Coagulant and anticoagulants

1. Coagulants and anti-coagulants
Dr. Rupendra K. Bharti
MBBS MD

2. Coagulants
• Coagulation: The process of changing of blood
from a fluid state to a solid state is known as
coagulation. Normally, this is a natural process in
the body to prevent blood loss by plugging the
injured site.
• The vascular system must maintain an intricate
balance between the tendency to clot or form a
solid state, and the need to “unclot,” or reverse
coagulation, to keep the vessels open and the
blood flowing.

3. After an injury to the body tissues, there is a natural
mechanism, which helps to stop the blood loss by
involvement of a complex haemostatic mechanism.
This mechanism is as follows:

4. BLOOD
CLOTTING
FACTORS
Component or
Factor
Common Synonym
I Fibrinogen
II Prothrombin
III Tissue thromboplastin
IV Calcium
V Proaccelerin
VI Accerin, supposed to be active form of
factor V
VII Proconvertin
VIII Antihemophilic factor (AHF)
IX Christmas factor, plasma thromboplastin
component (PTC)
X Stuart-Prower factor
XI Plasma thromboplastin antecedent (PTA)
XII Hageman factor
XIII Fibrin-stabilizing factor
XIV Prekallekrein
XV kallekrein
XVI Platelet factor

5. COAGULANTS
Coagulants are the drugs that promote
coagulation and control bleeding.
• They are also called hemostatic agents.
• These drugs are of two types
– Systemic coagulants.
– Local coagulants (styptics).

6. COAGULANTS
Systemic coagulants Local coagulants (styptics)
1. Vitamin-K
2. Ethamsylate
3. Desmopressin
4. Fibrinogen
5. Anti-hemophillic factor
6. Tranexamic acid
7. Epsilon aminocaproic
acid
1. Adrenaline
2. Fibrin glue
3. Gelatin
4. Thrombin
5. Oxidizes cellulose
6. Hemocoagulase
7. Tranexamic acid

7. Systemic coagulants
Vitamin-K
• Vitamin K (Coagulation vitamin) is essential for
the coagulation process.
• It is not directly involved in the clotting
process but required for the synthesis of four
clotting factors in the liver: Factor II,VII,IX and
X.

8. • It occurs naturally in two forms:
– Phylloquinone (K1) from plant source and
– Menaquinone (K2) which is synthesized by colonic
bacteria (E.coli) in the colon.
• K3 is the synthetic form and is available as
– Fat-soluble forms (Menadione,
Acetomenaphthone) and
– water-soluble forms (Menadione sod. Bisulfate
and Menadione sod. Diphosphate).

9. • Dietary sources:
– Green leafy vegetables such as cabbage, spinach
and liver, cheese, cereals, nuts, and egg yolk etc.
– Wheat germ oil is the richest source.
• Physiological functions:
– Vit-K is essential for formation of clotting factor-II,
VII, IX, X, protein-C & S.

10. Deficiency Symptoms
• Vit-K is only temporarily concentrated in liver and
this store can be exhausted within one week.
• The deficiency of vit-K occurs due to liver disease,
obstructive jaundice, malabsorption, long-term
antimicrobial therapy, which alters intestinal
flora.
• The most important manifestation is bleeding
tendency due to lowering of the levels of
prothrombin and other clotting factors in blood.

11. • Haematuria is usually first to occur; other
common sites of bleeding are gastrointestinal
tract, nose and under the skin where it
presents in the form of haemorrhagic spots.
• Recommended dietary allowance (RDA)
– Normal adult requirement is 50–100 μg/day.
– As it can be synthesized in the colon, even 3–10
μg/day may be sufficient.

12. Vit-K use:
• For prevention of haemorrhagic disease of the
newborn: All newborns especially premature
infants have low levels of prothrombin and
other clotting factors.
– Vit- K: 1 mg IM soon after birth has been
recommended routinely.
– Alternatively, 5–10 mg IM to the mother 4–12
hours before delivery can be given.

13. • Patients on prolonged antimicrobial therapy.
• As an antidote in overdose of oral
anticoagulants.
• In patients suffering from liver disease
(cirrhosis, viral hepatitis).

14. • Patients with obstructive jaundice or
malabsorption syndromes (sprue, regional
ileitis, steatorrhoea, etc).
– The therapy given is Vit-K 10 mg IM/day, or
orally along with bile salts for better
absorption.
• Menadione (K3) should not be used in patients
with G-6-PD deficiency.
• In the newborn menadione or its salts can
precipitate kernicterus.

15. Ethamsylate
• It increases capillary wall stability by
antihyaluronidase action.
• It decreases PGI2 synthesis, and corrects
abnormalities of platelet adhesion and
promotes platelet aggregation.
• It is used in the prevention and treatment of
capillary bleeding.

16. • Common indications
– menorrhagia, PPH, after abortion, epistaxis, after
tooth extraction and hematuria.
• Side effects
– nausea, rash, headache, and acute hypotension if
given by fast IV injection.
• It is given in a dose of 250–500 mg TDS orally
or IV.

17. Desmopressin
• It is an analogue to vasopressin & increases
the plasma concentration of factor-VIII, von
Willebrand factor and directly activates
platelets.
• It is a selective V2 agonist, 12 times more
potent than AVP.
• Desmopressin is useful for the treatment of
hemophilia-A and von-willebrand disease.

18. Fibrinogen
• It is obtained from human plasma and is a
promising haemostatic agent.
• It is used to control bleeding in
– Haemophilia
– Hypofibrinogenemia
– Antihaemophilic globulin deficiency.
• It is available as IV infusion 0.5 per bottle.

19. Anti-hemophillic factor
• It contains coagulation factor VIII and is
concentrated human (Antihaemophilic globulin)
AHG obtained from pooled human plasma.
• It is also synthesized by recombinant DNA
technology.
• It is therapeutically used in haemophilia and AHG
deficiency.
• It is given in a dose of 10–20 IU/kg by IV infusion,
repeated 6–12 hourly.

20. Tranexamic acid & Epsilon aminocaproic acid
• They are antifibronolytic agent.
• They inhibit the activation of plasminogen and
dissolution of clot.
• They are available as oral and IV form.
• Tranexamic acid is given in a dose of 500-1000mg
TDS, orally & IV.
• Side effects
– nausea, vomiting, thromboembolic states, allergic
reactions, disturbed colour vision, etc.

21. • They are indicated in:
– To counteract the effect of fibrinolytic drugs.
– For controlling the bleeding in
• tonsillectomy,
• prostatic surgery,
• tooth extraction in haemophiliacs.
– Menorrhagia, menometrorrhagia & DUB.
– Recurrent epistaxis.

22. LOCAL COAGULANTS (STYPTICS)
• Local coagulants are also known as styptics or
haemostatics (haemo-blood and statics- to
stop).
• These substances are used locally to stop the
bleeding from the oozing surfaces such as
abrasions, bleeding tooth socket after tooth
extraction etc.

23. • Normal haemostasis involves three steps:
– Vasoconstriction or contraction of injured vessel wall
for a few minutes.
– Adhesion and aggregation of platelets to form a plug.
– Formation of a blood clot.

24. • This is followed by dissolution of the clot by
the process of fibrinolysis and maintenance of
normal circulation.
• The most preferred and effective method of
stopping the external bleeding is manual
pressure, cotton-gauze pressure pack or by
suturing.

25. Role of adrenaline
• Control of bleeding may be aided by applying
adrenaline locally as it causes local vasoconstriction.
• A cotton pad soaked with 0.1% adrenaline is used to
control capillary bleeding such as epistaxis and after
tooth extraction etc.
• Adrenaline is available in combination with
lignocaine to provide better surgical field, but should
be avoided in patients suffering from hypertension or
cardiovascular disease.

26. Thrombin
• Obtained from bovine plasma is used topically
to control capillary bleeding.
• It may cause hypersensitivity reactions also.

27. Gelatin foam, oxidized cellulose
• Theses are absorbable materials, available as film or
sponge and are used in surgical procedures to
control the bleeding of capillaries or arterioles.
• After applied dry, they swell up and form meshwork,
which helps in the clotting mechanism and stops
bleeding.
• These materials are absorbed within 4 weeks.
• The main adverse effects seen with these are tissue
necrosis, vascular stenosis & nerve damage.

30. Astringents
• Such as tannic acid or
metallic salts (alum)
are occasionally
applied for bleeding
gums, cuts during
shaving, bleeding piles,
etc.

31. ANTI-COAGULANTS

32. Blood Vessel Injury
IX IXa
XI XIa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin Thrombin
Fibrinogen Fribrin monomer
Fibrin polymer
XIII
Intrinsic Pathway Extrinsic Pathway
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Recall !

33. Why anticoagulants ?
 To reduce the coagulability of blood
 Blood clots – Thrombus
 Arterial Thrombosis:
 Adherence of platelets to arterial walls – “White” in color -
Often associated with MI, stroke and ischemia
 Venous Thrombosis:
 Develops in areas of stagnated blood flow (deep vein
thrombosis), “Red” in color- Associated with Congestive
Heart Failure, Cancer, Surgery
 Thrombus dislodge from arteries and veins and become an
embolus
 Venous emboli can block arterioles in the lung and pulmonary
circulation
 Thromboembolism

34. Figure. Classification of established anticoagulants and new anticoagulants that
were recently licensed for use or are in advanced stages of clinical
development. fIXa indicates factor IXa. *Indirectly inhibit coagulation by
interacting with antithrombin. †AVE5026 is an ultralow-molecular-weight
heparin that primarily inhibits fXa and has minimal activity against thrombin.

35. Anticoagulant drugs to treat
thromboembolism
Drug Class Prototype Action Effect
Anticoagulant
Parenteral
Heparin Inactivation of clotting
Factors
Prevent venous
Thrombosis
Anticoagulant
Oral
Warfarin Decrease synthesis of
Clotting factors
Prevent venous
Thrombosis
Antiplatelet
drugs
Aspirin Decrease platelet
aggregation
Prevent arterial
Thrombosis
Thrombolytic
Drugs
Streptokinase Fibinolysis Breakdown of
thrombi

36. Available Anticoagulants
Parenteral anticoagulants:
– Indirect thrombin inhibitors:
– Heparin,
– Low molecular weight heparin,
– Fondaparinux,
– Danaparoid
– Direct thrombin inhibitors:
– Lepirudin,
– Bivalirudin

37. CLASSIFICATION OF ORAL
ANTICOAGULANTS
 Coumarin Derivatives
 Warfarin, Acenocoumarol (Acitrom)
 Indandione Derivatives
 Phenindione, Anisindione
 Newer anticoagulants
• Direct thrombin inhibitor
– Dabigatran etexilate (Pradaxa)
• Direct factor Xa inhibitors
– Rivaroxaban (Xarelto)
– Apixaban
– Edoxaban (DU-176b)
– Betrixaban

38. WARFARIN
• 1948: synthesis of warfarin by student Harold
Campbell.
• Most widely used anticoagulant in the world
• Coumarin derivative, water soluble vit K
antagonist.
• Low cost and highly effective, if given in right
way.
The name warfarin is derived from WARF (Wisconsin Alumni
Research Foundation) and –arin from coumarin.

39. Vitamin K-dependent clotting factors
(FII, FVII, FIX, FX, Protein C/S/Z)
Epoxide
Reductase
 -Carboxylase
(GGCX)
MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle
Warfarin
Inactivation
CYP2C9
Pharmacokinetic
Post translational modification

41. PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT
PROTEINS
Peak anticoagulant effect may be delayed by 72 to 96 hours
COAGULATION FACTORS HALF-LIFE (h)
II 60
VII 4-6
IX 24
X 48-72
Protein –C 8
Protein- S 30

42. VKORC1: New Target Protein for Warfarin
Epoxide
Reductase
 -Carboxylase
(GGCX)
Clotting Factors
(FII, FVII, FIX, FX, Protein C/S/Z)
Rost et al. & Li, et al., Nature (2004)
(VKORC1)

43. Effect of VKORC1 Genotype on Anticoagulation
• Three polymorphic variants of VKORC1
• Non-A, Non-A : wild type – Requiring more warfarin dose
• Non-A/A : Heterozygous – Requiring 25% dose reduction
• A/A : Homozygous - Requiring 50% dose reduction
• Means wild type having more resistance to warfarin while
homozygous is more sensitive.
• Asians have the highest prevalence of VKORC1 variants,
followed by whites and blacks
• Polymorphisms in VKORC1 likely explain 30% of the variability
in warfarin dose requirements.
• VKORC1 variants are more prevalent than variants of CYP2C9
Genotype Freq in Asians (%) Dose reduction
Non-A,Non-A : wild type 7 --
Non-A/A : Heterozygous 30 26
A/A : Homozygous 63 50

44. DOSING
• Usual dose is 5 mg/day (1-20 mg)
• Lower doses require in
• Elderly
• Pt on increased risk of bleeding eg. Pt on aspirin
• Heart failure
• Liver disease
• Renal impairment
• Malnutrition
• Thyrotoxicosis
• Asian patients: Explained by genetic variation in
hepatic enzymes (CYP3C9 & VKORC1 Polymorphism)
• High intake dietary Vit-K (green vegetables e.g.
broccoli) reduces the efficacy of Warfarin.
• Practically best time to give warfarin is ~ 6 PM.

45. Why to add concomitant parenteral anticoagulation ?
• Because of delayed onset of action, concomitant
parenteral anticoagulant should be given in pts with
established thrombosis or high risk for thrombosis
until INR has been in therapeutic range for at least 2
days.
• Warfarin monotherapy decreases the levels of two
endogenous anticoagulants, proteins C and S, thus
increasing thrombogenic potential. Overlapping
warfarin for at least 5 days with an immediately
effective parenteral anticoagulant counteracts the
procoagulant effect of unopposed warfarin.
• Usually a minimum 5 days of concomitant parenteral
anticoagulation is recommended.

46. Commencement of oral anticoagulant therapy
• If the baseline INR≤1.3 the patient will receive 5mg of
warfarin once daily on days 1 and 2.
• The INR is checked on day 3 and 4 and the warfarin
dose is adjusted according to the schedule.

47. Monitoring
• B/z of narrow therapeutic window of warfarin
• Standard procedure is to check the PT-INR as
follows:
INR daily until it is in therapeutic range
3 times weekly for 2 weeks
Once stable & warfarin dose is known
INR every 3-4 weeks or more frequently if
introduction of any new medications

48. What is PT-INR
• Warfarin therapy is most often monitored using the
prothrombin time, a test sensitive to reductions in
the levels of prothrombin, factor VII, and factor X.
• This test involved addition of thromboplastin (a
reagent containing TF, phospholipid & Ca++) to
citrated plasma and determining the time to clot
formation.
• Thromboplastins vary in their sensitivity to
reductions in the levels of the vitamin K–dependent
clotting factors
• INR represent the PT according to international
reference thromboplastin, as approved by WHO.

49. INTERNATIONAL NORMALISED RATIO (INR)
INR = [PTpt] ISI
[PTRef]
PTpt – prothrombin time of patient
PTRef – prothrombin time of normal pooled sample
ISI – International Sensitivity Index
 Highly sensitive thromboplastins have an ISI of 1.0
 Most current thromboplastins have ISI values that range from 1.0 to 1.4

51. Common drugs influencing INR values :
INR  / PT decreases INR  /PT increases
amoxicillin
Quinolones
cephalosporin's
macrolid antibiotics
paracetamol
salicylate
amiodaron
allopurinol
omeprazole
heparin
NSAID & COX2 inh.
tricyclic antidepressants
Rifampicin
Antihistamines
barbiturates
carbamazepine
digoxin
Diuretics
Caffeine's
pentoxiphyllin
Vitamin K

52. Indications
• Atrial fibrillation
• Prosthetic heart valve
• Venous thromboembolism
• Primary pulmonary hypertension
• Rarely after Acute MI
(If associated with high risk of thromboembolism e.g. AF, mobile or pedunculated
mural thrombus or prior venous thromboembolism)

53. Side effects of Warfarin
 Bleeding
 Skin necrosis
 Purple toe syndrome
 Teratogenicity
 Osteoporosis
 Others: Agranulocytosis, leukopenia, diarrhoea,
nausea, anorexia.

54. Bleeding
• Most common complication
• In form of
• Mild: epistaxis, hematuria
• Severe: Retroperotoneal or gastrointestinal bleeding
• Life-threatening : Intracranial bleed
• Rate of major bleeding (defined as any visit to hospital for
hemorrhage) is 1- 3% per person-year
• Half of the complications occurs because INR
exceeds therapeutic range
• Can be minimized by keeping INR in therapeutic
range

55. Interventions according to INR/symptoms
Asymptomatic pts with raised INR
INR INTERVENTION
3.5 - 4.5 Withhold warfarin until in therapeutic
range
Decrease the dose of warfarin
> 4.5 Low dose sublingual/oral Vit K (not
routinely)
4.5 – 9.0 Vit k 1 mg
> 9.0 Vit k 2-3 mg
Higher doses of vitamin K (up to 10 mg) can be administered if more rapid reversal of the
INR is required
Although vitamin K administration results in a more rapid reduction in the INR,
there is no evidence that it reduces the risk of hemorrhage

56. Symptomatic pts with raised INR
SYMPTOMS INTERVENTION
Mild bleeding Withhold warfarin
Severe bleeding Vit K 10 mg slow i/v infusion ± FFP (15
ml/kg)
Life threatening bleeding or pt can’t
tolerate volume overload
Prothrombin complex concentrate
(II,IX & X)
Prosthetic valves pts Vit K should be strictly avoided,
unless there is life threatening
intracranial bleed (Valve thrombosis)
Subcutaneous Vit K gives variable results and should be avoided

57. SKIN NECROSIS
• Rare but very serious complication of warfarin
(prevalence of 0.01-0.1 %)
• Occurs 2 to 5 days after initiation of warfarin
• Usually occurs after high dose of warfarin
• Typical presentation is :
– 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 borders of
these lesions reveals thrombi in the microvasculature

58. Warfarin (Coumadin)–induced skin necrosis on the lower abdomen & breast

59. • Mechanism : Not well understood but a precipitous fall in
plasma protein C or S levels (natural anticoagulants) before
warfarin exert anticoagulant effect, results in procoagulant
state triggering thrombosis of adipose tissue
microvasculatures.
• Treatment :
– Discontinuation of warfarin and reversal with vitamin K, if needed
– An alternative anticoagulant, such as heparin or LMWH, should be
given to patients with thrombosis
– Protein C concentrates or recombinant activated protein C may
accelerate healing of the skin lesions in protein C deficient patients
– Frozen plasma may be useful for those with protein S deficiency
– Occasionally, skin grafting is necessary when there is extensive skin
loss.
• Prevention :
– Start with low dose warfarin in pts with known Protein C or S
deficiency
– Overlapping with a parenteral anticoagulant when initiating warfarin
therapy

60. Purple toes syndrome
• Extremely uncommon cutaneous
complication
• Characterized by the sudden appearance of
bilateral, painful, purple nonhemorrhagic
lesions on the toes and sides of the feet that
blanch with pressure
• Usually develops 3-8 weeks after the start of
warfarin therapy
• Mechanism: release of atheromatous plaque
emboli
• Discontinue COUMADIN therapy if such
phenomena are observed. Consider
alternative drugs if continued anticoagulation
therapy is necessary.
Pharmacotherapy. 2003 May;23(5):674-7

61. Teratogenicity
• Occurs in 3.5 – 6 %
• Depends on time of gestation and dose of warfarin given
• Usually in first trimester of pregnancy
• It causes characteristic embryopathy consist of :
• Nasal hypoplasia and
• Chondrodysplasia punctata (epiphyseal and vertebral
bone stippling)
• Cleft lip and (or) palate
• Choanal stenosis/atresia
• Central nervous system abnormalities
• Coarctation of aorta (Rare malformations described
following first trimester exposure to warfarin)
• Occurs especially if warfarin dose is > 5 mg/day

62. Lateral view X-ray showing calcifications and irregular
ossification of lumbar and sacral vertebrae, consistent with
warfarin embryopathy

63. OSTEOPOROSIS
• Long- term use of warfarin (> 1 yr)
• More common in males
• 60% increased risk of osteoporosis-related
fracture in men
• Mechanism: combination of reduced intake of
vitamin K, which is necessary for bone health,
and inhibition by warfarin of vitamin K-mediated
carboxylation of certain bone proteins, rendering
them nonfunctional
• Beta-adrenergic antagonists may protect against
osteoporotic fractures

64. Warfarin in special conditions…

65. Pregnancy
• It causes…
• Fetal abnormalities (Teratogenic)- in first trimister
• Chances of intracranial bleeding in baby while passage
through birth canal – in third trimister
• Because of this, warfarin is contraindicated in
1st (first 12 weeks) & 3rd trimsters (last 2
weeks)
• Warfarin does not passes in breast milk & is
safe for nursing mothers.

66. ACENOCOUMAROL (acitrom)
• Same as warfarin with following differences:
– Shorter half life 10-16 hrs
– More rapid onset of action
– Shorter duration of action (2 days)
– Causes GI disturbances, oral ulcerations and
dermatitis
• 4 mg on day one, 4-8 mg on the day 2nd then
maintenance dose 1-8 mg according to
response by PT test

67. THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH
WARFARIN AS COMPARED TO ACENOCOUMAROL
72%
67%
64%
66%
68%
70%
72%
%Responders
Warfarin Acenocoumarol
Thrombosis And Haemostasis 1994; 71(2): 188-191

68. Newer Oral Anticoagulants

69. What’s wrong with warfarin?
1. Narrow therapeutic range
2. Slow onset of action
3. Slow offset of action (long duration of action,
long elimination half life)
4. Multiple drug and dietary interactions
5. Monitoring required to maintain in therapeutic
range
6. Difficult to manage for invasive procedures
7. Under-use of therapy due to fear of adverse
events and complexity of management

70. Newer oral anticoagulants

71. Classification
• Direct thrombin (IIa) inhibitor
• Dabigatran (Pradaxa)
• Factor Xa inhibitors
• Rivaroxaban (Xarelto)
• Apixaban
• Edoxaban

73. Dabigatran etexilate (Pradaxa)
• Oral Direct thrombin
(factor IIa) inhibitor
• It is a prodrug & does
not exhibit any
pharmacological
activity
• Initially recommended
by FDA on October 19,
2010 for Non-valvular
AF

74. Mechanism of Action
• Dabigatran and its acyl glucuronides are competitive,
direct thrombin inhibitors.
• Both free and clot-bound thrombin, and thrombin-
induced platelet aggregation are inhibited by the
active moieties.

75. Pharmacokinetics
• Dabigatran etexilate mesylate is absorbed as the
dabigatran etexilate ester.
• The ester is then hydrolyzed, forming dabigatran,
the active moiety.
• The t1/2 is 15 to 17 hrs.
• 90% is excreted unchanged in urine.
• The absolute bioavailability of dabigatran following
oral administration is approximately 3 to 7% .

76. • Dabigatran is also a substrate for P-
glycoprotein ( a trans-membrane pump
expelling drugs out of cell).
• So P- glycoprotein inhibitors (e.g. amiodarone,
verapamil & clarithromycin) can increase
whereas inducers (e.g. rifampicin, st. john’s
wart) may reduce dabigatran level in plasma.

77. INDICATIONS AND USAGE
 Reduction of Risk of Stroke and Systemic Embolism
in Non-valvular Atrial Fibrillation
 Treatment of Deep Venous Thrombosis and
Pulmonary Embolism
 Reduction in the Risk of Recurrence of Deep Venous
Thrombosis and Pulmonary Embolism

78. Recommended dose

79. SOME SPECIAL POINTS TO
MENTION….

80. • If a dose of dabigatran is not taken at the scheduled
time, the dose should be taken as soon as possible on
the same day;
• the missed dose should be skipped if it cannot be taken
at least 6 hours before the next scheduled dose.
• The dose of dabigatran should not be doubled to make
up for a missed dose.

81. Converting pts from or to Warfarin
• From warfarin to dabigatran
– Stop warfarin & start dabigatran once INR fall below 2
• From dabigatran to warfarin
– Adjust the starting time of warfarin based on creatinine clearance
CrCL (ml/min) Days before stopping
dabigatran
> 50 3 days
50 - 30 2 days
30 - 15 1 day
< 15 or dialysis not recommended

82. Converting pts from or to parenteral anticoagulants
From parenteral anticoagulants to dabigatran
– Intermittent parenteral anticoagulant
– Start dabigatran 0-2 hrs before next dose
– Continuous parenteral anticoagulant (e.g. UFH)
– Start dabigatran at the time of stopping parenteral anticoagulant
• From dabigatran to parenteral anticoagulants
• Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min)
after last dose of dabigatran before starting parenteral
anticoagulant

83. Dabigatran in pts planned for elective surgery
• If possible, stop dabigatran 1-2 days before
(CrCl> 50 ml/min) or 3-5 days before (CrCl<
50 ml/min) invasive or surgical procedures.
• Longer periods may be considered if pt
undergoing
1. Major surgery
2. Spinal puncture
3. Placement of spinal or epidural catheter or port

84. BLEEDING ON DABIGATRAN TREATMENT
Pcc: prothrombin complex concn.

85. Monitoring anticoagulant effect of dabigatran
• Need not to assess regularly (ex. In the setting of
emergency surgery)
• In emergency most accessible tests are
1. TCT
2. aPTT
• If the TCT is normal, it is safe to assume that the
level of dabigatran is very low and that the
patient’s risk of bleeding development is similar
to that of other patients undergoing the
procedure

86. Antidote
• Specific agent not available
• Though limited data, following agents may be
used
– Activated prothrombin complex concentrate
– Recombinant factor VIIa
– Concentrate of coagulant factors II, IX and X
– Hemodialysis (because only 35% of dabigatran is bound to
plasma proteins)
Protamine sulfate and Vit-K are not helpful

87. Adverse effects
• Bleeding – increases with age
• GI events
– Dyspepsia (12%)
– Abdominal pain
– Gastritis including GERD, esophagitis, erosive gastritis,
gastric hemorrhage and GI ulcers
• Hypersensitivity reaction (<0.1%)
• An unexplained increase in acute myocardial
infarction in the dabigatran group versus warfarin
(~0.2% increased risk for a AMI re-ly trial)

88. Factor Xa inhibitors
»Rivaroxaban
»Apixaban

89. Rivaroxaban (Xarelto)

90. Rivaroxaban (Xarelto)
• Direct factor Xa inhibitor
• Half life: 7 - 9 hours
• Peak plasma concentration 0.5 – 3 hours after
administration
• Have excellent bio-availability of 80-100%
• 2/3rd of rivaroxaban is metabolized by CYP3A4
system in liver
• 1/3rd of rivaroxaban excreted unchanged in urine
while ½ of the metabolized excreted renally while
other half via fecal route.

91. • To reduce the risk of DVTs and PEs in patients
undergoing knee or hip replacement surgery
(Jul 1, 2011)
• For prevention of thromboembolism and
stroke in patients with nonvalvular atrial
fibrillation (Nov 4, 2011 )
• Treatment of deep vein thrombosis (DVT) and
pulmonary embolism (PE), as well as to reduce
the risk of recurrent DVT and PE (Nov 2, 2012)
Rivaroxaban: FDA Approval
(First approved in July 1st, 2011)

92. Doses of rivaroxaban
– Therapeutic dose : 20 mg once daily
– Prophylactic dose : 10 mg once daily
• No specific dose adjustment advised in
moderate renal function impairment but it
should be used with caution
• Contraindicated in severe renal impairment
• No dose adjustment required for body weight

94. Apixaban (Eliquis)

95. Apixaban (Eliquis)
• Direct factor Xa inhibitor
• Half life – 8 to 11 hours
• Peak plasma concentration 1 – 3 hours after
administration
• Have excellent bio-availability of 66%
• Metabolized in liver
• 25 % of apixaban is renally excreted, so no dose
adjustment are required in renal failure pts
• 75% excreted by fecal route

96. • Apixaban only partially metabolized by CYP3A4
system, so strong CYP3A4 inhibitor/ inducer may
affect its plasma level but this appears to be
minimal as per its anticoagulants effect are
concerned
• Apixaban is minimally interact with P glycoprotein
hence its effects are not affected significantly.
Hence no clinically significant drug interactions

97. • To reduce the risk of stroke and dangerous
blood clots (systemic embolism) in patients
with atrial fibrillation that is not caused by a
heart valve problem (Dec 28, 2012 )
FDA recommendation
(FDA first approved on Dec. 28, 2012)

98. Recommended Dose
Reduction of Risk of Stroke and Systemic Embolism in
Patients with Nonvalvular Atrial Fibrillation
– The recommended dose of apixaban for most patients is 5 mg
taken orally twice daily.
– The recommended dose is 2.5 mg twice daily in patients with any
2 of the following characteristics:
• age ≥80 years
• body weight ≤60 kg
• serum creatinine ≥1.5 mg/dL

99. Prophylaxis of Deep Vein Thrombosis Following Hip or
Knee Replacement Surgery
The recommended dose is 2.5 mg taken orally twice
daily. The initial dose should be taken 12 to 24 hours
after surgery.
• In patients undergoing hip replacement surgery, the
recommended duration of treatment is 35 days.
• In patients undergoing knee replacement surgery, the
recommended duration of treatment is 12 days.

100. Treatment of DVT and PE
The recommended dose of apixaban is 10 mg taken
orally twice daily for 7 days, followed by 5 mg taken
orally twice daily.
Reduction in the Risk of Recurrence of DVT and PE
The recommended dose of apixaban is 2.5 mg taken
orally twice daily after at least 6 months of treatment
for DVT or PE.

103. Parenteral anticoagulants
• A. Parenteral anticoagulants
– (i) Indirect thrombin inhibitors :
• Heparin,
• Low molecular weight heparins,
• Fondaparinux, Danaparoid
– (ii) Direct thrombin inhibitors :
• Lepirudin, Bivalirudin, Argatroban

104. Low-Molecular-Weight Heparin
and
Unfractionated Heparin

105. Heparin
• In 1916, McLean discovered an anticoagulant
substance in liver.
• In 1918, Howell and Holt named it heparin (due to its
extraction from liver).
• In 1937, heparin was used in clinical practice after
extracting the purified form.
• It is a strong organic acid having molecular weight of
10,000-30,000 Da.

106. • As it is present in the mast cells, it is normally
present in all body tissues, which contain mast
cells.
• Commercially, it is obtained from pig
intestinal mucosa & ox lung.
• It acts as anticoagulant both in vivo & vitro.
• It is also known as unfractionated heparin
(UFH).

107. Mechanism of action
• Heparin binds to antithrombin III (natural
endogenous anticoagulant) and heparin-antithrombin-
III complex is formed.
• This heparin-antithrombin-III complex inactivates the
clotting factors of both intrinsic & common pathway
(XIIa, XIa, IX, Xa, XIIIa, II) by binding to them.
• Thus, the anticoagulant effect is exerted mainly by
inhibition of factor Xa & thrombin mediated
conversion of fibrinogen to fibrin (refer coagulation
cascade).

108. Coagulation Cascade
XIIa
XIa
IXa
Intrinsic Pathway
(surface contact)
Xa
Extrinsic Pathway
(tissue factor)
VIIa
Thrombin (IIa)
Thrombin-Fibrin
Clot
aPTT
PT
Heparin / LMWH
(AT-III dependent)
Hirudin/Hirulog
(direct antithrombin)
Courtesy of VTI

109. • Only approximately one third of an administered
dose of heparin binds to AT, and this fraction is
responsible for most of its anticoagulant effect.
• The remaining two thirds has minimal anticoagulant
activity at therapeutic concentrations, but at
concentrations greater than those usually obtained
clinically, both high- and low affinity heparin catalyze
the AT effect of a second plasma protein,
heparin cofactor II

110. • The heparin-AT complex inactivates a number of
coagulation enzymes, including
• thrombin factor (IIa) and
• factors Xa, IXa, XIa, and XIIa.
• Thrombin and factor Xa are the most responsive to
inhibition, and human thrombin is 10-fold more
sensitive to inhibition by the heparin-AT complex
than factor Xa.
• For inhibition of thrombin, heparin must bind to
both the coagulation enzyme and AT, but binding to
the enzyme is less important for inhibition of
activated factor X (factor Xa).

111. • Molecules of heparin with fewer than 18
saccharides do not bind simultaneously to thrombin
and AT and therefore are unable to catalyze
thrombin inhibition.
• In contrast, very small heparin fragments containing
the high-affinity pentasaccharide sequence
catalyze inhibition of factor Xa by AT.
• By inactivating thrombin, heparin not only prevents
fibrin formation but also inhibits thrombin-induced
activation of factor V and factor VIII

113. Pharmacological effects of heparin
• As anticoagulant
• As antiplatelet agent: by inhibiting the platelet
aggregation.
• By activating lipoprotein lipase from the
vessels wall & tissues, it acts as lipaemia
clearing agent.

114. Pharmacokinetics
• It is not absorbed by oral route due to its large size &
highly ionized nature.
• Therefore, it is given by IV route (acts immediately)
and subcutaneous route (acts within an hour).
• It does not cross BBB & placenta. Hence, can be given
safely in pregnancy.
• It is metabolized in liver by heparinase enzyme and
excreted through kidneys.
• The plasma t ½ is 1-2 hours and is dose dependent.
• It is prolonged in kidney & liver diseases and shortened
in pulmonary embolism.

115. Dose
 Adult: 5000–10,000 IU, IV bolus dose
followed by 750–1000 IU/hr IV infusion.
 Children: 50–100 IU/kg.

116. Indications
• Prophylaxis of postoperative venous
thrombosis.
• Post MI.
• Pulmonary embolism.
• Deep venous thrombosis.
• Heparinization of center line & chemo-pods.

117. Adverse effects
• First clinical sign of adverse effect of heparin
is: hematuria.
• The other side effects are
– bleeding,
– thrombocytopenia,
– reversible alopecia,
– osteoporosis,
– hepatotoxicity, and
– rarely hypersensitivity reaction.

118. • Heparin induced thrombocytopenia is a
common entity and was generally manifested
as decreased platelet count. In this condition,
withdrawal of drug is helpful.
• On intramuscular injection, it may cause
hematomas.
• The monitoring of activated partial
thromboplastin time (aPTT) ratio is
mandatory, if the ratio of aPTT is greater than
three, there is increase risk of bleeding.

119. Protamine sulfate (heparin
antagonist)
• It is a strong base and obtained from fish
sperm.
• Protamine sulfate acts as an antidote for
heparin overdose and is given in a dose of 1
mg IV for every 100 IU of heparin.
• It is used after cardiovascular surgeries when
it has been administered in higher doses and
the action needs to be terminated rapidly.

120. Low-molecular-weight heparin
• UH (mw 3k - 30k) is a heterogeneous
mixture of polysacchride chains
(glycosaminoglycans)
• LMWH (mw 5k) is obtained by alkaline
degradation of heparin benzyl ester
• LMWH molecules are enriched with short
chains with higher anti-Xa:IIa ratio

121. Low-Molecular-Weight Heparins
Anti-Factor Xa : Anti - Factor IIa Ratios
Agent Xa:IIa Mol Wt (d)
Enosaparin 3.8 : 1 4,200
Dalteparin 2.7 : 1 6,000
Ardeparin 1.9 : 1 6,000
Nadroparin 3.6 : 1 4,500
Reviparin 3.5 : 1 4,000
Tinzaparin 1.9 : 1 4,500

122. Heparin Sodium Injection, USP (porcine), preserved with
benzyl alcohol, is available as follows:
• Each mL of the 5,000 Units per mL preparation
contains:
• 5,000 USP Heparin Units (porcine);
• 6 mg sodium chloride;
• 15 mg benzyl alcohol (as a preservative);
• Water for Injection q.s. Hydrochloric acid
and/or sodium hydroxide may have been added
for pH adjustment (5.0-7.5).

123. Advantages of LMWH over UH
• Decreased “heparin resistance”
– pharmacokinetics of UH are influenced by its
bindings to plasma protein, endothelial cell
surfaces, macrophages, and other acute phase
reactants
– LMWH has decreased binding to
nonanticoagulant-related plasma proteins

124. Advantages of LMWH over UH
• No need for laboratory monitoring
– when given on a weight-adjusted basis, the
LMWH anticoagulant response is predictable and
reproducible
• Higher bioavailability - 90% vs 30%
• Longer plasma half-life
– 4 to 6 hours vs 0.5 to 1 hour
– renal (slower) vs hepatic clearance

125. Advantages of LMWH over UH
• Less inhibition of platelet function
– potentially less bleeding risk, but not shown in
clinical use
• Lower incidence of thrombocytopenia and
thrombosis (HIT syndrome)
– less interaction with platelet factor 4
– fewer heparin-dependent IgG antibodies

126. Monitoring of LMWH
• Unnecessary in majority of patients
• May be useful in specific instances
– renal insufficiency (creatinine >2.0 mg/dl)
– obese patients with altered drug pK
– major bleeding risk factors
• aPTT not useful - low anti-IIa activity
• anti-factor Xa assay is more appropriate, but
not widely available

127. Various LMWHs with dose
Drug Therapeutic Dose Prophylactic Dose
Enoxaparin 1mg/kg, subcutaneously, twice
daily .
20-40 mg, subcutaneously,
once daily.
Deltaparin 200 IU/kg subcutaneously, once
daily.
2500 IU subcutaneously, once
daily.
Parnaparin 6400 IU subcutaneously, once
daily.
3200 IU subcutaneously, once
daily.
Reviparin 3436 IU subcutaneously, once
daily.
0.25 mL (1432 IU)
subcutaneously, once daily.
Ardeparin 2500-5000 IU subcutaneously,
once daily.
2500 IU subcutaneously, once
daily.
Nadroparin 4000-6000 IU subcutaneously,
once daily/ twice daily.
3000 IU subcutaneously, once
daily/ twice daily.
Tinzaparin 3500 IU subcutaneously, once
daily.
1700 IU subcutaneously, once
daily.
*All are available in prefilled syringes forms.

128. Indications of LMWHs
• Prophylaxis of deep venous thrombosis (DVT)
in immobilized patients such as post-surgical
or coma patients.
• Post MI .
• Prophylaxis of pulmonary embolism.
• Treatment of deep venous thrombosis.
• For the maintenance of patency of cannula in
dialysis patient, centre line & chemo-pods.

129. Fondaparinux
• It is a synthetic derivative of heparin.
• It has pharmacological similarity to LMWHs with
longer plasma half-life (17-21 hours).
• It has 100% bioavailability.
• It is given in a dose of 5-10mg SC, OD.
• The adverse effects like thrombocytopenia &
osteoporosis are even lesser than LMWHs.
• Idraparinux is an ultra long acting derivative of
fondaparinux with t ½ of 5-6 days.

130. Danaparoid
• It is a mixture of heparin like natural
substances (84% heparin sulfate +12%
dermatan salfate + 4% chondroitin sulfate).
• It is obtained from pig intestinal mucosa.
• It has longer plasma t ½ of 24 hours.
• It is used in patient with heparin induced
thrombocytopenia as an alternative therapy.

131. DIRECT THROMBIN INHIBITORS
(Lepirudin, Bivalirudin, Argatroban)

132. Lepirudin
• It is a recombinant preparation of hirudin.
• It inhibits thrombin directly.
• Indicated in heparin induced
thrombocytopenia.
• It cannot be given repeatedly due to formation
of anti-hirudin antibodies and higher risk of
anaphylaxis.
• There is no antidote available against
lepirudin.

133. Bivalirudin
• Synthetic analogue of hirudin with
pharmacological actions similar to lepirudin.
• It has fast onset & offset of action due to its
reversible binding nature.
• It does not form anti-hirudin antibodies.

134. Argatroban
• It is a reversible direct thrombin inhibitor and
given by IV infusion.
• It is used in-patients with heparin-induced
thrombocytopenia as an alternative therapy.

136. COLOUR CODING OF VIALS

137. EDTA
Ethylene
Diamine
Tetra
Acetic
acid
FOR
ROUTINE
HAEMATOL
OGY
BUFFERED
SODIUM
CITRATE
FOR
COAGULATI
ON STUDIES
POTTASIUM
OXALTE OR
SODIUM
FLOURIDE
GLUCOSE
DETERMINA
TION
NO
ADDITIVE
COLLECTION
OF SERUM
ACD
Acid
Citrate
Dextrose
PRESERVE
RBC FOR
BLOOD
BANKING
&
HLA
Typing
HEPARIN
INHIBIT
THROMBIN
ACTIVATION