1. COAGULANTS
&
ANTI-COAGULANTS

2. Thrombosis
• Venous thrombosis is associated with stasis of blood
Has small platelet component and large component of fibrin
• Arterial thrombosis is associated with atherosclerosis
-initiated due to endothelial injury leads to atheromatous plaque
formation
Plaque rupture, platelet adhesion, activation, aggregation initiates
thrombus growth, it has large platelet component
Arterial thrombus may break away, emboli form leads to ischemia
and infarction

3. Hemostasis
• Spontaneous Arrest of Bleeding from a Damaged Blood
Vessel; This occurs by the following steps
1. Vasospasm
2. Platelet Adhesion
3. Platelet Aggregation
4. Platelet Plug
5. Fibrin Reinforcement of platelet plug

4. Coagulation
This is the conversion of blood in the liquid form to a solid gel or clot.
Normally there is a balance b/n Procoagulants (TXA2,
thrombin, activated platelets etc.) and Anti-coagulants
(heparan sulfate, Antithrombin III, Nitric oxide and Prostacyclin)
• Imbalance occurs coagulation
• Procoagulants > Anticoagulants
• Injury to blood vessel
• Blood stasis

5. Clotting Factors
•
•
•
•
•
•
•
•
•
•
•
•
I - Fibrinogen
II - Prothrombin
III - Tissue Thromboplastin
IV - Calcium
V - Proaccelerin
VII - Proconvertin
VIII- Antihemophilic globulin
IX - Christmas Factor
X - Stuart Power Factor
XI - Plasma Thromboplastin anticedent (PTA)
XII - Hageman Factor
XIII -Fibrin-stabilizing factor

6. Intrinsic Pathway
Extrinsic Pathway
Tissue Injury
Blood Vessel Injury
Tissue Factor
XIIa
XII
HMW-Kininogen
Thromboplastin
XIa
XI
XIIa, Xia,
Kallikrein
ca+
IXa
IX
VIIa
ca+
ca+
Xa
X
VII
X
XIII
ca+
Factors affected
Prothrombin
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
ca+
Thrombin
XIIIa
Fibrinogen
Fribrin insoluble
Stabilised
Fibrin threads

7. COAGULANTS
• These are substances which promote
coagulation & are indicated in
haemorrhagic states

8. Classification
1 .Vitamin K
• K1(from plants, fat-soluable)
– Phytonadione (phylloquinone)
• K3(synthetic)
– Fat-soluble :menadione,acetomenaphthone
– Water soluble :menadione sod.bisulphate
menadione sod.diphosphate
2 .Miscellaneous
– Fibrinogen (human), Antihaemophilic factor,
Desmopressin, Adrenochrome
monosemicorbazone, Ruti, Ethamsylate

9. VITAMIN K
• ACTION:
- Acts as cofactor in the synthesis
of coagulation factors II, VII, IX, X
• DEFICIENCY:
- Haematuria
- GIT & Nose Bleeding
- Ecchymoses

10. Use of Vitamin K:
•
•
•
•
•
•
•
Dietary deficiency
Prolonged antimicrobial therapy
Obstructive jaundice
Malabsorption syndromes
Liver disease
Premature newborn
To reverse effect of overdose of oral
anticoagulants
• Prolonged high dose salicylate therapy

11. MOA
Decorboxy prothrombin
(or VII, IX, X )
Prothrombin
(or VII, IX, X )
Vit K hydroquinone
Vit K epoxide
NAD
BLOCKED BY ORAL
ANTICOAGULANTS
NADH

12. MISCELLANEOUS
Fibrinogen
• The fibrinogen fraction of human plasma is
employed to control bleeding in haemophilia,
antihaemophilic globulin (AHG) deficiency and acute
afibrinogenemic states; 0.5 gm i.v infusion

13. Antihaemophilic factor
• It concentrated human AHG prepared from pooled
human plasma.
Indicated (along with human fibrinogen) in
haemophilia and AHG deficiency
• Highly effective in control bleeding episodes, but
action is short-lasting (1-2 days)
• Dose; 5-10 U /kg by i v infu, repeated 6-12 hrly

14. Desmopressin
• It releases factor VIII and von Willebrand's factor
from vascular endothelium and checks bleeding in
haemophilia and von Willebrand's disease

15. Adrenochrome
monosemicarbazone
• It believed to reduce capillary fragility, control oozing
from raw surfaces and prevent microvessel
bleeding, ex:epistaxis, haematuria, retinal
haemorrhage, secondary haemorrhage from
wounds, etc Its efficacy is uncertain
• Dose: 1-5 mg oral, i.m.

16. Rutin
• A plant glycoside claimed to reduce capillary
bleeding
• Dose 60 mg oral BD-TDS along with vit C which is
believed to facilitate its action
• Its efficacy is uncertain.

17. Ethamsylate
• It reduces capillary bleeding when platelets are
adequate; probably exerts antihyaluronidase action
improves capillary wall stability, but does not stabilize
fibrin (not an antifibrinolytic)
• in the prevention and treatment of capillary bleeding
in menorrhagia, after abortion, PPH, epistaxis,
malena, hematuria and after tooth extraction, but
efficacy is unsubstantiated
• S/E:N,H, rash & ↓ BP (only after i.v inj)
• Dose: 250-500 mg TDS oral/i.v

18. LOCAL HAEMOSTATICS(STYPTICS)
•
•
•
•
•
•
•
•
Astringents
Vasoconstrictors (Adrenaline)
Thrombin
Fibrin
Gelatin Foam
Calcium alginate
Oxidized cellulose
Russell's viper venom

19. ANTICOAGULANTS

20. CLASSIFICATION
These are drugs used to reduce the coagulability of blood classified into:
USED IN VIVO
Parenteral anticoagulants
a) Heparins (ITI)
• High Molecular Weight Heparin
Unfractionated Heparin (UFH)
• Low molecular weight heparin
(Enoxaparin, Dalteparin, Tinzaparin, Reviparin,
Danaparoid)
b) Heparinoids (DTI)-Heparan sulfate, Hirudin, Lepirudin,
Bivalirudin, Argatroban

21. Oral anticoagulants
(1)Coumarin derivatives :Bishydroxycoumarin
(dicumarol), Warfarin sod, Acenocoumarol
(Nicoumalone), Ethylbiscoumacetate
(2)Indandione derivative: Phenindione.
USED IN VITRO
(a)Heparin
(b)Sod. citrate :used in blood banks to store the blood
(c)Sod. oxalate :
used as an anticoagulant in laboratory
(d)Sod. editate :

22. Parenteral anticoagulants
History of Heparin
•
•
•
•
•
•
McLean
Howell and Holt in 1918 named it heparin
Occurs in mast cells (richest source of mast cells are
lungs, liver and intestinal mucosa)
Commercial heparin , porcine intestinal mucosa and
bovine lungs
A mixture of straight chain anionic (negative charge)
glycosaminoglycan with a wide range of mol wt
It is strongly acidic because of presence of sulfate and
carboxylic acid groups

23. PK of Heparin
• Heparin is highly charged, thus crosses cell
membranes very poorly, hence given Parenterally
• Low dose: S.c
• High Dose: S.c /IV Inj
• Metabolized by liver, half life depends on dose

24. Intrinsic Pathway
Extrinsic Pathway
Tissue Injury
Blood Vessel Injury
Tissue Factor
XIIa
XII
HMW-Kininogen
Thromboplastin
XIa
XI
XIIa, Xia,
Kallikrein
ca+
IXa
IX
VIIa
ca+
ca+
Xa
X
VII
X
XIII
ca+
Factors affected
Prothrombin
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
ca+
Thrombin
XIIIa
Fibrinogen
Fribrin insoluble
Stabilised
Fibrin threads

25. Mechanism
Heparin
No heparin
Active clotting factors
Active clotting factors
Slow
AT III
Fast
AT III
+
Heparin
Inactive clotting factors
Inactive clotting factors

29. Character
HMW Heparins
LMW Heparins
Molecular Weight
High
Low
(30000 Daltons)
(5000 Daltons)
Biotransformation
Low
High (90%)
Half Life
Shorter-depends on
dose
Longer-independent of
dose
Mechanism of Action
Inactivate both factor IIa Inactivate Xa
& Xa
Anti-coagulant effect
More effective
less effective

30. Monitoring
By aPTT
Adverse
Can be given once or twice daily
without monitoring, but requires
special assay if necessary
Less chance of
thrombocytopenia and long term
osteoporosis
Effects
Excretion
Cleared by the
Cleared unchanged by kidneys
Reticuloendothelial system
Reversal
By protamine
Not fully reversed by protamine
Expense
Not expensive
Expensive

31. Dose
Response
Use
Less predictable dose
response because of binding to
plasma proteins, macrophages
and endothelial cells
Has a more predictable
dose-response because it
does not bind to plasma
proteins, macrophages, or
endothelial cells.
More effective for
a) Orthopedic procedures
on lower limb
b) Pulmonary Embolism
c) Unstable Angina

32. Advantages of LMWH over UFH
• Better S.c, BA (70-90%) compared to UFH(20-30%)
• Longer and more consistent half life: once daily S.c
administration
• Since aPTT/clotting times are not prolonged, lab.
monitoring is not needed
• Lower incidence of haemorrhagic complications
• Appear to have lesser antiplatelet action so less
interference with haemostasis

33. Uses of Heparin (Anti-coagulants in
General)
1.Treatment & Prevention of Deep Venous Thrombosis in
• Bedridden (Immobilized patients)
• Old people
• Post-operative
• Post-stroke patients
• Leg fractures
• Elective Surgery

34. 2. Ischemic Heart Disease
Unstable angina
After MI
After angioplasty CABG, stent replacement; Prevent
recurrence
3. Rheumatic Heart Disease/ Atrial Fibrillation
Warfarin, heparin, low dose aspirin,
Decrease stroke due to emboli

35. 4. Cerebrovascular Diseases
Cerebral Emboli (Prevention of recurrence)
5. Vascular Surgery, Prosthetic heart valves, Retinal vessel
thrombosis, Extracorporeal circulation, Hemodialysis
To prevent Thromboembolism
6. Defibrination syndrome or DIC
Abruptio placenta, malignancies, infections; increased
consumption of clotting factors

36. Adverse Effects
1. Bleeding(most common)
2. Allergy and Anaphylaxis
3. Increased hair loss
4. Long term-Osteoporosis, spontaneous fractures
5. Thrombocytopenia

37. Heparin-induced Thrombocytopenia
• Once thrombocytopenia is determined, heparin
must be stopped. Direct thrombin inhibitor should
be given
• Platelets must NOT be given because they will
react with antibody already being produced against
them, causing greater chance of thrombosis.

38. Heparin in Pregnancy
• It not cross placenta, it must be used instead of
warfarin in cases of requiring anticoagulant therapy
in pregnancy.
• Warfarin cross placenta and induces changed in the
fetus to produce the fetal warfarin syndrome – not
good.

39. Contraindications
1. Hypersensitivity
2. Bleeding Disorders like Hemophilia
3. Thrombocytopenia
4. Intracranial Hemorrhage
5. GIT Ulcerations
6. Threatened abortion
7. Advanced renal or hepatic disease

40. Antidote –Protamine Sulfate
• Is highly basic peptide that combines with heparin
as an ion pair to form a stable complex devoid of
anticoagulant activity
• Hemorrhage – can be reversed by protamine sulfate
titrated so that 1 mg of Protamine sulfate is
administered for every 100 U of heparin remaining
in the pt.
• Is also an anticoagulant because it interacts with
platelets, fibrinogen, and other clotting factors – so it
can make hemorrhage worse if more is given than
necessary.

41. Direct Thrombin Inhibitors (DTIs)
or Heparinoids
• The DTIs bind thrombin without additional binding
proteins, such as anti-thrombin, and they do not bind
to other plasma proteins such as platelet factor 4.
• Hirudin and Bivalirudin bind at both the catalytic or
active site of thrombin as well as at a substrate
recognition site
• Argatroban bind only at the thrombin active site

42. Lepirudin
• Monitored by aPTT
• Action independent of antithrombin
• Use in thrombosis related to heparin induced
thrombocytopenia
• No antidote
• Adverse effect: Antibody formation against
thrombin-lepirudin complex

43. Bivalirudin: Inhibits platelet activation also
Use in percutaneous coronary angiography
Argatroban: Used in heparin induced
thrombocytopenia with or without thrombosis
Monitored by aPTT
Dose reduction in liver disease

44. ORAL ANTICOAGULANTS

45. Wisconsin Alumni Research Foundation
Coumarin=Warfarin
Warfarin-Pk
1. Rapidly and completely absorbed after oral
administration
2. 100% Bioavailability
3. Highly PPB (99%)
4. Crosses the placenta (teratogenic)
5. Appears in milk; infants given Vit K
6. Variable but slow clearance;depends on hepatic
P450s
7. Biotransformation by the liver: Oxidation,
Glucuronidation
8. Takes 12-16 hrs before effect is observed

46. Vitamin K-Dependent Clotting
Factors
Vitamin K
VII
IX
X
II
Synthesis of
Functional
Coagulation
Factors

47. Warfarin Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
No Synthesis
of Functional
Coagulation
Factors

48. Mechanism of Action
• Coumarins block the Gamma Carboxylation of
glutamic acid residues of Clotting factors II,VII, IX,
X , endogenous anti-coagulants C & S.
• This is coupled with oxidative deactivation of Vit K
• Coumarins and Indanediones (-) enzyme Vit K
epoxide reductase that converts Vit K epoxide to
its active hydroquinone (reduced form)
• Thus they prevent the activation of Vit K and hence
along with it carboxylations of clotting factor residues

49. Why Carboxylation is necessary?
• Necessary for ability of clotting factors to bind Ca+
and to get bound to phospholipid surfaces which is
necessary for coagulation
• Factor VII affected first, then IX, X, and finally Factor
II (depends upon half lives of circulating factors)

51. H
N
Glu residues
in prothrombin
O
H
N
O
H
COOH
COOH
COOH
O
OH
CH3
CH3
vitamin K
hydroquinone
Gla residues
in prothrombin
O
R
R
vitamin K
2,3-epoxide
O
OH
vitamin K
reductase
vitamin K
epoxide
reductase
O
CH3
R
O
vitamin K
Anticoagulant coumarins
and 1,3-indandiones

52. Uses
• Same as Heparin and other Anticoagulants
• Monitoring necessary because of its low therapeutic
index
• PT noted; time taken for blood to clot
• Pts on Heparin are shifted to oral warfarin after 3-5
days

53. Adverse Effects
1. Bleeding
Common ,serious adverse effect;
Epistaxis, hematuria, GIT Bleeding, internal
hemorrhages
2. Cutaneous Necrosis
This is due to decreased activity of Protein C
Protein C and Protein S found in bone & other tissues
also require Gamma carboxylations
3. Infarction of breast, fatty tissues, intestine and
extremities due to venous thrombosis caused by
again decreased activity of Protein C

55. Antidote of Warfarin
• Stop Warfarin
• Give Vit K (Antidote)
• Also Fresh frozen plasma, Prothrombin complex
concentrates and Recombinant factor VIIa can be
administered

56. Contraindications
1. Pregnancy
Fetal protein in bone and blood affected
-Causes birth defects including abnormal bone
formation, bone hyperplasia
-CNS Defects, fetal hemorrhage, fetal
hypoprothrombinemia and fetal death may occur
2. Other contraindications same as heparin

57. Drug Interactions of Warfarin
A.Pharmacokinetic Interactions
1. Agents that inhibit metabolism of warfarin
• Cimetidine
• Imipramine
• Cotrimoxazole
• Chloramphenicol
• Ciprofloxacin
• Metronidazole
• Amiodarone

58. 2. Drugs that increase metabolism of Warfarin
• Barbiturates
• Rifampin
3. Drugs that displace warfarin from binding sites on
plasma albumin
• Chloral hydrate
• NSAIDs
4. Drugs that decrease GIT absorption of warfarin
• Cholestyramine

59. B. Pharmacodynamic Interactions
1. Synergistic effect
• Heparin
• Aspirin
• Antibiotics: Decrease bacterial flora—decrease Vit K
synthesis—increased warfarin effect

60. Physiological/Pathological Factors affecting
Warfarin Action
1. Increased warfarin action
• Malnutrition, debility (Decreased Vit. K)
• Liver disease, chronic alcoholism (Decreased
clotting factors)
• Hyperthyroidism (Increased degradation of Clotting
factors)
• Newborns (Decreased Vit K)

61. 2. Decreased Warfarin Action
• Pregnancy (Increased clotting factors)
• Nephrotic syndrome
• Warfarin resistance (Genetic)

62. Character
HEPARIN
WARFARIN
Route of
Administration
Parenteral
Oral
Polarity
Polar charged molecule Uncharged
Onset of Action
Rapid
Mechanism of
Action
Accelerates inactivation Inhibits gamma
of clotting factors by
Carboxylation of glutamic
Antithrombin III
acid residues of clotting
factors
12-16 Hours

63. Therapeutic Index
Not low; safe
Low; not safe
Monitoring
aPTT
PT
Adverse Effect
Differences
Thrombocytopenia,,Oste Cutaneous Necrosis,
oporosis, alopecia,
Infarction of breast, fatty
anaphylaxis
and other tissues
Management of Patient
Start with Heparin
Switch over to warfarin in
3-5 days
Antidote
Protamine Sulfate
Vitamin K
Contraindication
Not
Pregnancy
Interactions
Not significant
Significant