Coagulants and anticoagulants ppt

COAGULANTS &
ANTICOAGULANTS
Prepared by- Miss Rashmin Kulabkar
M. Pharm (Pharmacology)

HEMOSTASIS
Hemostasis is a sequence of responses that stops bleeding. When blood vessels are
damaged or ruptured, the hemostatic response must be quick, localized to the region of
damage, and carefully controlled in order to be effective.
Three mechanisms reduce blood loss:
(1)vascular spasm,
(2) platelet plug formation, and
(3) blood clotting (coagulation).

1. Vascular Spasm
When arteries or arterioles are damaged, the circularly arranged smooth
muscle in their walls contracts immediately, a reaction called vascular
spasm.
This reduces blood loss for several minutes to several hours.
The spasm is probably caused by damage to the smooth muscle, by
substances released from activated platelets.

PLATELET PLUG FORMATION
• Considering their small size, platelets store an impressive array of chemicals.
• Within many vesicles are clotting factors, ADP, ATP, Ca2+, and serotonin.
• Also present are enzymes that produce thromboxane A2, a prostaglandin; fibrin-
stabilizing factor (factor – XIII), which helps to strengthen a blood clot; lysosomes; some
mitochondria;
• Also within platelets is platelet-derived growth factor (PDGF), a hormone that can cause
proliferation of vascular endothelial cells, vascular smooth muscle fibers, and fibroblasts
to help repair damaged blood vessel walls.

• Initially, platelets contact and stick to parts of a damaged blood vessel, such as
collagen ﬁbers of the connective tissue underlying the damaged endothelial cells.
This process is called platelet adhesion.
• Due to adhesion, the platelets become activated, and their characteristics change
dramatically.
• They extend many projections that enable them to contact and interact with one
another, and they begin to liberate the contents of their vesicles.This phase is
called the platelet release reaction.
• Liberated ADP and thromboxane A2 play a major role by activating nearby platelets.
Serotonin and thromboxane A2 function as vasoconstrictors.
• The release ofADP makes other platelets in the area sticky, and the stickiness of the
newly recruited and activated platelets causes them to adhere to the originally
activated platelets.
• This gathering of platelets is called platelet aggregation. Eventually, the
accumulation and attachment of large numbers of platelets form a mass called a
platelet plug.

 Platelets adhere (platelet adhesion) to the exposed collagen fibrils in the subendothelium of the
injured vessel via a specific, platelet-collagen receptor, glycoprotein Ia/IIa.
 This causes platelet activation and release of preformed platelet granule constituents (5HT) and
adenosine diphosphate (ADP).
 This promotes platelet aggregation (more platelets sticking to each other), thus forming a primary
hemostatic plug.
 Activated platelets lose their individual membranes, form a viscous mass and promote the assembly
of clotting factors, thereby amplifying thrombin formation.
 Activated platelets generate thromboxane A2 , a potent platelet agonist that also stimulates
additional platelets.
 The other platelet agonists include collagen, ADP, adrenaline and thrombin.
 ADP elicits its effects on the platelet through P2Y1 and P2Y12 receptors while thrombin interacts
with protease activated receptors PAR -1 and - 4.
 Circulating fibrinogen binds to an activated platelet receptor glycoprotein IIb/IIIa (Integrin) and is
converted to fibrin.
 The process of deposition of fibrin is called coagulation.

BLOOD CLOTTING
•Normally, blood remains in its liquid form as long as it stays
within its vessels.
•If it is drawn from the body, however, it thickens and forms
a gel.
•Eventually, the gel separates from the liquid.
•The straw-colored liquid, called serum, is simply blood
plasma minus the clotting proteins.
•The gel is called a clot.
•It consists of a network of insoluble protein fibers called
fibrin in which the formed elements of blood are trapped
•The process of gel formation, called clotting or
coagulation, is a series of chemical reactions that culminates
in formation of fibrin threads.
• If blood clots too easily, the result can be thrombosis—
clotting in an undamaged blood vessel.
•If the blood takes too long to clot, hemorrhage can occur.

•Clotting involves several substances known as clotting (coagulation) factors.
•These factors include calcium ions , kallekrein, several inactive enzymes that are
synthesized by hepatocytes (liver cells)
•Some of the factors (II or prothrombin; VII, IX and X) are vitamin K dependent
for their synthesis.
•During the process of clotting, each factor undergoes partial proteolysis to form an
enzyme

Clotting can be divided into three stages
1) Two pathways, called the extrinsic pathway and the intrinsic pathway , lead
to the formation of prothrombinase.
2) Prothrombinase converts prothrombin (a plasma protein formed by the liver)
into the enzyme thrombin.
3) Thrombin converts soluble ﬁbrinogen (another plasma protein formed by
the liver) into insoluble ﬁbrin.
Fibrin forms the threads of the clot.

The Extrinsic Pathway
•The extrinsic pathway of blood clotting has fewer steps than the intrinsic
pathway and occurs rapidly—within a matter of seconds if trauma is severe.
•It is so named because a tissue protein called tissue factor (TF), also known
as thromboplastin, leaks into the blood from cells outside (extrinsic to)
blood vessels and initiates the formation of prothrombinase.
•In the presence of Ca2, TF begins a sequence of reactions that ultimately
activates clotting factor X
•Once factor X is activated, it combines with factor V in the presence of Ca2
to form the active enzyme prothrombinase, completing the extrinsic pathway

THE INTRINSIC PATHWAY
 The intrinsic pathway occurs more slowly, usually requiring several minutes.
 The intrinsic pathway is so named because its activators are either in direct contact with blood or contained
within (intrinsic to) the blood; outside tissue damage is not needed.
 If endothelial cells become roughened or damaged, blood can come in contact with collagen fibers in the
connective tissue around the endothelium of the blood vessel.
 In addition, trauma to endothelial cells causes damage to platelets, resulting in the release of phospholipids
by the platelets.
 Contact with collagen fibers (or with the glass sides of a blood collection tube) activates clotting factor XII ,
which begins a sequence of reactions that eventually activates clotting factor X.
 Platelet phospholipids and Ca2 can also participate in the activation of factor X.
 Once factor X is activated, it combines with factor V to form the active enzyme prothrombinase (just as
occurs in the extrinsic pathway), completing the intrinsic pathway

 The formation of prothrombinase marks the beginning of the common pathway.
 In the second stage of blood clotting prothrombinase and Ca2 catalyze the
conversion of prothrombin to thrombin.
 In the third stage, thrombin, in the presence of Ca2, converts fibrinogen, which is
soluble, to loose fibrin threads, which are insoluble.
 Thrombin also activates factor XIII (fibrin stabilizing factor), which
strengthens and stabilizes the fibrin threads into a sturdy clot.

THE FIBRINOLYTIC SYSTEM
After the clot has formed, the process of removing it and healing the damaged blood vessel begins.
 The breakdown of the clot, or fibrinolysis, is the first stage.
 Plasminogen, trapped within the clot as it forms, is converted to the enzyme plasmin
 Plasmin breaks down fibrin to soluble products that are treated as waste material and removed
by phagocytosis.
 As the clot is removed, the healing process restores the integrity of the blood vessel wall.
 Plasminogen ----Plasmin ----Fibrin ----Breakdown products
 Both body tissues and blood contain substances that can activate plasminogen to plasmin
(fibrinolysin), an active plasma enzyme.
 Among these substances are thrombin, activated factor XII, and tissue plasminogen
activator (t-PA).
 Once plasmin is formed, it can dissolve the clot by digesting fibrin threads.

 Several other mechanisms also control blood clotting.
 For example, endothelial cells and white blood cells produce a prostaglandin called prostacyclin
that opposes the actions of thromboxane A2.
 Prostacyclin is a powerful inhibitor of platelet adhesion and release.
 In addition, substances that delay, suppress, or prevent blood clotting, called anticoagulants, are
present in blood.
 These include antithrombin, which blocks the action of several factors, including XII, X, and II
(prothrombin).
 Heparin, an anticoagulant that is produced by mast cells and basophils, combines with
antithrombin and increases its effectiveness in blocking thrombin.
 Another anticoagulant, activated protein C (APC), inactivates the two major clotting factors not
blocked by antithrombin and enhances activity of plasminogen activators.
 Babies that lack the ability to produce APC due to a genetic mutation usually die of blood clots in
infancy.

Drugs used for hemostatic therapy are:
I. Agents acting locally
II. Transfusional agents such as specific coagulation factors
III. Nontransfusional agents, e.g., Vitamin K and antifibrinolytic agents
e.g. Epsilon aminocaproic acid and Tranexamic acid, misc

COAGULANTS
I. Agents acting locally: These agents control oozing of blood from minute vessels but are not effective in
controlling bleeding from large vessels.
1. THROMBIN: Thrombin is obtained from bovine/human plasma. It is stable as a dry powder stored
between 2 0C to 8 0C. It is, however, inactive below pH 5. Thrombin therapy is restricted to local
application in oozing of blood. It has also been used, mixed with plasma, to anchor skin grafts.
2. THROMBOPLASTIN: Thromboplastin is a powder prepared from the acetone extracts of brain and/or
lung tissue of freshly killed rabbits. It is used for determination of prothrombin time and as a local
haemostatic in surgery.
3. FIBRIN: Fibrin obtained from human plasma is used in the dehydrated form as sheets to cover bleeding
surfaces. When used in combination with a thrombin solution, it also acts as a mechanical barrier and holds
thrombin in position over the bleeding area.
4. GEL FOAM: Gel foam is a porous, pressed form of gelatin sponge used in conjunction with thrombin to
control oozing of blood from surface wounds. Gel foam is moistened with isotonic saline before use. It is
completely absorbed within 4 to 6 weeks and hence, may be left in place after suturing of a wound. It is
available as cones, packs, sponges and powder

5. OXIDISED CELLULOSE, Oxycel, is surgical gauze treated with nitrogen dioxide. It promotes clotting by a
reaction between hemoglobin and cellulosic acid. Oxycel, when wet with tissue fluid, becomes sticky and gummy
and exerts its haemostatic effect by mechanical blockage. Oxycel is usually absorbed completely within 2 to 10
days.
6. MICROFIBRILLAR COLLAGEN: This hemostatic material is prepared from purified, bovine corium [cattle
skin]collagen. When applied to a bleeding surface, it attracts platelets to initiate formation of a platelet plug
followed by a natural clot. Used along with manual pressure, it is effective in controlling capillary bleeding, even in
patients on heparin or oral anticoagulants, and in hemophiliacs. It is non-allergenic but can promote local infection
and abscess formation.

II. TRANSFUSIONALAGENTS:
1. HUMAN FIBRINOGEN: Fibrinogen, a sterile fraction from human plasma, is used for restoring normal fibrinogen levels in
haemorrhagic complications caused by acute afibrinogenemia. Fibrinogen and thrombin may be employed together for local
haemostasis.
2. ANTIHAEMOPHILIC GLOBULIN (AHG): Haemophilia A and Christmas disease (haemophilia B) are the two commonest
hereditary haemorrhagic states, due to deficiency of specific clotting factors VIII and IX respectively. Antihaemophilic globulin or
concentrate of factor VIII (AHG) is highly effective in the treatment of classical haemophilia-A. High potency human AHG is prepared
from pooled, normal, human plasma; it is now prepared by recombinant DNA technique. In case of non-availability of AHG, fresh
plasma or blood transfusion is used. Desmopressin which causes release of AHG from its stores, transiently increases its blood level and
may be helpful in mild-moderate hemophilic bleeding.
3. Pure recombinant factor VIII, factor IX and activated factor VII (rFVIIa) are available. They are very expensive and may be
associated with a greater risk of inducing IgG antibodies to factor VIII, thus reducing the efficacy of specific therapy. rFVIIa has also
been used in major bleeding from surgery, trauma and other medical causes. In patients with Christmas disease, fresh or stored plasma
infusion is indicated.
4. PLASMA or BLOOD: Fresh frozen plasma is suitable for the treatment of most coagulation disorders, since it provides all the clotting
factors. Concentrate of factor VIII (purified) and a partially purified preparation containing factors II, VII, IX and X are also available
for specific deficiencies. Whole blood for replacement of coagulation factors may not be ideal as large volumes required carry the risk of
transfusion reactions.

III NON-TRANSFUSIONALAGENTS:
These are substances which promote coagulation, and are indicated in haemorrhagic states.
e.g., Vitamin K and antifibrinolytic agents e.g. Epsilon aminocaproic acid and Tranexamic acid.

VITAMIN K
It is a fat-soluble dietary principle required for the synthesis of clotting factors.
Dam (1929) produced bleeding disorder in chicken by feeding deficient diet.
This was later found to be due to decreased concentration of prothrombin in blood and that it could be
cured by a fat soluble fraction of hog liver.
This factor was called Koagulations vitamin (vit K) and soon its structure was worked out.
A similar vitamin was isolated in 1939 from alfalfa grass and labelled vit K1, while that from sardine
(sea fish) meal was labelled K2. Synthetic compounds have been produced and labelled K3.
Dietary sources are—green leafy vegetables, such as cabbage, spinach; and liver, cheese, etc.
Daily requirement It is uncertain, because a variable amount of menaquinone (vit K2) produced by
colonic bacteria becomes available.
Action Vit K acts as a cofactor at a late stage in the synthesis by liver of coagulation proteins—
prothrombin, factors VII, IX and X.
The vit K dependent change (γ carboxylation of glutamate residues of these zymogen proteins;
confers on them the capacity to bind Ca2+ and to get bound to phospholipid surfaces—properties
essential for participation in the coagulation cascade.

Absorption, fate and excretion: Fat-soluble forms of vit K are absorbed from the
intestine via lymph and require bile salts for absorption, while water-soluble forms
are absorbed directly into portal blood. An active transport process in the jejunum has
been demonstrated for K1, while K2 and K3 are absorbed by simple diffusion. Vit K is
only temporarily concentrated in liver, but there are no significant stores in the body.
Deficiency: 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.
 Haematuria is usually first to occur; other common sites of bleeding are g.i.t., nose.

Adverse reactions:
1. These are rare after oral administration.
2. However, serious anaphylactoid reactions can occur after IV use.
3. Large doses of synthetic menadione have produced haemolytic anaemia, hyper-
bilirubinemia and kernicterus in newborn, especially in premature infants.
4. Menadione competes with bile salts for glucuronide detoxification mechanism causing the
accumulation of bile salts in the blood and this results in jaundice.
5. Haemolysis with menadione is usually seen in infants, whose RBC lack the enzyme G6PD.
Patients with liver disease should not be given repeated, large doses of vitamin K.

Therapeutic uses:
• Adult vitamin K deficiency which may be produced by
Malabsorption syndrome or obstructive jaundice. Menadione may be used.
• Vitamin K deficiency in infants during acute diarrhoea. Menadione may be used.
• Neonatal vitamin K deficiency, for prevention and treatment.
• Overdose of oral anticoagulants: This is the most important indication of vit K. Phytonadione (K1) is the
preparation of choice, because it acts most rapidly;
Vitamin K can generally be given orally but being fat soluble requires the presence of bile salts for its
absorption. It can also be given SC, IM or IV.
Preparations:
(i) Vitamin K1 tablets and injection for IV use.
(ii) Menadione 5 mg tablets. It is water
(iii) Menadione sodium diphosphate injection

Why neonates are susceptible to menadione or its salts?
Menadione and its water-soluble derivatives can cause haemolysis in a dose-
dependent manner.
Patients with G-6-PD deficiency and neonates are especially susceptible.
In the newborn menadione or its salts can precipitate kernicterus:
(a) by inducing haemolysis and increasing bilirubin load.
(b) by competitively inhibiting glucuronidation of bilirubin.
Glucuronide conjugation is, as such, inadequate in neonates.
Because of poor efficacy and higher toxicity, there is little justification to use
menadione and its water soluble salts for any indication

ANTIFIBRINOLYTIC DRUGS
THESE ARE DRUGS WHICH INHIBIT PLASMINOGEN
ACTIVATION AND DISSOLUTION OF CLOT, AND ARE
USED TO CHECK FIBRINOLYSIS ASSOCIATED BLEEDING.

1. EPSILON AMINOCAPROIC ACID (EACA):
This is a water soluble analogue of the amino acid lysine
Mechanism of action:
a) Lysine analogues reversibly occupy the lysine binding sites on plasminogen and inhibits fibrin
binding to plasminogen.
b) Activation of plasminogen to plasmin is thus inhibited.
c) This impairs fibrinolysis with consequent stabilisation of clot.
Orally, it is rapidly absorbed; About 60-90% of the dose is excreted in the urine within 24 hours.
Adverse reactions: nasal stuffiness, abdominal discomfort, dyspepsia, hypotension, conjunctival
erythema, nausea, vomiting, diarrhoea and skin rash. A rare, lethal complication is disseminated
intravascular thrombosis
Therapeutic uses:
The drug has been found to be useful e.g. • Primary menorrhagia. • During prostatic surgery. • Major
trauma with risk of bleeding • Upper GI bleeding. • Bleeding following dental extraction and • Bleeding
associated with thrombocytopenia and postpartum hemorrhage.

2. TRANEXAMIC ACID (TA)
It is also a derivative of lysine, is about 10 times more potent than EACA and has a longer
duration of action.
Adverse reactions are mild and include nausea, diarrhoea and hypotension.
Both EACA and TA are contraindicated in patients with subarachnoid haemorrhage because
they may induce vasospasm and ischemic stroke.

 MISCELLANEOUS DRUGS
1. ETHAMSYLATE
 It reduces capillary bleeding when platelets are adequate;
 MOA- probably corrects abnormalities of platelet adhesion, but does not stabilize fibrin (not an antifibrinolytic).
Ethamsylate has been used in the prevention and treatment of capillary bleeding in menorrhagia, after abortion,
PPH, hematuria and after tooth extraction.
 Side effects are nausea, rash, headache, and fall in BP (only after i.v. injection)
2. DESMOPRESSIN:
 MOA - It releases factor VIII and von Willebrand’s factor from vascular endothelium and checks bleeding in
haemophilia and von Willebrand’s disease.
 This is given IV or SC
 Demopressin is considered a treatment of choice for patients with mild hemophillia-A or type I von Willebrand
disease.
 Adverse effects are mild and include headache, water retention and hyponatremia.

3. CONJUGATED ESTROGENS : Given IV in the dose of 0.6 mg/kg, daily, they improve platelet
function, shorten the prolonged bleeding time. They can be combined with desmopressin for synergistic
effect. They have been used daily for 5-7 days with hardly any adverse reaction.
4. VITAMIN C: Vitamin C (50-100 mg tid) specifically controls bleeding due to scurvy.
5. SNAKE VENOMS: Snake venoms, especially Russel Viper and Copper Head snake venoms, enhance
coagulation by stimulating thrombokinase.
6. Adrenochrome monosemicarbazone It is believed to reduce capillary fragility, control oozing from raw
surfaces and prevent microvessel bleeding, e.g. epistaxis[bleeding from nose], haematuria, secondary
haemorrhage from wounds, etc.
7. RUTIN It is a plant glycoside claimed to reduce capillary bleeding. It has been used in a dose of 60 mg
oral BD– TDS along with vit C which is believed to facilitate its action.

ANTICOAGULANTS
These are drugs used to reduce the coagulability of blood. They may be classified into:

Several other mechanisms also control blood clotting.
 For example, endothelial cells and white blood cells produce a prostaglandin called prostacyclin
that opposes the actions of thromboxane A2.
 Prostacyclin is a powerful inhibitor of platelet adhesion and release.
 In addition, substances that delay, suppress, or prevent blood clotting, called anticoagulants, are
present in blood.
 These include antithrombin, which blocks the action of several factors, including XII, X, and II
(prothrombin).
 Heparin, an anticoagulant that is produced by mast cells and basophils, combines with
antithrombin and increases its effectiveness in blocking thrombin.
 Another anticoagulant, activated protein C (APC), inactivates the two major clotting factors not
blocked by antithrombin and enhances activity of plasminogen activators.
 Babies that lack the ability to produce APC due to a genetic mutation usually die of blood clots in
infancy.

PARENTRAL / FAST ACTING ANTICOAGULANT
HEPARIN
 McLean, a medical student, discovered in 1916 that liver contains a powerful anticoagulant.
 Howell and Holt (1918) named it ‘heparin’ because it was obtained from liver.
 However, it could be used clinically only in 1937 when sufficient degree of purification was achieved.
 Heparin is a mucopolysaccharide composed of a number of sulfated D-glucosamine and D-
glucuronic acid units linked through an oxygen bridge (glucosaminoglycans) with more than 40-45
saccharides per chain.
 The content of esterified sulfuric acid is very high, which makes heparin a strongly electronegative
compound.
 It is thus the strongest organic acid occurring in the body.
 The anticoagulant activity is attributed to its strong electronegative charge
 It occurs in mast cells.
 Thus, heparin is present in all tissues containing mast cells; richest sources are lung, liver and
intestinal mucosa.
 Commercially it is produced from ox lung and pig intestinal mucosa.

ACTIONS
1.Anticoagulant
Heparin is a powerful and instantaneously acting anticoagulant, effective both in vivo and in vitro.
It acts indirectly by activating plasma antithrombin III (AT III, a serine proteinase inhibitor).
The heparin-AT III complex then binds to clotting factors of the intrinsic and common pathways
(Xa, IIa, IXa, XIa, XIIa and XIIIa) and inactivates them but not factor VIIa operative in the
extrinsic pathway.
The anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin (IIa)
mediated conversion of fibrinogen to fibrin.

Antithrombin III is itself a substrate for the protease clotting factors; binds with the protease to form a stable
complex
However, in the absence of heparin, the two interact very slowly.
Heparin enhances the action of AT III in two ways:
(a) Long heparin molecule provides a scaffolding for the clotting factors (mainly Xa and IIa) as well as AT
III to get bound and interact with each other.
(b) Heparin induces conformational change in AT III to expose its interactive sites. A specific
pentasaccharide sequence, which is present in only some of the heparin molecules, binds to AT III with
high affinity to induce the conformational change needed for rapid interaction with clotting factors. This
has been synthesized and named fondaparinux.
(c) Inhibition of IIa requires both the mechanisms, but Xa inhibition can occur by mechanism ‘b’ alone.
(d) This probably explains why low molecular weight heparin, which is insufficient to provide a long scaffolding,
selectively inhibits factor Xa

2. Antiplatelet
Heparin in higher doses inhibits platelet aggregation and prolongs bleeding time.
3. Lipaemia clearing
Injection of heparin clears turbid post-prandial lipaemic plasma by releasing a lipoprotein lipase from the vessel wall
and tissues, which hydrolyses triglycerides and very low density lipoproteins to free fatty acids. These then pass into
tissues and the plasma looks clear. This action requires lower concentration of heparin than that needed for
anticoagulation.
PHARMACOKINETICS
a) Heparin is a large, highly ionized molecule; therefore not absorbed orally.
b) Injected i.v. it acts instantaneously, but after s.c. injection anticoagulant effect develops after ~60 min.
c) Heparin does not cross blood-brain barrier or placenta (it is the anticoagulant of choice during pregnancy).
d) It is metabolized in liver by heparinase and fragments are excreted in urine.
e) Heparin should not be mixed with penicillin, tetracyclines, hydrocortisone or NA in the same syringe or infusion
bottle.
f) Heparinized blood is not suitable for blood counts (alters the shape of RBCs and WBCs)

Adverse reactions:
• Allergic and anaphylactoid reactions are rare and include asthma, urticaria, rhinitis, and fever.
• Bleeding: heparin may produce hemorrhage from various sites such as peptic ulcer, kidneys and
hemorrhoids,
• Thrombocytopenia: Heparin causes transient, mild thrombocytopenia in 25% of patients and severe
thrombocytopenia in a few
The incidence is less with low molecular weight (LMW) heparins which interact less readily with platelets than
unfractionated heparin.
• Alopecia: Transient alopecia may occur after prolonged heparin therapy.
• Osteoporosis: Use of heparin has been reported to cause osteoporosis.
• Miscellaneous: SGOT and SGPT levels may rise during therapy with heparin

Contraindications
1. Bleeding disorders, history of heparin induced thrombocytopenia.
2. Severe hypertension (risk of cerebral haemorrhage), threatened abortion, piles,
g.i. ulcers (risk of aggravated bleeding).
3. Subacute bacterial endocarditis (risk of embolism), large malignancies (risk of
bleeding in the central necrosed area of the tumour).
4. Chronic alcoholics, cirrhosis, renal failure.
5. Aspirin and other antiplatelet drugs should be used very cautiously during heparin
therapy.

Low molecular weight heparins (LMWH) are prepared by fractionation of native heparin; they are more
homogeneous molecularly with molecular weight between 4000 and 6500 and have 15-17 saccharide chains.
MOA
LMW heparins have a different anticoagulant profile; i.e. selectively inhibit factor Xa with little effect on IIa. They
act only by inducing conformational change in AT III and not by providing a scaffolding for interaction of AT III
with thrombin.
Their advantages are that, they:
• Are absorbed more uniformly than the native heparin after SC administration.
• Have a longer duration of action (t½ 4h).
• Inactivate factor Xa selectively; their action against thrombin is minimal. (ratio of anti-Xa to anti-IIa activity is 2:1
to 4:1)
• Have a predictable anticoagulant effect because they bind less avidly to cells and to heparin binding proteins.
• Interact relatively less with platelets and lead to fewer bleeding episodes; and
• Are less antigenic and cause thrombocytopenia and osteoporosis less frequently.
Examples of LMW heparins are enoxaparin, dalteparin sodium, tinzaparin, pamaparin and reviparin.
They vary in their pharmacokinetic properties and dose. Their uses are similar to those of native heparin. However,
native heparin still remains the parenteral anticogualant of choice in cardiopulmonary bypass and DIC

Fondaparinux:
 The pentasaccharide with specific sequence that binds to AT III with high affinity to selectively inactivate factor
Xa without binding thrombin (factor IIa), has been recently produced synthetically and given the name
fondaparinux.
 The bioavailability of fondaparinux injected s.c. is 100% and it is longer acting (t½ 17 hours).
 Fondaparinux is less likely to cause thrombocytopenia
 Risk of osteoporosis after prolonged use is also minimal.
 Fondaparinux does not require laboratory monitoring of aPTT, and is a longer acting alternative to LMW heparins
with the above advantages.
 Dose: 5–10 mg s.c. once daily
Danaparoid is a preparation containing mainly heparan sulfate which is a heparin-like substance found in
many tissues, having less potent anticoagulant action than heparin. Danaparoid is obtained from pig gut mucosa,
and is used in cases with heparin induced thrombocytopenia.

Heparin antagonists: The anticoagulant effects of heparin can be promptly arrested by the
administration of strongly basic compounds which react with the strongly acidic groups of heparin, thereby
abolishing the anticoagulant activity e.g. protamine sulfate.
PROTAMINE SULFATE: Protamine is a mixture of simple, low molecular weight polypeptides, found in the
sperms of certain fish. It binds firmly to heparin and inactivates it.
Protamine sulfate as 1% solution, is administered slowly, IV.
One mg of protamine sulfate neutralises the anti-coagulant effect of 100 units of heparin activity
Protamine IV injection may cause a sudden fall in BP, bradycardia, dyspnoea and transitory flushing.

DIRECT THROMBIN INHIBITORS – factor IIa
HIRUDIN:
MOA This is a potent antithrombin polypeptide obtained from the leech Hirudo medicinalis. It has now been
synthesised by recombinant DNA technique (lepirudin,). It binds irreversibly to thrombin and inactivate free
as well as fibrin–bound thrombin. Its effect does not require antithrombin or other co-factors.
It not only prevents conversion of fibrinogen to fibrin, but also blocks thrombin-catalysed platelet aggregation, and
activation of other clotting factors.
It has a short duration of action and hence it is given by IV infusion.
There is no antidote. It inhibits disseminated intravascular coagulation, and venous and arterial thrombosis.
BIVALIRUDIN:
MOA is a synthetic analogue of hirudin, with rapid onset and offset of action (due to reversible binding; t½ 25
min). It does not form antihirudin antibodies.
DESIRUDIN is also an analogue of hirudin.
ARGATROBAN: is also a reversible direct thrombin inhibitor, given as IV infusion. Its t½ is 45 min. It is used as
an alternative to lepirudin.

2. ORALANTICOAGULANTS / SLOW ACTING AC
ORAL DIRECT THROMBIN INHIBITOR
DABIGATRAN:
Dabigatran etexilate is a prodrug. Given orally, it is converted to the active agent dabigatran which is a direct inhibitor of
thrombin. Given once daily, it is claimed to be as effective as enoxaparin for the treatment and prevention of venous
thromboembolism.
HUMAN ANTITHROMBIN CONCENTRATE: This is prepared from pooled human plasma or by recombinant
technology. It is used either alone or along with heparin to treat patients with a rare hereditary disorder, antithrombin III
deficiency

DIRECT FACTOR Xa INHIBITORS
Recently some orally active drugs have been produced which directly bind to and inactivate factor Xa, instead of
inhibiting its synthesis.
They, therefore, act rapidly without a lag time (as in case of warfarin, etc.), and have short-lasting action.
RIVAROXABAN
i. It is an orally active direct inhibitor of activated factor Xa
ii. Its anticoagulant action develops rapidly within 3–4 hours of ingestion and lasts for ~24 hours.
iii. It is largely metabolized, but also excreted unchanged in urine;
iv. Another advantage is that it requires no laboratory monitoring of PT or aPTT, and is recommended in a fixed
dose of 10 mg once daily.
v. Rivaroxaban has also been found equally effective as warfarin for preventing stroke in patients with atrial
fibrillation.
vi. Side effects reported are bleeding, nausea, hypotension, tachycardia and edema.

ORALANTICOAGULANTS / SLOW ACTING AC
A haemorrhagic disease was described in cattle in 1924 which was due to feeding them on spoiled sweet clover hay. The
disorder was found to be due to prothrombin deficiency and the toxic principle was identified as bishydroxycoumarin in
1939. It was cured by feeding alfalfa grass.
First clinical use of bishydroxycoumarin was made in 1941
Warfarin was initially used as rat poison; demonstration of its safety led to clinical trial; it is now a commonly
employed oral anticoagulant.
Action and mechanism
 Warfarin and its congeners act as anticoagulants only in vivo, not in vitro.
 This is so because they act indirectly by interfering with the synthesis of vit K dependent clotting factors in liver.
 They apparently behave as competitive antagonists of vit K and lower the plasma levels of functional clotting
factors in a dose-dependent manner.
 In fact, they inhibit the enzyme vit K epoxide reductase (VKOR) and interfere with regeneration of the active
hydroquinone form of vit K which acts as a cofactor for the enzyme γ-glutamyl carboxylase that carries out the
final step of γ carboxylating glutamate residues of prothrombin and factors VII, IX and X.
 This carboxylation is essential for the ability of the clotting factors to bind Ca2+ and to get bound to phospholipid
surfaces, necessary for the coagulation sequence to proceed.

 Factor VII has the shortest plasma t½ (6 hr), its level falls first when warfarin is given,
followed by factor IX (t½ 24 hr), factor X (t½ 40 hr) and prothrombin (t½ 60 hr).
 Though the synthesis of clotting factors diminishes within 2–4 hours of warfarin
administration, anticoagulant effect develops gradually over the next 1–3 days as the levels of
the clotting factors already present in plasma decline progressively.
Absorption, fate and excretion:
1. The intestinal absorption of coumarin is slow and incomplete.
2. The drugs are extensively bound to plasma proteins.
3. They cross the placental barrier and are also secreted in milk.
4. They are mainly metabolised in the liver.

Adverse reactions:
 Bleeding: The incidence of hemorrhage is 5-6%. Similar degree of hypoprothrombinemia may be found in patients
who bleed and those who do not. The hemorrhage induced by coumarins can be treated by large doses of vitamin
K1 which enables the liver to synthesise active clotting factors. Immediate treatment of severe hemorrhage,
prompt administration of fresh whole blood is necessary.
 Fetal toxicity: Coumarin anticoagulants may cause fatal hemorrhage in the fetus; further they are teratogenic
 Cutaneous gangrene: Necrosis/gangrene occur occasionally within 3-8 days after starting treatment with large
doses of warfarin.
 Miscellaneous: Rarely, coumarins may cause urticaria, anorexia, vomiting and diarrhoea

RACEMIC WARFARIN SODIUM:
It is a racemic mixture of two isomers, S (t ½ 35 hours) and R (t ½ 50 hours), in almost equal proportions.
Its advantages are:
• It is almost 99% absorbed and gives more steady plasma levels; approximately 97% of the drug is bound to
plasma albumin.
• It has rapid onset and predictable duration of action; therefore, the therapy is easier to regulate; and
• It is water soluble and can be given parenterally.
Adverse reactions: Comparatively few toxic effects other than haemorrhage have been reported. These include
alopecia, urticaria and dermatitis. It can cross the placenta but is not secreted in the milk. It is contraindicated
during pregnancy. Women on long term warfarin therapy should avoid pregnancy

Bishydroxycoumarin (Dicumarol) It is slowly and unpredictably absorbed orally.
Its metabolism is dose dependent—t½ is prolonged at higher doses. Has poor g.i.
tolerance; not preferred now.
DICOUMAROL 50 mg tab. Acenocoumarol (Nicoumalone) The t½ of
acenocoumarol as such is 8 hours, but an active metabolite is produced so that
overall t½ is about 24 hours. Acts more rapidly.
Ethyl biscoumacetate It has a rapid and brief action; occasionally used to initiate
therapy, but difficult to maintain.
Phenindione Apart from risk of bleeding, it produces more serious organ toxicity;
should not be used. DINDEVAN 50 mg tab.

Adverse effects
Bleeding as a result of extension of the desired pharmacological action is the most
important problem causing ecchymosis a discoloration of the skin resulting from bleeding underneath, epistaxis,
hematuria, bleeding in the g.i.t. Intracranial or other internal haemorrhages may even be
fatal. Bleeding is more likely if therapy is not properly monitored.
Treatment: of bleeding due to oral anticoagulants consists of:
• Withhold the anticoagulant.
• Give fresh blood transfusion;
• Give vit K1 which is the specific antidote but it takes 6–24 hours for the clotting
factors to be resynthesized and released in blood after vit K administration.

Factors enhancing effect of oral anticoagulants are:
• Debility, malnutrition, malabsorption and prolonged antibiotic therapy: the supply of vit K to liver is
reduced in these conditions.
• Liver disease, chronic alcoholism: synthesis of clotting factors may be deficient.
• Hyperthyroidism: the clotting factors are degraded faster.
• Newborns: have low levels of vit K and clotting factors
Factors decreasing effect of oral anticoagulants are:
• Pregnancy: plasma level of clotting factors is higher.
• Nephrotic syndrome: drug bound to plasma protein is lost in urine.
• Genetic warfarin resistance: the affinity of warfarin (as well as of vit K epoxide) to bind to the reductase
(VKOR) enzyme, which generates the active vit K hydroquinone, is low.

Contraindications
 All contraindications to heparin apply to these drugs as well.
 Oral anticoagulants should not be used during pregnancy.
 Warfarin given in early pregnancy increases birth defects, especially skeletal
abnormalities.
 It can produce foetal warfarin syndrome—hypoplasia of nose, eye socket,
hand bones, and growth retardation.
 Given later in pregnancy, it can cause CNS defects, foetal haemorrhage, foetal
death and accentuates neonatal hypoprothrombinemia.

DRUG INTERACTIONS
A large number of drugs interact with oral anticoagulants at pharmacokinetic or pharmacodynamic level, and either
enhance or decrease their effect. These interactions are clinically important (may be fatal if bleeding occurs)
A. Enhanced anticoagulant action
1. Broad-spectrum antibiotics: inhibit gut flora and reduce vit K production.
2. Newer cephalosporins (ceftriaxone, cefoperazone) cause hypoprothrombinaemia by the same mechanism as
warfarin —additive action.
3. Aspirin: inhibits platelet aggregation and causes g.i. bleeding—this may be hazardous in anticoagulated patients.
4. Long acting sulfonamides, indomethacin, phenytoin and probenecid: displace warfarin from plasma protein
binding.
5. Chloramphenicol, erythromycin, celecoxib, cimetidine, allopurinol, amiodarone and metronidazole: inhibit
warfarin metabolism.
6. Tolbutamide and phenytoin: inhibit warfarin metabolism and vice versa.
7. Liquid paraffin (habitual use): reduces vit K absorption.

A. Reduced anticoagulant action
1. Barbiturates (but not benzodiazepines), carbamazepine, rifampin and griseofulvin induce the
metabolism of oral anticoagulants.
2. Oral contraceptives: increase blood levels of clotting factors.

The disadvantages of oral anti-coagulants are:
(i) Delayed onset of action, (ii) Variable therapeutic effect and (iii) Need for an elaborate laboratory control.
Indications for anticoagulant therapy:
• Prevention and treatment of deep venous thrombosis (DVT) and pulmonary embolism: Anticoagulants are most
useful in this condition and are used prophylactically. Low fixed dose heparin considerably reduces the incidence of
pulmonary embolism, if used prophylactically in post-operative therapy and in patients with acute MI..
• Myocardial infarction
• Mitral valve disease
• Cerebrovascular disease: As a rule, anticoagulants are not indicated in cerebrovascular disease for fear of causing
cerebral hemorrhage.
• Miscellaneous: They are also used in case of artificial heart valves in order to prevent emboli and during cardiac
bypass surgery

In Vitro Anticoagulants
1. Physical methods: Clotting can be delayed by cooling the blood or by collecting it in coated
vessels so that platelets are not broken up. The coating used is paraffin, collodion or
silicone.
2. Oxalates and citrates: These act by removal of calcium ions.
3. Potassium oxalate 0.1% precipitates serum calcium as calcium oxalate.
4. Sodium citrate combines with calcium and forms calcium sodium citrate
5. Citrate is usually employed as an anticoagulant for blood to be transfused.
6. EDTA (Ethylenediamine tetraacetic acid) a chelating agent, has a great affinity for calcium
and its sodium salt has been used as an anticoagulant
7. Heparin: discussed earlier

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