Coagulants and anticoagulants work to maintain a balance in the coagulation system. Coagulants such as fresh whole blood and factors promote clotting, while anticoagulants like antithrombin and the fibrinolytic system inhibit clot formation and maintain blood fluidity. Vitamin K is essential for the production of coagulation factors and warfarin is an oral anticoagulant that works by inhibiting vitamin K. Heparin is commonly used as an injectable anticoagulant that prevents clotting by binding to antithrombin. Newer oral anticoagulants directly inhibit thrombin or factor Xa.

1. COAGULANTS AND
ANTICOAGULANTS
Dr.M.Karthiga
M.D., DNB., Pharmacology

2. • Hemostasis - finely regulated dynamic process
of maintaining fluidity of the blood, repairing
vascular injury, and limiting blood loss while
avoiding vessel occlusion (thrombosis) and
inadequate perfusion of vital organs.
Injured vessel
wall
Platelets
Coagulation
factors

4. ANTITHROMBOSIS-
Some factors also oppose clot formation, rather
lyse it
To check the balance, these anticoagulants are
present
They operate to maintain blood in fluid state in
circulation & allows rapid haemostatis following
injury
E.g. antithrombin, protein C, protein S,
antithromboplastin & fibrinolysin system
NOTE – PT is raised in common & extrinsic
pathway disturbance & a PTT is raised in common
& intrinsic pathway damage
Normally, PT=12-14 S, a PTT= 26-32 S units

5. COAGULANTS
Are substances which promote coagulation
Are indicated in hemorrhagic states
FFP / Fresh whole blood  all factors for
clotting + immediately  used for factor
deficiency
Systemic
Local

7. VITAMIN K
Fat soluble vitamin
Activation of prothrombin(II) & factors VII, IX, X by
participating in their post ribosomal modification
Dietary requirement is low  it is synthesized by
intestinal bacteria
Vitamin K1 & K2 require bile salts for absorption
Vitamin K1 is available in oral & parenteral forms
Onset of activity is 6 hours; peaks after 24 hours

8. USES
1) Dietary deficiency- rare in adults; Rx :
parenteral vitamin K/ oral 5-10 mg/d
2) Prolonged anti microbial therapy- similar Rx
3) Obstructive jaundice/ mal absorption
syndromes- vitamin K 10 mg/kg i.m. / oral along
with bile salts
4) Liver disease- if its absorption is due to lack of
bile salts, vitamin K is of some help in bleeding
5) Newborns- all have low prothrombin levels due
to less synthesis due to less vitamin K  vitamin K
1 mg i.m. soon after birth

9. CONTD…1.
6) Hemorrhagic disease of newborn- menadione is
not used for this, vitamin K1 is used
7) oral anticoagulant overdose- K1 is the most
important drug as it acts rapidly; dose depends on
INR; in severe cases use 10 mg i.m. followed by
5 mg 4-hourly-effect lasts for 7-10 days; in
moderate cases use 10 mg i.m. followed by 5 mg
once/ twice; in mild over dosage avoid few doses
of anticoagulants only
8) prolonged high dose salicylate therapy  hypo
prothrombinemia

10. TOXICITY-
Rapid i.v. injection of emulsified vitamin K 
flushing, breathlessness & a sense of constriction
in chest, hypotension & deaths
Menadione  dose-dependent hemolysis 
avoided in those with G6PD deficiency
Menadione  kernicterus in newborn by inducing
hemolysis & by competitively inhibiting
glucoronidation of bilirubin  C.I.

11. OTHER COAGULANTS
1) FIBRINOGEN – used to control
hemophilia, acute afibrinogenemic state-
associated bleeding  0.5 mg i.v.
2) ANTI HEMOPHILIC FACTOR – Short
acting, same uses as fibrinogen  5-10
U/Kg i.v. infused every 9 hrs
3) DESMOPRESSIN – hemophilia & Von
Willebrandt factor deficiency

12. 4) ADRENOCHROME
MONOSEMICARBAZONE – use in epistaxis,
hematuria, retinal hemorrhage, secondary
hemorrhage from wounds, 1-5 mg oral/ i.m.
5) RUTIN – a plant glycoside; used with vitamin
C to control capillary bleeding; 60 mg oral BD-
TDS
6) ETHAMSYLATE – anti hyaluronidase if
platelets are sufficiently numbered; not anti
fibrinolytic  used in menorrhagia, tooth
extraction, PPH, malena, post abortion &
epistaxis; ADR = nausea, rash, headache, fall in
BP

13. STYPTICS
LOCAL HEMOSTATICS  control small vessel
bleeds
E.g.
dried fibrin;
Gelatin foam;
Oxidized cellulose;
Thrombin;
Vasoconstrictors (Adr. soln. soaked in cotton);
Astringents- tannic acid

14. SCLEROSING AGENTS-
Are irritants  inflammation  coagulation 
fibrosis
Locally injected in piles or varicose vein mass
E.g.
5% phenol in almond oil 2-5 ml
Ethanolamine oleate in glycerine/ benzyl alcohol
1-5 ml inj.
3% sodium tetra decyl sulfate in benzyl alcohol
3% polydocanol inj. 2 ml

16. Drugs to reduce coagulability of blood
Inhibition of formation of fibrin clots
1) USED IN-VIVO-
PARENTERAL (Heparin LMW);
ORAL- Coumarins & Indandiones (Warfarin, dicoumarol)
2) USED IN-VITRO-
Heparin
CALCIUM COMPLEXES- sodium citrate/ oxalate/
edetate
16

17. Antithrombin

18. HEPARIN

19. HEPARIN
UFH
Large sulfated polysaccharide
polymer obtained from animal
sources.
Average molecular weight- 15,000–
20,000.
Highly acidic and can be neutralized
by basic molecules (eg, protamine).
IV/SC- avoid the risk of hematoma
associated with intramuscular
injection.

20. Low-molecular-weight (LMW)
heparin
Breakdown by alkalisation of heparin
benzyl ester
Molecular weights of 2000–6000
Greater bioavailability and longer
durations of action than
unfractionated heparin
SC
Fondaparinux is a small
pentasaccharide fragment of heparin

21. MOA

22. • Binds to clotting factors
Xa, IIa, IXa, XIa, XIIa,
XIIIa  inactivates
intrinsic pathway only
• Heparin provides
anticoagulation
immediately after
administration because
it acts on preformed
blood components
• aPTT
• LMW heparins and
fondaparinux, like
unfractionated heparin,
bind ATIII.
• These complexes have
the same inhibitory
effect on factor Xa as
the unfractionated
heparin–ATIII complex
• Provide a more
selective action
because they fail to
affect thrombin

25. systemic hypercoagulable
immunological reaction
degradation of platelets
T/t - argatroban
.

31. Direct Thrombin Inhibitors
• Hirudin ,
• Lepirudin ,
• Bivalirudin
• Argatroban
Parenteral
• Ximelagatran Melagatran
• Dabigatran
Oral
Based on proteins made by Hirudo
medicinalis, the medicinal leech.

32. • Lepirudin - recombinant form
of the leech protein hirudin,
while desirudin and
bivalirudin are modified forms
of hirudin.
Predictable pharmacokinetics,
which allows for fixed dosing,
as well as a predictable
immediate anticoagulant
response
• Lepirudin bind simultaneously
to the active site of thrombin
and to thrombin substrates.
• Argatroban binds solely to the
thrombin-active site.
• Inhibit both soluble thrombin
and the thrombin enmeshed
within developing clots.
• Bivalirudin also inhibits
platelet activation.
• Bleeding.
• No reversal agents
• Prolonged infusion of
lepirudin can induce
antibodies that form a
complex with lepirudin and
prolong its action, and it can
induce anaphylactic
reactions.
Dabigatran
Prevention of stroke and
systemic embolism in
nonvalvular atrial fibrillation.

35. 98% weakly protein bound
Half life >30 hrs
Metabolised by liver
Can cross the placenta.

36. Has no effect on previously formed thrombus

37. PLASMA HALF-LIVES OF VITAMIN K-
DEPENDENT PROTEINS
Though the synthesis of
these factors declines in
2-4 h , peak
anticoagulant effect
may be delayed by 72
to 96 hours due to
existing factors
present!!
Factors Half life
Factor VII 6h
Factor IX 24h
Factor X 36h
Factor II 50h
Protein C 8h
Protein S 30h

38. Common INDICATIONS of
warfarin
 Prophylaxis and treatment of venous
thromboembolism (deep vein thrombosis and
pulmonary embolism)
 Prophylaxis and treatment of Atrial
fibrillation
 Valvular stenosis
 Heart valve replacement
 Myocardial infarction

39. WHY TO MONITOR WARFARIN THERAPY?
Narrow therapeutic range
Can increase risk of bleeding

40. MONITORING OF WARFARIN
THERAPY
 Prothrombin time
 PT ratio
 INR (International Normalized Ratio)

41. PROTHROMBIN TIME (PT)
Time required for blood to coagulate is
called PT
Performed by adding a mixture of
calcium and thromboplastin to citrated
plasma
As a control, a normal blood sample is
tested continuously
PT ratio (PTR) = Patient’s PT
Control PT

42. INTERNATIONAL NORMALISED RATIO (INR)
INR = [PTpt] ISI
[PTRef]
PTpt – prothrombin time of patient
PTRef – prothrombin time of normal
pooled sample
ISI – International Sensitivity Index

43. OPTIMIZING WARFARIN THERAPY-
Dosage
Dosage to be individualized according to
patient’s INR response.
Use of large loading dose may lead to
hemorrhage and other complications.
Initial dose: 2-5 mg once daily
Maintenance dose: 2-10 mg once daily
Immediate anticoagulation required: Start
heparin along with loading dose of warfarin 10
mg. Heparin is usually discontinued after 4-5
days. Before discontinuing, ensure INR is in
therapeutic range for 2 consecutive days
Monitor daily until INR is in therapeutic
range, then 3 times weekly for 1-2 weeks,
then less often (every 4 to 6 weeks)

44. OPTIMAL THERAPEUTIC RANGE
Indication INR
Prophylaxis of venous
thromboembolism
2.0-3.0
Treatment of venous
thromboembolism
2.0-3.0
Atrial fibrillation 2.0-3.0
Mitral valve stenosis 2.0-3.0
Heart valve replacement
Bioprosthetic valve
Mechanical valve
2.0-3.0
2.5-3.5
Myocardial infarction 2.0-3.0
2.5-3.5 (high risk patients)

45. DURATION OF THERAPY
Venous thromboembolism: Minimum 3
months, usually 6 months
AMI: During initial 10-14 days of
hospitalization or until patient is
ambulatory
Mitral valve disease/Mechanical heart
valves: Lifelong
Bioprosthetic heart valves: 3 months
Atrial fibrillation: Lifelong
Prevention of cerebral embolism: 3-6
months

46. SIDE EFFECTS
 Hemorrhage
 Rx – withdraw warfarin , Fresh BT or FFP & give
VIT K phytonadione (antidote).
 Skin necrosis (transient Pr.C deficiency)
 Purple toe syndrome (due to cholesterol
emboli released from the atheramatous
plaque)
 Microembolization
 Teratogenecity
 Agranulocytosis, leukopenia, diarrhoea,
nausea, anorexia.

47. CONTRAINDICATIONS AND
PRECAUTIONS
 Hypersensitivity to warfarin
 Condition with risk of hemorrhage
 Hemorrhagic tendency
 Inadequate laboratory techniques
 Protein C & S deficiency
 Vitamin K deficiency
 Intramuscular injections
 Pregnancy

48. Warfarin Drug interactions
Extensive but weak Pr binding easily
displaced by other drugs which increase its
free conc. , increasing anticoagulant effect.
e.g.ASA , Sulfonamides , phenytoin
Slow hepatic metab by P450
Inducers decrease activity (barbiturates ,
carbamezepine , rifampin)
Inhibitors increase activity (cemetidine ,
macrolides ,azoles )

50. Direct Oral Factor Xa inhibitors
• Rivaroxaban,
apixaban, and
edoxaban
• Rapid onset of action
and shorter half-lives
• Rivaroxaban - prevention and
treatment of venous
thromboembolism following hip or
knee surgery and for prevention of
stroke in patients with atrial
fibrillation, without valvular heart
disease.
• Apixaban - prevention of embolic
stroke in patients with nonvalvular
atrial fibrillation.
• Directly bind to and
inhibit both free factor
Xa and factor Xa bound
in the clotting complex.
• Bleeding.