COAGULATION AND ANTICOAGULANTS -Introduction - Theory - pathways - classifaction - Adverse reaction - Advance drugs - uses

1. COAGULANTS
AND
ANTI-COAGULANTS
PRESENTED BY : verma
simran
M.Pharm (Pharmacology)
Supervisor : Dr.Jagdish
kakadiya

2. COAGULANTS

3. What is coagulations ?
❖ The process of changing of blood from a fluid state to a solid state is known as
coagulation normally this is natural process in the body to prevent blood loss by
plugging the injury site.
❖ Involves complex interactions between injured vessels wall , platelets &
coagulation factors.
❖ After an injury to the body tissues there is a natural mechanism which help to
stop the blood loss by involvement of complex hemostatic(arrest of blood loss)
mechanism.
❖ COAGULANTS: These are substances which promote coagulation. They are
indicated in hemorrhagic states.
❖ Fresh whole blood or plasma provide all the factors needed for coagulation & are
the best therapy. Also, they act immediately.

4. INTRODUCTION
❖ The concept of blood coagulation dates back to 1960's when Davie, Ratnoff and
Macfarlane described the “waterfall” and “cascade” theories outlining the
fundamental principle of cascade of proenzymes leading to activation of
downstream enzymes.
❖ Haemostasis , defined as arrest of bleeding, comes from Greek, haeme meaning
blood and stasis meaning to stop. This thrombo hemorrhagic balance is
maintained in the body by complicated interactions between coagulation and
the fibrinolytic system as well as platelets and vessel wall.
❖ Usually, the coagulation process is under the inhibitory control of several
inhibitors that limit the clot formation, thus avoiding the thrombus propagation.
❖ This delicate balance is interrupted whenever the procoagulant activity of the
coagulation factors is increased, or the activity of naturally occurring inhibitors
is decreased. Pathological situations requiring surgery or anaesthesia or any
other invasive procedure trigger the haemostatic system. This balance is also
disturbed by trauma, cytokines or infectious agents.

5. MECHANIMSM OF BLOOD
CLOTTING
❑ The clotting mechanism is broken into 2 stages:
1. Primary hemostasis: Formation of a weak
platelet plug.
2. Secondary hemostasis: Stabilizing the weak
platelet plug into a clot by the fibrin network.

6. A. PRIMARY HEMOSTASIS
❑ Primary hemostasis is the formation of a weak platelet plug which is achieved
in four phases:
I. vasoconstriction
II. platelet adhesion
III. platelet activation and
IV. platelet aggregation.
❑ Vasoconstriction is the initial response whenever there is vessel injury.
Vasospasm of the blood vessels occurs first in response to injury of the
vasculature.
❑ This vasospasm, in turn, stimulates vasoconstriction. Vasoconstriction is
primarily mediated by endothelin-1, a potent vasoconstrictor, which is
synthesized by the damaged endothelium.
❑ Damaged endothelium exposes sub-endothelial collagen.
❑ Platelet adhesion is the process by which platelets attach to the exposed
subendothelial vWF. Post vascular damage, platelets begin to roll along vessel
walls and adhere to areas of exposed subendothelial collagen and vWF.(VON
WILLBRAND FACTOR)

7. ❑ Platelet activation is mediated via thrombin by two mechanisms. Thrombin
directly activates platelets via proteolytic cleavage by binding the protease-
activated receptor.
❑ Thrombin also stimulates platelet granule release which includes serotonin,
platelet activating factor, and Adenosine Diphosphate (ADP).
❑ ADP is an important physiological agonist which is stored specifically in the
dense granules of platelets.
❑ Platelet aggregation begins once platelets have been activated.
❑ Once activated, the Gp IIb/IIIa receptors adhere to vWF and fibrinogen.
Fibrinogen is found in the circulation and forms a connection between the
Gp IIb/IIIa receptors of platelets to interconnect them with each other.
❑ This ultimately forms the weak platelet plug. Ultimately, primary hemostasis
allows the culmination of a weak platelet plug to temporarily protect from
hemorrhage until further stabilization of fibrinogen to fibrin via thrombin
occurs in secondary hemostasis.

8. SECONDARY HEMOSTASIS
- Secondary hemostasis involves the clotting factors acting in a cascade to ultimately stabilize the weak platelet
plug. This is accomplished by completing three tasks:
(1) triggering activation of clotting factors
(2) conversion of prothrombin to thrombin, and
(3) conversion of fibrinogen to fibrin.
These tasks are accomplished initially by 1 of 2 pathways:
- The extrinsic and intrinsic pathway
- Which converge at the activation of factor X and then complete their tasks via the common pathway. The
extrinsic pathway includes tissue factor (TF) and factor VII (FVII). It is initiated when TF binds to FVII, activating FVII
to factor VIIa (FVIIa), forming a TF-FVIIa complex. This complex, in turn, activates factor X (FX).
- Note, the TF-FVIIa complex can also activate factor IX of the intrinsic pathway, which is called the alternate
pathway. Once Factor X is activated to FXa by TF-FVIIa complex .
- The intrinsic pathway includes Hageman factor (FXII), factor I (FXI), factor IX (FIX), and factor VIII (FVIII).
- The process is initiated when FXII comes into contact with exposed subendothelial collagen and becomes
activated to FXIIa.
- Subsequently, FXIIa activates FXI to FXIa, and FXIa activates FIX to FIXa. FIXa works in combination with activated
factor VIII (FVIIIa) to activate factor X. Once Factor X is activated by FIXa-FVIIIa complex, The common pathway is
initiated via the activation of Factor Xa.
- Factor Xa combines with Factor Va and calcium on phospholipid surfaces to create a prothrombinase complex
ultimately activating prothrombin (aka Factor II) into thrombin.
- This activation of thrombin occurs via serine protease cleaving of prothrombin. Now, thrombin activates factor
XIIIa (FXIIIa). FXIIIa crosslinks with fibrin forming the stabilized clot.

10. COAGULATION FACTORS
Factor / name Alternate name Function
Associated Genetic Disorders

12. ❑ Cofactors
❑ Calcium and phospholipid
❑ Vitamin K
❑ Regulators
❑ Protein C
❑ Antithrombin
❑ Tissue factor pathway inhibitor (TFPI)
❑ Plasmin
❑ Prostacyclin (PGI2)
❑ DISORDERS OF COAGULATION
❑ A balance between clotting and bleeding is always maintained in the
body under normal physiology. However any pathological scenario
will tilt this balance to either haemorrhagic or thrombotic
complications. Hence as a corollary disorders of haemostasis can be
categorised into those that lead to abnormal bleeding and those that
lead to abnormal clotting.

13. ❑ Hemophilia: A genetic disorder that passes through families .Trusted
Source and prevents proper blood clotting. It causes excessive bleeding,
swelling, and bruising. The most common types are hemophilia A and B,
where the body lacks certain proteins in the blood for clotting.
❑ von Willebrand’s disease: Another genetic disorder that prevents clotting
due to insufficient von Willebrand factor, a blood-clotting protein.
Females are more likely to notice the condition than males due to heavy
or bleeding that characterizes the condition during menstrual periods or
birth.
❑ Liver disease-associated bleeding: People with liver disease can
experience scarring that increases the risk Trusted Source of bleeding
disorders or thrombosis.
❑ Vitamin K deficiency bleeding: The body requires vitamin K to form blood
clots. Babies born with low vitamin K levels who do receive supplements
may develop vitamin K deficiencies Trusted Source, which can lead to
excessive internal or external bleeding.

14. CLASSIFICATION OF
COAGULANTS

15. SYSTEMIC AGENTS
1. Vitamin k :
K1( from plants )- phytonadiones
K2 (from bacteria) menaquinones
K3 (synthetic)- fat soluble –menadione , acetomenaphthone
Water soluble – menadione sod.bisulfite
VITAMINE K
▪ Fat soluble, required for the synthesis of clotting factors.
▪ Daily requirements: it is uncertain, variable amount becomes
available from colonic bacteria. 50-100µg/day.
▪ Dietary sources: green leafy vegetables. Liver, cheese etc.
▪ SOURCES : Beef liver , green tea , turnip green , broccoli , kale ,
spinach , dark green lettuce ,cheese .

16. UTILIZATION:
▪ Fat soluble forms are absorbed from intestine via lymph and
require bile salts for absorption.
▪ Stored mainly in liver.
▪ Metabolites are excreted in bile or urine.
▪ DEFICIENCY:
▪ Liver disease,
▪ obstructive jaundice
▪ Malabsorption
▪ Long term antimicrobial therapy

17. USE
▪ Dietary deficiency >5-10mg/day oral/parenteral vit K.
▪ Prolonged antimicrobial therapy.
▪ Obstructive jaundice/malabsorption syndromes >vit K 10mg/day
i.m./orally
▪ Liver disease (cirrhosis, viral hepatitis)V. Newborns>vit K 1mg i.m.
▪ Overdose of oral anticoagulants:K1.dose depends on the severity of
bleeding & hypoprothrombinaemia
▪ Prolonged high dose salicylate therapy.
TOXICITY
▪ Flushing,
▪ breathlessness,
▪ constriction in chest,
▪ fall in BP.
▪ Sweating
▪ Cyanosis, etc.

18. MISCELLANEOUS
Fibrinogen-
▪ control bleeding in haemophilia, Antihaemophilic globulin (AHG)
deficiency & acute fibrinogenemic states.
▪ It is obtained from human plasma and is a promising haemostatic
agent.
▪ It is available as IV infusion 0.5 per bottle.
.

19. ANTIHAEMOPHILIC FACTOR-
▪ Concentrated human AHG (Anti-human globulin) prepared from
pooled human plasma.
▪ Used to control bleeding in haemophiliacs.
ADVERSE EFFECTS: fever with chills, headache and skin rashes.

20. Ethamsylate:
▪ It decreases capillary bleeding when platelets are adequate; probably
exerts antihyaluronidase action & improves capillary wall stability, but
does not stabilize fibrin.
▪ It is used in capillary bleeding in menorrhagia, after abortion, PPH,
epistaxis, haematuria, malena, after tooth extraction.
ADVERSE EFFECT:
▪ Nausea,
▪ Rash, headache,
▪ fall in BP

21. Desmopressin:
▪ Releases factor VIII & von Willebrand's factor from vascular
endothelium.
▪ Used to control bleeding in haemophilia and von willebrands's
disease.
▪ THERAPEUTIC USES:
▪ It shortens or normalize bleeding time in
▪ patients with congenital defects of platelets. Acquired bleeding
during uremia or use of aspirin.

22. Adrenochrome monosemicarbazone:
▪ Reduce capillary fragility, control oozing from raw surfaces
& prevent microvessel bleeding.
▪ e.g. epitaxis, haematuria, etc.

23. Rutin:
-Plant glycoside.
-reduce capillary bleeding
-Used along with vit C
USES : Antimicrobial , antifungal and anti-allergic.

24. LOCAL HAEMOSTATICS (STYPTICS)
▪ These are substances used to stop bleeding from a local &
approachable site. Effective on oozing surfaces.
▪ E.g. bleeding following tooth extraction, abrasion, epistaxis, etc.

25. Thrombin-
obtained from bovine plasma. It is applied as dry powder on the bleeding
surface. Used in haemophilia, neurosurgery, skin grafting.

26. Fibrin-
obtained from human plasma and is dried; it is used as sheets or foam
for covering or packing bleeding surfaces. It is left in situ.

27. Gelatin foam-
▪ spongy gelatin Moistened with saline or thrombin solution & used for
packing wounds.
▪ Absorbed in 1-2 months. It is left inside.

28. 4. Russels viper venom- applied locally. Acts as
thromboplastin. Used to stop external bleeding in
haemophiliacs.
5. Vasoconstrictors -0.1% solution adrenaline To stop
epistaxis.
6. Astringent- tannic acid or metallic salts. Bleeding gums,
bleeding piles.

29. ADVERSE EFFECTS.
1. Fever
2. Nausea
3. Dizziness
4. Swelling or redness at the injection site
5. Allergy reaction
6. Rash , stuffy nose
7. Severe diseases of liver and kidney

30. CURRENT CONCEPT OF COAGULATION
▪ Initiation
▪ It occurs by expression of TF( TISSUE FACTORS) in damaged vessel which
binds factor VIIa to activate factor IX and factor X. This activation of factor
IX by TF-VIIa complex serves as the bridge between classical extrinsic and
intrinsic pathways. Factor Xa then binds to factor II to form thrombin
(factor IIa).
▪ Thrombin generation through this reaction is not robust and can be
effectively terminated by TF pathway inhibitor .

31. PROPAGATION
The accumulated enzyme complexes (tenase complex and
prothrombinase complex) on platelet surface support robust
amounts of thrombin generation and platelet activation. This
ensures continuous generation of thrombin and subsequently fibrin
to form a sufficiently large clot.

32. ANTICOAGULANTS

34. DEFINATION
Which inhibit clotting .

35. INTRODUCTION
▪ Clotting is good at sites of injury because it minimizes blood loss and prevents
infectious agents from getting into our systems.
▪ Clotting can be bad when occurs inappropriately in normal vessels [called thrombus]
.clot can break free [called embolus] and lodge in heart, causing myocardial infarction,
or in brain, causing stroke.
▪ Thrombosis is caused by abnormalities in blood composition, vessel wall quality, and/or
nature of the blood flow.
▪ Drugs that help prevent the clotting (coagulation) of blood.
▪ Coagulation will occur immediately once a blood vessel has been severed Blood begins
to solidify to prevent excessive blood loss and to prevent invasive substances from
entering the bloodstream.
▪ Anticoagulants are a family of medications that stop your blood from clotting too easily.
They can break down existing clots or prevent clots from forming in the first place.
These medications can help stop life-threatening conditions like strokes, heart attacks
and pulmonary embolisms, all of which can happen because of blood clots.

36. The most common SIDE EFFECTS
OF ANTI-COAGULANTS is blood thinners

37. MOA-
▪ By decrease action of coagulation factors
▪ By interfering synthesis of factors
Uses of Anticoagulants
▪ Deep vein thrombosis
▪ Pulmonary embolism
▪ Myocardial infarction
▪ Unstable angina
▪ Atrial fibrillation
▪ Vascular surgery

38. CLASSIFICATION OF
ANTICOAGULANTS

39. Heparin-
▪ Heparin is a non-uniform mixture of straight chain mucopolysaccharides .
▪ It contains polymers of two sulphated disaccharide units
▪ D-glucosamine- L-iduronic acid
▪ D-glucosamine - D-glucuronic acid
▪ It is present in all tissues containing mast cell .
Characteristics
▪ Discovery – 1916
▪ Extracted from liver
▪ Contains strong electronegative charges Strong anticoagulant - act by in-vivo
& in-vitro Present in endoplasmic reticulum of mast cells Richly present in
lung, liver and intestinal mucosa.

40. ▪ Source: intestinal mucosa and lung ,liver .
▪ Structure: Sulfated mucopolysaccharide (acidic molecule)
▪ Formulations: Standard, unfractionated heparin (UFH) polymer
(3,000-30,000)Average 12,000 to 15.000 g/mol
▪ Route of administration : Continuous (infusion
pump)Intermittent (subcutaneous)Not oral due to lack of
absorption Not IM due to risk of haematoma at injection site
▪ Onset of action: Immediate

42. Mechanism of action
▪ Heparin inhibits coagulation, both in vivo and in vitro, by activating
antithrombin III . Antithrombin III inhibits thrombin and other serine
proteases by binding to the active serine site.
▪ Heparin modifies this interaction by binding, via a unique penta-saccharide
sequence, to anti-thrombin III, changing its conformation and increasing its
▪ affinity for serine proteases.
▪ Thrombin is considerably more sensitive to the inhibitory effect of the
heparin–antithrombin III complex than is factor Xa.
▪ To inhibit thrombin, it is necessary for heparin to bind to the enzyme as
well as to antithrombin III; to inhibit factor Xa, it is necessary only for
heparin to bind to antithrombin III .
▪ Antithrombin III deficiency is very rare but can cause thrombophilia and
resistance to heparin therapy.
▪ The LMWHs increase the action of antithrombin III on
▪ factor Xa but not its action on thrombin, because the molecules are too
small to bind to both enzyme and inhibitor, essential for inhibition of
thrombin but not for that of factor Xa .

43. Administration and
pharmacokinetic aspects
▪ Heparin is not absorbed from the gut because of its charge and high molecular weight, and it
is therefore given intra-venously or subcutaneously (intramuscular injections
▪ would cause haematomas).
▪ After intravenous injection of a bolus dose, there is a phase of rapid elimination followed by
a more gradual disappearance owing both to saturable processes (involving binding to sites
on endothelial cells and macrophages) and to slower non-saturable processes including
▪ renal excretion.
▪ As a result, once the dose exceeds the saturating
▪ concentration, a greater proportion is dealt with by these slower proc-
▪ esses, and the apparent half-life increases with increasing dose (saturation kinetics).

44. ▪ Heparin acts immediately following intravenous adminis-tration, but the onset
is delayed by up to 60 min when it is given subcutaneously. The elimination half-
life is approximately 40–90 min. In urgent situations, it is therefore usual
▪ to start treatment with a bolus intravenous dose, followed by a constant-rate
infusion. The activated partial thrombo-plastin time (APTT), or some other in
vitro clotting test,

45. ▪ ANTIDOTE
▪ Protamine sulfate Protamine is a basic peptide that binds to
heparin (acid/base or anion/cation interaction)
▪ Excessive antidote must be avoided because protamine itself is
an anticoagulant Administer 1 mg protamine sulfate IV for each
100 units of heparin remaining in the patient Protamine is much
less capable of reversing the effects of LMWH
Disadvantage of LMWH

46. Low-molecular weight heparin
▪ Low-molecular weight heparin is gradually replacing
heparin for treatment of most patients with venous
thromboembolism and acute coronary syndromes
because it has more convenient and cost-effective.
▪ It has similar results to heparin.
▪ Administered by subcutaneous injection.
▪ Example : Dalteparin, Enoxaparin and Tinzaparin .

47. ▪ Low-molecular-weight heparins are given subcutaneously.
▪ They have a longer elimination half-life than unfractionated
heparin, and this is independent of dose (first-order kinetics),
so the effects are more predictable and dosing less frequent
(once or twice a day).
▪ Unlike unfractionated heparin, the effect of a standard dose
is sufficiently predictable that monitoring is not required
routinely.
▪ LMWHs are eliminated mainly by renal excretion, and
unfractionated heparin is preferred in renal failure, but with
this exception LMWHs are at least as safe and effective as
unfractionated heparin and are more convenient to use,
because patients can be taught to inject themselves at home
and there is generally no need for blood tests and dose
adjustment.

48. Pharmacokinetics
▪ As it is large molecule, it is not absorbed orally.
▪ Given by SC or IV Route
▪ Should not be given as IM - Causes Haematos
▪ Does not cross BBB and placenta, hence drug of choice
during pregnancy
▪ Metabolized in liver by heparinase.
▪ Excreted in urine.

49. MOA OF HEPARINE

50. MACHANISM
▪ LMWHs are anticoagulants acting by inhibition of the final common pathway of the
coagulation cascade.
▪ The coagulation cascade's goal is to fluid blood into a clot, thus preventing bleeding. The
final common pathway is the conversion of fibrinogen into fibrin by the activity of
thrombin.
▪ LMWH inhibits coagulation by activating antithrombin III. Antithrombin III binds to and
inhibits factor Xa.
▪ In doing so, it prevents activation of the final common path; Xa inactivation means that
prothrombin is not activated to thrombin, thereby not converting fibrinogen into fibrin
for the formation of a clot.
▪ LMHW is a small fragment of a larger mucopolysaccharide, heparin.
▪ Heparin works similarly by binding antithrombin III and activating it. Heparin also has a
binding site for thrombin so that thrombin can interact with antithrombin III and
heparin, thus inhibiting coagulation.
▪ Heparin has a faster onset of anticoagulant action as it will inhibit Xa and thrombin,
while LMWH acts only on Xa inhibition.

51. CLINICAL USES
▪ Prophylaxis: Anticoagulants are required to prevent the risk of perioperative
deep vein thrombosis and fatal pulmonary embolism after major general
surgery, orthopedic surgery like hip and knee transplants, spinal cord injury
and multiple trauma.
▪ The risk is increased with increased duration of surgery, increasing age and
the presence of co-morbid conditions like coronary artery disease,
malignancy and thrombo-philic states.
▪ LMWH are probably more effective than heparin and warfarin.
▪ Dalteparin or Enoxaparin in a dose of 2500 units SC 1 to 2 hours before
general surgery followed by once daily for 10 days is recommended in high
risk cases.
▪ In high risk orthopedic cases 5000 units SC may be started 12 hours after the
surgery.

52. ADVERSE EFFECT
▪ Adverse effects are similar to heparin except that their incidence is reduced.
▪ Bleeding, thrombocytopenia and osteoporosis occur less frequently .
▪ Anaphylactoid reaction can occur.
▪ Non-surgical bleeding due to overdosage of LMWH is not as easily reversed by
protamine as with heparin.
▪ In patients of heparin induced thrombocytopenia,
▪ LMWH cannot be used because of cross-reactivity.
▪ Although they are more costly than heparin, cost advantage of heparin is offset
by the cost of hospitalization and frequent monitoring.
▪ With LMWH monitoring of APTT is not recommended except of renal failure
and those who have a body weight less than 50 Kg or more than 80 Kg. Like
heparin LMWH are safe in pregnancy.

53. Warfarin
▪ Warfarin is an oral medication .It is a synthetic derivative of coumarin, a
chemical found naturally in many plants.
▪ It decreases blood coagulation by interfering with vitamin K metabolism. It
stops the blood from clotting within the blood vessel stops existing clots
from getting bigger .It stops parts of clots breaking off and forming
Warfarin .
▪ Warfarin and other vitamin K antagonists require frequent blood tests to
individualize dose, and are consequently inconvenient as well as having a
low margin of safety.
▪ The most common side effect of warfarin is bleeding.
▪ The bleeding can be in the form of prolonged bleeding from cuts; bleeding
that does not stop by itself.
▪ Treatment is monitored by regular blood testing using the International
Normalized Ratio (INR).
▪ INR values are used to calculate optimum dose of warfarin.

54. CHARACTERISTICS
▪ Discovery = 1951
▪ They are antagonists of Vit-K
▪ Reduces the plasma levels of functional clotting factors
▪ Warfarin reduces the total amount of each vitamin K -
dependent coagulation factors by 30-50%
Pharmacokinetics
▪ Warfarin (COUMARIN) is 5 mg/day for 2-4 days, followed by 2-
10 mg/day
▪ Completely absorbed in oral, i.v and rectal route
▪ Almost bound to plasma proteins mainly to albumin
▪ It is metabolized by Cytochrome P 450 enzymes CYP2C9.

55. MOA of vitamin k & warfarin

56. MECHANISM OF ACTION
▪ Vitamin K antagonists act only in vivo and have no effect on clotting if added to blood
in vitro.
▪ They interfere with the post-translational γ-carboxylation of glutamic acid residues in
clotting factors II, VII, IX and X.
▪ They do this by inhibiting vitamin K epoxide reductase component 1 (VKORC1), thus
inhibiting the reduction of vitamin K epoxide to its active hydroquinone form .
▪ Inhibition is competitive (reflecting the structural similarity between warfarin and
vitamin K . The VKORC1 gene is polymorphic and different haplotypes have different
affinities for warfarin.
▪ Genotyping to determine the haplo-type, combined with genotyping CYP2C9 ,while
not yet routine, can reduce the variability in response to warfarin by around one-
third.
▪ The effect of warfarin takes several days to develop because of the time taken for
degradation of preformed carboxylate clotting factors.
▪ Onset of action thus depends on the elimination half-lives of the relevant factors.
Factor VII, with a half-life of 6 h, is affected first, then IX, X and II, with half-lives of 24,
40 and 60 h, respectively.

57. Uses: DVT (deep vein thrombosis), Pulmonary embolism and
atrial fibrillation (drug of choice - 3-4wks before and after
conversion)
ADRs:
▪ Bleeding - epistaxis, haematuria, bleeding GIT Intracranial
haemorrhage Minor bleeding - Vit K (takes long)
▪ Fresh blood transfusion or blood factors
▪ Other ADRs: Alopecia, dermatitis and diarrhoea etc.

58. DIFFERENCE BETWEEN HEPARIN WARFARIN
HEPARIN
1. Direct anticoagulant, a mixture of high
molecular weight sulfated
mucopolysaccharides.
2. Prevents the correct work of fibrin and
thrombin.
3. Heparin works faster than warfarin. It
is recommended when an immediate
effect is needed.
4. Given as an injection (subcutaneously
or intravenously). After oral intake, it is
inactive and is not absorbed.
5. Does not cross the placental barrier
and is not excreted in breast milk.
6. It is effective and safe for use during
pregnancy and during lactation.
• WARFARIN
1. Indirect anticoagulant, an organic
compound (4-hydroxycoumarins).
2. Prevents the correct work of vitamin K.
3. Warfarin works slower than heparin
The clinical effect occurs after 12 to 72
hours. It is not recommended when an
immediate effect is needed.
4. Used in tablet form. After oral intake,
warfarin is rapidly and completely
absorbed from the gastrointestinal
tract.
5. Penetrates in the breast milk and
passes through the placental barrier.
6. When using this preparation during
pregnancy leads to the develops of a
characteristic dysmorphism.

59. • HEPARIN
1. Affects the intrinsic pathway
2. Rapid onset of action
3. Few drug interactions
4. Eliminated renally
5. Monitor Aptt
6. Variability in response is limited
7. Sources –hog lungs , pig intestine.
8. Activity invitro and vivo
9. Antidote: Protamine
• WARFARIN
1. Affects the extrinsic pathway
2. Slow onset (several day)
3. Many drug interactions
4. Eliminated hepatically
5. Monitor INR
6. Variability in response is marked
7. Sources- synthetic
8. Activity – in vivo only
9. Antidote: Vitamin K

60. CURRENT DEVELOPMENT

61. NEW ORAL ANTICOAGULANTS :
▪ Dabigatran (Pradaxa) - thrombin inhibitor FDA approval 2010: stroke
prevention in non- valvular Afib
▪ Rivaroxaban (Xarelto) - Xa inhibitor FDA approval 2010/11: postop
VTE prophylaxis, stroke prevention in Afib , treatment of VTEA
▪ Apixaban (Eliquis®) - Xa inhibitor FDA approval 2012: stroke
prevention in Afib ; approved 2014 for VTE prophylaxis after major
orthopedic surgery.
▪ Edoxaban - Xa inhibitor Not yet FDA approved

62. ▪ Dabigatran
▪ Dose: Stroke prevention in A fib: 110-150 mg bid 110 mg
dose not available in US .
▪ For patients with CrCI 15-30: 75 mg bid Not
recommended for CrCI < 15 or dialysis dependent Postop
VTE prophylaxis*: 150-220 mg once daily Prevention of
recurrent VTE": 150 mg bid Less than 10% absorbed;
relatively high rate of Gl side effects Crosses the placenta
- do not use during pregnancy .
▪ Drug may degrade over time after exposure to air-must
be kept in original packaging

63. ▪ Rivaroxaban
▪ Dose: Stroke prevention in Afib: 15-20 mg once daily
▪ Post op VTE prophylaxis: 10 mg once daily ,Acute VTE treatment: 15 mg twice daily
▪ Secondary prevention of VTE: 20 mg once daily Acute coronary syndrome*: 2.5-5 mg
twice daily
▪ Use with caution in moderate renal impairment (CrCL 30-49); 15 mg/day dose
recommended Avoid use if CrCI < 30 (not dialyzable)Avoid use in severe liver disease
▪ Apixaban
▪ Dose: Stroke prevention in Afib: 5 mg bid2.5 mg bid if age >80, weight < 60 kg, or
serum creatinine > 1.5
▪ Post op VTE prophylaxis*: 2.5 mg bid
▪ Secondary prevention of VTE*: 2.5-5 mg bid
▪ Treatment of acute VTE*: 10 mg bid
▪ Secondary prevention of VTE": 5 mg bid Avoid use in severe liver disease (75% biliary
excretion)

64. Edoxaban
Recently edoxaban , as another factor X inhibitor, was approved by
the US Food and Drug Administration (FDA) to reduce the risk of
thromboembolic events in patients with non-valvular atrial
fibrillation.
The FDA also approved edoxaban for treating patients with deep
vein thrombosis (DVT) and pulmonary embolism (PE), who have
already been treated with a parenteral anticoagulant for 5 to 10
days.

65. This review summaries the role of FXI and FXIa in
hemostasis, provides evidence of initial success with FXI
pathway inhibitors in clinical trials (such as IONIS-FXIRx,
fesomersen, osocimab, abelacimab, milvexian, asundexian
or xisomab 3G3) and highlights the opportunities and
challenges for this next generation of anticoagulants.

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