterial endocarditis, blood
dyscrasias, menorrhagia, dissecting aneurysm, major surgery, spinal
anesthesia, hemophilia, GI ulcerative lesions, liver disease, impaired
hemostasis)

40. ADVERSE EFFECTS
Bleeding
• The risk of bleeding rises as the dose of heparin is increased.
Concomitant administration of drugs such as antiplatelet or
fibrinolytic agents, increases the risk of bleeding, as does recent
surgery or trauma.
• Heparin-treated patients with serious bleeding can be given
protamine sulfate to neutralize the heparin.
• Protamine sulfate binds heparin with high affinity, and the resultant
protamine-heparin complexes are then cleared.
• Typically, 1 mg of protamine sulfate neutralizes 100 units of heparin.

41. Heparin induced thrombocytopenia (HIT)
• Antibody-mediated process that is
triggered by antibodies directed against
neoantigens on PF4 that are exposed
when heparin binds to this protein.
• Usually of the IgG isotype; bind
simultaneously to the heparin-PF4
complex and to platelet Fc receptors.
• Such binding activates the platelets and
generates platelet microparticles.
• Circulating microparticles are
prothrombotic because they express
anionic phospholipids on their surface and
can bind clotting factors and promote
thrombin generation.

43. DIAGNOSIS
• A commonly used score to predict the likelihood of HIT is the "4 Ts" score introduced
in 2003.
• A score of 0–8 points is generated; if the score is 0-3, HIT is unlikely.
• A score of 4–5 indicates intermediate probability, while a score of 6–8 makes it
highly likely

45. Osteoporosis
• Treatment with therapeutic doses of heparin for >1 month can cause
a reduction in bone density.
• This complication has been reported in up to 30% of patients given
long-term heparin therapy.
• Symptomatic vertebral fractures occur in 2–3% of these individuals.
• Heparin causes bone loss both by decreasing bone formation and by
enhancing bone resorption.
Elevated levels of transaminases
• Therapeutic doses of heparin are frequently associated with modest
elevations in the serum levels of hepatic transaminases without a
concomitant increase in the level of bilirubin. The levels of
transaminases rapidly return to normal when the drug is stopped. The
mechanism responsible for this phenomenon is unknown.

46. LOW-MOLECULAR-WEIGHT HEPARIN
• Consisting of smaller fragments of heparin, LMWH is prepared from
unfractionated heparin by controlled enzymatic or chemical
depolymerization.
• The mean molecular weight of LMWH is about 5000, one-third the
mean molecular weight of unfractionated heparin.
• LMWH has advantages over heparin and has replaced heparin for
most indications.

47. Mechanism of Action

48. PHARMACOLOGY
• Although usually given SC, LMWH also can be administered IV if a rapid
anticoagulant response is needed.
• Shorter heparin chains bind less avidly to endothelial cells, macrophages,
and heparin-binding plasma proteins.
• The clearance of LMWH is dose-independent and its plasma half-life is
longer (~4 hrs)
• LMWH is cleared almost exclusively by the kidneys, and the drug can
accumulate in patients with renal insufficiency.
• LMWH exhibits about 90% bioavailability after SC injection.
• Resistance to LMWH is rare.
• LMWH can be given SC once or twice daily without coagulation monitoring,
even when the drug is given in treatment doses.

49. Deep Vein Thrombosis (Prophylaxis)
• 4000-5000 U SC once daily
• 2500-3000 U SC twice daily
Abdominal surgery
•40 mg SC qDay; initiate 2 hr preoperatively
Knee or hip replacement surgery
•30 mg SC q12hr; initiate therapy 12-24 hr postoperatively and continued for 10 days or up to 35 days
postoperatively or until risk of DVT has been significantly reduced or patient is on anticoagulant therapy
•For hip replacement surgery, may consider administering 40 mg SC qDay, initiated 9-15 hr preoperatively
and continued for 10 days or up to 35 days postoperatively or until risk of DVT has been significantly
reduced or patient is on anticoagulant therapy
Medical patients with restricted mobility
•40 mg SC qDay; continue until risk of DVT has been significantly (6-11 days) reduced or patient is on
anticoagulant therapy
USES

50. Deep Vein Thrombosis (Treatment)
Inpatient treatment
•Acute DVT with or without PE, when administered in conjunction with warfarin sodium
•1 mg/kg SC q12hr, OR 1.5 mg/kg SC qDay (administer at same time each day)
Outpatient treatment
•Acute DVT without PE, when administered in conjunction with warfarin sodium
•1 mg/kg SC q12hr
Unstable Angina & Non-Q-Wave MI
Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when
concurrently administered with aspirin
1 mg/kg SC q12hr
Regimen includes aspirin (100-325 mg/day PO)

51. Acute STEMI
<75 years
•Loading dose: 30 mg IV bolus once plus 1 mg/kg SC once; not to exceed 100 mg cumulative loading
dose
•Maintenance: 1 mg/kg SC q12hr
>75 years
•No IV bolus
•0.75 mg/kg SC q12hr
•Not to exceed 75 mg/dose for first 2 doses only, followed by 0.75 mg/kg for remaining doses
With PCI
•If last enoxaparin was given <8 hr before balloon inflation, no additional dosing is needed
•If last enoxaparin was given 8-12 hr before balloon inflation, an IV bolus of 0.3 mg/kg should be
administered
•If PCI occurs >12 hr after last SC dose; use established anticoagulation therapy (full-dose
unfractionated heparin or LMWH
•Patient that has not received prior anticoagulant therapy: 0.5-0.75 mg/kg bolus dose

52. MONITORING
• In the majority of patients, LMWH does not require coagulation monitoring.
• If monitoring is necessary, anti-factor Xa levels must be measured. Therapeutic
anti-factor Xa levels with LMWH range from 0.5 to 1.2 units/mL when measured
3–4 h after drug administration. When LMWH is given in prophylactic doses, peak
anti-factor Xa levels of 0.2–0.5 units/mL are desirable.
• Indications for LMWH monitoring include renal insufficiency and obesity. LMWH
monitoring in patients with a creatinine clearance of ≤50 mL/min is advisable to
ensure that there is no drug accumulation.
• It may also be advisable to monitor the anticoagulant activity of LMWH during
pregnancy because dose requirements can change, particularly in the third
trimester.
• Monitoring should also be considered in high-risk settings, such as in patients
with mechanical heart valves who are given LMWH for prevention of valve
thrombosis, and when LMWH is used in treatment doses in infants or children.

53. ADVERSE EFFECTS
Bleeding
• Bleeding with LMWH is more common in patients receiving concomitant therapy
with antiplatelet or fibrinolytic drugs.
• Recent surgery, trauma, or underlying hemostatic defects also increase the risk of
bleeding with LMWH.
• Although protamine sulfate can be used as an antidote for LMWH, it incompletely
neutralizes the anticoagulant activity of LMWH because it only binds the longer
chains of LMWH.
• Because longer chains are responsible for catalysis of thrombin inhibition by
antithrombin, protamine sulfate completely reverses the anti-factor IIa activity of
LMWH.
• In contrast, protamine sulfate only partially reverses the anti-factor Xa activity of
LMWH because the shorter pentasaccharide-containing chains of LMWH do not
bind to protamine sulfate.
• Consequently, patients at high risk for bleeding may be more safely treated with
continuous IV unfractionated heparin than with SC LMWH.

54. Thrombocytopenia
• The risk of HIT is about fivefold lower with LMWH than with heparin.
• LMWH binds less avidly to platelets and causes less PF4 release.
• Furthermore, with lower affinity for PF4 than heparin, LMWH is less
likely to induce the conformational changes in PF4 that trigger the
formation of HIT antibodies.
• LMWH should not be used to treat HIT patients because most HIT
antibodies exhibit cross-reactivity with LMWH.
Osteoporosis
• Because the risk of osteoporosis is lower with LMWH than with
heparin, LMWH is the better choice for extended treatment.

56. FONDAPARINUX
• A synthetic analogue of the antithrombin-binding
pentasaccharide sequence, fondaparinux differs from LMWH
in several ways.
• Fondaparinux is licensed for thromboprophylaxis in general
medical or surgical patients and in high-risk orthopedic
patients and as an alternative to heparin or LMWH for initial
treatment of patients with established venous
thromboembolism.

58. Mechanism of Action

59. PHARMACOLOGY
• Fondaparinux exhibits complete bioavailability after SC injection.
• With no binding to endothelial cells or plasma proteins, the clearance
of fondaparinux is dose independent and its plasma half life is 17 h.
The drug is given SC once daily.
• It is cleared unchanged via the kidneys; contraindicated in patients
with a creatinine clearance <30 mL/min and should be used with
caution in those with a creatinine clearance <50 mL/min.
• Produces a predictable anticoagulant response after administration in
fixed doses.

60. Deep Vein Thrombosis/Acute Pulmonary Embolism
Treatment
<50 kg: 5 mg SC once daily
50-100 kg: 7.5 mg SC once daily
>100 kg: 10 mg SC once daily
Administer for 5-9 days; up to 26 days administered in clinical trials
Prophylaxis
>50 kg: 2.5 mg SC once daily for 5-9 days or up to 10 days following abdomonal
surgery; for hip replacement, 11 days recommended and a minimum 10-14 days
recommended for patients undergoing total hip or knee arthroplasty, or hip fracture
surgery; administered for up to 35 days in some instances
USES

61. Heparin-Induced Thrombocytopenia (Off-label)
Prophylaxis of deep vein thrombosis (DVT) in patient with history
of heparin-induced thrombocytopenia (HIT) until patient can
switch to warfarin
2.5 mg SC once daily
American College of Chest Physicians (ACCP) guidelines assign
low evidence rating to treatment of HIT with fondaparinux and
conclude that further studies evaluating its role in HIT treatment
are needed

62. ADVERSE EFFECTS
• The major side effect of fondaparinux is bleeding. There is no
antidote for fondaparinux.
• Protamine sulfate has no effect on the anticoagulant activity
of fondaparinux because it fails to bind to the drug.
• Recombinant activated factor VII reverses the anticoagulant
effects of fondaparinux in volunteers, but it is unknown
whether this agent controls fondaparinux-induced bleeding.

63. PARENTERAL DIRECT THROMBIN INHIBITORS
• Direct thrombin inhibitors bind directly to thrombin and block its
interaction with its substrates.
• Approved parenteral direct thrombin inhibitors include recombinant
hirudins (lepirudin and desirudin), argatroban, and bivalirudin.
• Lepirudin and argatroban are licensed for treatment of patients with
HIT, desirudin is licensed for thromboprophylaxis after elective hip
arthroplasty, and bivalirudin is approved as an alternative to heparin
in patients undergoing percutaneous coronary intervention, including
those with HIT.

64. Lepirudin and Desirudin
• These are bivalent direct thrombin inhibitors that interact with the active site and
exosite 1, the substrate-binding site on thrombin.
• For rapid anticoagulation, lepirudin is given by continuous IV infusion, but the
drug can be given SC.
• Lepirudin has a plasma half-life of 60 min after IV infusion and is cleared by the
kidneys.
• A high proportion of lepirudin-treated patients develop antibodies against the
drug; antibody formation is rare with SC desirudin.
• Although lepirudin-directed antibodies rarely cause problems, in a small subset of
patients, they can delay lepirudin clearance and enhance its anticoagulant
activity.
• Lepirudin is usually monitored using the aPTT, and the dose is adjusted to
maintain an aPTT that is 1.5–2.5 times the control.
• For thromboprophylaxis, desirudin is given SC twice daily in fixed doses; the half-
life of desirudin is 2–3 h after SC injection.
• When used for thromboprophylaxis, desirudin does not require monitoring.

65. Argatroban
• A univalent inhibitor that targets the active site of thrombin, argatroban is
metabolized in the liver.
• Argatroban is administered by continuous IV infusion and has a plasma
half-life of ~45 min.
• The aPTT is used to monitor its anticoagulant effect, and the dose is
adjusted to achieve an aPTT 1.5–3 times the baseline value, but not to
exceed 100 s.
• Argatroban also prolongs the international normalized ratio (INR), a feature
that can complicate the transitioning of patients to warfarin.
• This problem can be circumvented by using the levels of factor X to monitor
warfarin in place of the INR. Alternatively, argatroban can be stopped for
2–3 h before INR determination.

66. Bivalirudin
• A synthetic 20-amino-acid analogue of hirudin, bivalirudin is a
divalent thrombin inhibitor. Thus, the N-terminus of bivalirudin
interacts with the active site of thrombin, whereas its C-terminus
binds to exosite 1.
• Bivalirudin has a plasma half-life of 25 min, the shortest half-life of all
the parenteral direct thrombin inhibitors.
• Bivalirudin is degraded by peptidases and is partially excreted via the
kidneys.

67. WARFARIN
• A water-soluble vitamin K antagonist initially developed as a
rodenticide
• Warfarin interferes with the synthesis of the vitamin K–
dependent clotting proteins, which include prothrombin
(factor II) and factors VII, IX, and X.
• The synthesis of the vitamin K–dependent anticoagulant
proteins, proteins C and S, is also reduced by vitamin K
antagonists.

68. MECHANISM OF ACTION

69. PHARMACOLOGY
• Warfarin is a racemic mixture of R and S isomers.
• It is rapidly and almost completely absorbed from the gastrointestinal tract.
• Levels in the blood peak about 90 min after drug administration.
• Racemic warfarin has a plasma half-life of 36–42 h, and more than 97% of
circulating warfarin is bound to albumin.
• Only the small fraction of unbound warfarin is biologically active.
• It accumulates in the liver where the two isomers are metabolized via distinct
pathways. CYP2C9 mediates oxidative metabolism of the more active S isomer.
• In addition to genetic factors, the anticoagulant effect is influenced by diet, drugs,
and various disease states. Fluctuations in dietary vitamin K intake affect the
activity.
• A wide variety of drugs can alter absorption, clearance, or metabolism.
• Because of the variability in the anticoagulant response to warfarin, coagulation
monitoring is essential to ensure that a therapeutic response is obtained.

70. Venous Thrombosis
Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE)
Initial dose: 2-5 mg PO/IV qDay for 2 days, OR 10 mg PO for 2 days in healthy individuals
Initiate warfarin on day 1 or 2 of LMWH or unfractionated heparin therapy and overlap until desired
INR, THEN discontinue heparin
Check INR after 2 days and adjust dose according to results
Typical maintenance dose ranges between 2 and 10 mg/day
DVT and PE treatment
•Initiate warfarin on day 1 or 2 of parenteral anticoagulation therapy (eg, LMWH or
unfractionated heparin)
•Overlap warfarin and parenteral anticoagulant for at least 5 days until desired INR
(>2.0) maintained for 24 hours, then discontinue parenteral therapy
USES

71. Stroke & Thromboembolism
Prophylaxis and treatment of systemic embolic complications (eg, stroke) associated with atrial
fibrillation (AF)
Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals
Typical maintenance dose ranges between 2-10 mg/day
Cardiac Valve Replacement
Prophylaxis and treatment of thromboembolic complications associated with cardiac valve
replacement
Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals
Post-Myocardial Infarction
Reduction in the risk of death, recurrent MI, and thromboembolic events (eg, stroke, systemic
embolization) after MI
Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

72. MONITORING
• Because warfarin has a narrow therapeutic window, frequent coagulation monitoring
is essential to ensure that a therapeutic anticoagulant response is maintained.
• Warfarin therapy is most often monitored using the prothrombin time and INR.
• For most indications, warfarin is administered in doses that produce a target INR of
2.0–3.0.
• An exception is patients with mechanical heart valves, particularly those in the mitral
position or older ball and cage valves in the aortic position, where a target INR of 2.5–
3.5 is recommended.
• Studies in atrial fibrillation demonstrate an increased risk of cardioembolic stroke
when the INR falls to <1.7 and an increase in bleeding with INR values >4.5.
• Even patients with stable warfarin dose requirements should have their INR
determined every 3–4 weeks.
• More frequent monitoring is necessary when new medications are introduced
because so many drugs enhance or reduce the anticoagulant effects of warfarin

73. ADVERSE EFFECTS
Bleeding
• Bleeding complications may be mild, such as epistaxis or hematuria, or more
severe, such as retroperitoneal or gastrointestinal bleeding. Life-threatening
intracranial bleeding can also occur. To minimize the risk of bleeding, the INR
should be maintained in the therapeutic range.
• In asymptomatic patients whose INR is between 3.5 and 10, warfarin should
be withheld until the INR returns to the therapeutic range. If the INR is over
10, oral vitamin K should be administered, at a dose of 2.5–5 mg, although
there is no evidence that doing so reduces the bleeding risk.
• Higher doses of oral vitamin K (5–10 mg) produce more rapid reversal of the
INR but may render patients temporarily resistant to warfarin when the drug
is restarted.

74. • Patients with serious bleeding need more aggressive treatment. These
patients should be given 5–10 mg of vitamin K by slow IV infusion.
Additional vitamin K should be given until the INR is in the normal range.
• Treatment with vitamin K should be supplemented with fresh-frozen
plasma as a source of the vitamin K–dependent clotting proteins.
• Four factor prothrombin complex concentrates, which contain all four
vitamin K–dependent clotting proteins, are the treatment of choice for (1)
life-threatening bleeds, (2) rapid restoration of the INR into the normal
range in patients requiring urgent surgery or intervention, and (3) patients
who cannot tolerate the volume load of fresh-frozen plasma.
• Warfarin-treated patients who experience bleeding when their INR is in the
therapeutic range require investigation into the cause of the bleeding.
Those with gastrointestinal or genitourinary bleeding often have an
underlying lesion.

75. Skin necrosis
• A rare complication of warfarin, skin necrosis usually is seen 2–5 days
after initiation of therapy. Well-demarcated erythematous lesions
form on the thighs, buttocks, breasts, or toes. Typically, the center of
the lesion becomes progressively necrotic.
• Examination of skin biopsies taken from the border of these lesions
reveals thrombi in the microvasculature.
• Warfarin-induced skin necrosis is seen in patients with congenital or
acquired deficiencies of protein C or protein S.
• Initiation of warfarin therapy in these patients produces a precipitous
fall in plasma levels of proteins C or S, thereby eliminating this
important anticoagulant pathway before warfarin exerts an
antithrombotic effect through lowering of the functional levels of
factor X and prothrombin.

76. • The resultant procoagulant state triggers thrombosis.
• Treatment involves discontinuation of warfarin and reversal with vitamin K,
if needed.
• An alternative anticoagulant, such as heparin or LMWH, should be given in
patients with thrombosis. Protein C concentrate can be given to protein C–
deficient patients to accelerate healing of the skin lesions; fresh-frozen
plasma may be of value if protein C concentrate is unavailable and for
those with protein S deficiency.
• Because of the potential for skin necrosis, patients with known protein C or
protein S deficiency require overlapping treatment with a parenteral
anticoagulant when initiating warfarin therapy.
• Warfarin should be started in low doses in these patients, and the
parenteral anticoagulant should be continued until the INR is therapeutic
for at least 2–3 consecutive days

77. Pregnancy
• Warfarin crosses the placenta and can cause fetal abnormalities or bleeding.
• The fetal abnormalities include a characteristic embryopathy, which consists of
nasal hypoplasia and stippled epiphyses.
• The risk is highest if warfarin is given in the first trimester of pregnancy. Central
nervous system abnormalities can also occur with exposure to warfarin at any
time during pregnancy.
• Finally, maternal administration of warfarin produces an anticoagulant effect in
the fetus that can cause bleeding. This is of particular concern at delivery when
trauma to the head during passage through the birth canal can lead to
intracranial bleeding.
• Because of these potential problems, warfarin is contraindicated in pregnancy,
particularly in the first and third trimesters.
• Instead, heparin, LMWH, or fondaparinux can be given during pregnancy for
prevention or treatment of thrombosis.
• Warfarin does not pass into the breast milk. Consequently, warfarin can safely be
given to nursing mothers

78. NEW ORAL ANTICOAGULANTS
• New oral anticoagulants are now available as alternatives to warfarin.
• These include dabigatran, which targets thrombin, and rivaroxaban
apixaban, and edoxaban, which target factor Xa.
• All of these drugs have a rapid onset and offset of action and have
half-lives that permit once- or twice-daily administration.
• Designed to produce a predictable level of anticoagulation, the new
oral agents are more convenient to administer than warfarin because
they are given in fixed doses without routine coagulation monitoring.

80. Indications
• The new oral anticoagulants have been compared with warfarin for
stroke prevention in patients with nonvalvular atrial fibrillation.
• Overall, the new agents demonstrate a favorable benefit-to-risk
profile compared with warfarin, and their relative efficacy and safety
are maintained across a wide spectrum of atrial fibrillation patients,
including those over the age of 75 years and those with a prior history
of stroke.
• Dabigatran, rivaroxaban, and apixaban have been compared with
enoxaparin for thromboprophylaxis after elective hip or knee
arthroplasty.

81. Monitoring
• Although designed to be administered without routine monitoring,
there are situations where determination of the anticoagulant activity
of the new oral anticoagulants can be helpful.
• These include assessment of adherence, detection of accumulation or
overdose, identification of bleeding mechanisms, and determination
of activity prior to surgery or intervention.
• For qualitative assessment of anticoagulant activity, the prothrombin
time can be used for factor Xa inhibitors and the aPTT for dabigatran.
• Because apixaban has such a limited effect on the prothrombin time,
anti-factor Xa assays are needed to assess its activity.

82. Adverse effects
• Like all anticoagulants, bleeding is the most common side effect of
the new oral anticoagulants.
• The new agents are associated with less intracranial bleeding than
warfarin.
• A downside of the new oral anticoagulants is the increased risk of
gastrointestinal bleeding.
• Dyspepsia occurs in up to 10% of patients treated with dabigatran;
• Dyspepsia is rare with rivaroxaban, apixaban, and edoxaban.

84. THANK YOU