THE HEMOSTATIC SYSTEM IS VERY COMPLEX

IT CONSISTS OF THE FOLLOWING

FORMATION OF FIBRIN (COAGULATION)

DEGRADATION OF FIBRIN
(FIBRINOLYSIS)
PLATELETS
BLOOD VESSELS
COMING TO COAGULATION WE HAVE

EXTRINSIC SYSYTEM
INTRINSIC SYSTEM

EXTRINSIC SYSTEM

DAMAGED TISSUE

TISSUE FACTOR
(VII)

INTRINSIC SYSTEM
VESSEL WALL
DAMAGE ( XII, XI)

FINAL COMMON PATHWAY

X, V, calcium, phospholipid
PROTHROMBIN

THROMBIN

FIBRINOGEN

FIBRIN

COAGULANTS

VITAMIN K - K1 PHYTONADIONE
K2 MENAQUINONE
K3 SYNTHETICMENADIONE
MISCELLANEOUS- FIBRINOGEN
ANTIHEMOPHILIC
FACTOR
ADRENOCHROME
ETHAMSYLATE

Vitamin K is a fat soluble vitamin essential for

synthesis of clotting factors II, VII, IX and X .
Vitamin K is obtained in part from food and in
part from bacterial flora in the bowel which
synthesizes the vitamin.
Dam in 1929 produced a bleeding disorder in
chicken by feeding a deficient diet. It was cured
by a soluble fraction of hog liver
DIETARY Green Leafy Vegetables, liver
RDA

50-100g/ day

ACTION - Acts As A Co Factor, Causes

carboxylation of glutamate residues of the
zymogen proteins
EXCRETION By glucuronide conjugation in the
bile and urine
DEFICIENCY- Liver Disease,
Obstructive Jaundice
Malabsorption
Long term antiomicrobial therapy

USES
1. Hemorrhage or threatened bleeding due to
coumarin or inandione anti coagulants
2. Hypoprothrombinemia of the premature infant
administration of phytomenadione to mother 1-5
mg, 4 to 24 hrs before delivery or 0.3 mg/kg im to
the baby
3 Hypoprothombinemia due to intestinal
malabsorption
4 Aspirin overdosage

TOXICITY

Rapid iv injection produces flushing

breathlessness sense of constriction in the chest
fall in BP. This is due to the castor oil in the
emulsified vitamin k
Menadione can cause hemolysis in a dose
dependant manner in patients with G6 PD
deficiency
In neonates it can precipitate kernicterus

FIBRINOGEN
This is given in hemophilia , auto afibrinogenemic states
0.5 g is infused iv
ANTI HEMOPHILIC FACTOR
Concentrated anti hemophilic globulin is used for
hemophilia
It is short acting . Action lasts for 1-2 days 5-10 IU /kg
iv repeated 6-12 hourly
ADRENOCHROME MONO SEMICARBAZONE
Reduces Capillary Fragility
Controls Oozing From Raw Surfaces
Prevents microvessel bleeding

Used in epistaxis
hematuria
micro retinal hemorrhage
secondary hemorrhage from wounds
ETHAMSYLATE
Reduces capillary bleeding when platelets are adequate.
Used in prevention and treatment of bleeding in menorrhagia,
after abortion, epistaxis, malena, hematuria,
SIDE EFFECTS
Nausea, Rash ,Fall In Bp,
Headache

LOCAL HEMOSTATICS OR STYPTICS

These are substances used to stop bleeding from a
local approachable site eg tooth sockets open
wound They should never be injected
1. THROMBIN Obtained from bovine plasma;
applied as a dry powder or freshly prepared
solution. It is left in situ. It gets absorbed in the
body.
2. FIBRIN Obtained from human plasma; it is dried
and used a sheets or foam for covering or packing
bleeding surfaces. Available as a gel or glue form
3. GELATIN FOAM Spongy gel available in various
shapes moistened with saline or thrombin solution.
Used to pack wounds. Gets absorbed in 1-2months

4 RUSSELS VIPER VENOM

Acts as a thromboplastin. Used to stop external bleeding
in hemophilics. Eg botropase converts fibrinogen to fibrin
5 VASOCONSTRICTORS eg Adrenaline
6 ASTRINGENT eg Tannic acid (20% in Glycerine)
Causes local protein coagulation. Denatures the surface
protein arrests microozing
commonly used in dentistry

ANTICOAGULANTS
1.

USED IN VITRO
A. HEPARIN
B. CALCIUM COMPLEXING
AGENTS
Sodium citrate,
Sodium oxalate,
Sodium edetate

2. USED IN VIVO
A. HEPARIN & HEPARINOIDS
B. ORAL ANTICOAGULANTS
COUMARIN- WARFARIN,DICUMAROL
INANDIONE-PHENINDIONE (not
used)

Heparin was discovered by a medical student

J Mclean working at the John Hopkins
medical school in 1916. he found that the
extracts of various tissues (brain liver heart)
accelerated clotting. But extract of liver not
only failed to accelerate but actually
retarded clotting.
ACTIONS
1. ANTICOAGULATION
2. ANTIPLATELET
3. LIPEMIA CLEARING

ANTICOAGULATION
Acts instantly, used in vivo and in vitro.Acts
indirectly by activating plasma anti thrombinIII
The complex then binds to the clotting factors
of the intrinsic and common pathways and
inactivates them. Inhibition of factor Xa as
well as the thrombin mediated conversion of
fibrinogen to fibrin.
Low concentrations prolong aPTT but the high
concentrations prolong both aPTT and PT

ANTIPLATELET ACTION
High dose inhibits platelet aggregation and prolongs
bleeding time
LIPEMIA CLEARANCE
Injection of heparin clears the post prandial lipemic
plasma in vivo. Heparin releases a lipoprotein lipase
from the vessel wall and tissues. This converts the
triglycerides of chylomicrons and vldl to free fatty
acids.
Heparin is not absorbed orally . It does not cross the
blood brain barrier or the placenta. not given im. as
it accumulates between muscle fibres causing
hematoma formation

ADVERSE DRUG EFFECT

1. Bleeding
2. Thrombocytopenia
3. Osteoporosis
4. Skin necrosis
5. Transient alopecia
6. Hypersensitivity

HEPARIN IS ANTAGONISED BY
PROTAMINE SULPHATE
NEUTRALISES HEPARIN WEIGHT BY
WEIGHT. 1MG IS NEEDED FOR EVERY
100IU OF HEPARIN. MAXIMUM DOSE
USED IS 50MG. GIVEN BY SLOW IV
INFUSION.

CONTRAINDICATIONS
1.

BLEEDING DISORDERS

2.

SEVERE HYPERTENSION

3.

SUB ACUTE BACTERIAL EMBOLISM

4.

OCULAR AND NEURO SURGERY

5.

CHRONIC ALCOHOLICS

6.

CIRRHOSIS

7.

RENAL FAILURE

8.

CONCURRENT ADMINISTRATION OF ASPIRIN

AND OTHER ANTIPLATELET DRUGS

LOW MOLCULAR WEIGHT HEPARIN

Selectively inhibits the factor Xa .
Acts by inducing a conformational change in
ATIII
Has a better cutaneous bioavailability. OD
aPTT and clotting times are not prolonged.
Lab monitoring is not needed during
administration
Dose is calculated on the body weIght basis

USES
1. Prophylaxis Of DVT And Pulmonary
Embolism
2. Maintains the Patency Of Cannulae and
Shunts In Dialysis Patients

ORAL ANTICOAGULANTS
HISTORY
In 1924 a hemorrhagic disease was
described in the cattle. The cattle were
feeded on spoiled sweet clover hay. This
contained a chemical bishydroxycoumarin
It was initially used as rat poison

MODE OF ACTION
Used only in vivo
Behave as competitive antagonists of
vitamin k
Interfere with the vitamin k dependent
clotting factors in the liver

Descarboxyprothrombin

Vitamin K (hydroquinone)

NAD

Prothrombin

vitamin K (epoxide)

NADH

BLOCKED BY ORAL ANTI COAGULANTS

The carboxylation is essential for the

ability of the clotting factors to bind
calcium and to get bound to
phospholipid surfaces
Examples :
Dicumarol prolonged half life. Frequent
GIT disturbance
Racemic Warfarin Sodium- most popular

ADVERSE DRUG EFFECT

1. ECCHYMOSIS
2. EPISTAXIS
3. HEMATURIA
4. BLEEDING IN GIT
5. INTRACRANIAL OR INTERNAL
HEMORRHAGE

TREATMENT OF OVERDOSAGE

WITHHOLD THE ANTI COAGULANT

GIVE FRESH BLOOD TRANSFUSION
ALTERNATIVELY FRESH FROZEN PLASMA
CAN ALSO BE GIVEN
SPECIFIC ANTIDOTE VITAMIN K IS GIVEN

FACTORS ENHANCING THE EFFECT OF

ORAL ANTI COAGULANTS
1. DEBILITY
2. MALNUTRITION, MALABSORPTION
( SUPPLY OF VITAMIN K TO LIVER IS
REDUCED)
3. LIVER DISEASE, CHRONIC ALCOHOLISM
4. HYPERTHYROIDISM( CLOTTING
FACTORS ARE DEGRADED FASTER)
5. NEW BORNS

FACTORS DECREASING THE EFFECT

OF ORAL ANTICOAGULANTS

1. PREGNANCY
2. NEPHROTIC SYNDROME
3. GENETIC WARFARIN RESISTANCE

USES OF ORAL ANTICOAGULANTS

1. DVT , PULMONARY EMBOLISM
2. MYOCARDIAL INFARCTION
3. RHEUMATIC HEART DISEASE
4. CEREBROVASCULAR DISEASE
5. VASCULAR SURGERY
6. PROSTHETIC VALVES
7. DISSEMINATED INTRAVASCULAR
COAGULATION

COMPARISON
HEPARIN

WARFARIN

Mucopolysaccharide

Coumarin

Iv, sc

oral

Immediate action

delayed action

Duration is 4-6 hrs

3-6 days

Invitro and Invivo

Invivo

Protamine sulphate

Vitamin k

Blocks X, thrombin

synthesis of clotting
factors inhibited

FIBRINOLYTICS ( THROMBOLYTICS)
These are drugs used to lyse thrombi or clot to recanalyse
occluded blood vessels.
PLASMINOGEN
ACTIVATORS
INHIBITORS
PLASMIN

FIBRIN

FIBRIN
DEGRADATION
PRODUCTS

Some 3 weeks after a clot is formed, the

firm fibrin threads are broken down by a
powerful enzyme, called Plasmin.

After the breaking down, broken down

fragments of fibrin, called, fibrin
degradation products, are dissolved in
the plasma and the clot disappears. This
is 'fibrinolytic mechanism

ACTIVATORS
TISSUE PLASMINOGEN ACTIVATOR
UROKINASE
STREPTOKINASE
INHIBITORS
EPSILON AMINO CAPROIC ACID
TRANEXAMIC ACID
APROTININ

STREPTOKINASE
From the hemolytic streptococcus group C
Antigenic, can cause anaphylaxis or
hypersensitivity
UROKINASE
Nonantigenic
ALTEPLASE
Nonantigenic
Very expensive
RETEPLASE

USES
1.
2.
3.
4.

ACUTE MYOCARDIAL INFARCTION

DEEP VEIN THROMBOSIS
PULMONARY EMBOLISM
PERIPHERAL ARTERIAL OCCLUSION

ANTIFIBRINOLYTICS
Inhibit plasminogen activator and dissolution of clot
Epsilon amino caproic acid is the specific antidote
of fibrinolytic agents
Tranexamic acid occupies the site on the fibrin at
which plasminogen is bound
USES:
Overdosage of fibrinolytics after tonsillectomy or
prostrate surgery
Tooth extraction in hemophiliacs

ANTIPLATELET DRUGS
Prostacyclin inhibit platelet aggregation
Thromboxane promotes platelet aggregation
DRUGS
1.
ASPIRIN
2.
DIPYRIDAMOLE
3.
SULFINPYRAZOLE
4.
TICLOPIDINE

ASPIRIN
Inhibits cyclooxygenase and thromboxane
synthesis
Inhibits release of ADP from platelets
1.

2. DIPYRIDAMOLE

Reversibly inhibits platelet phosphodiesterase

Cyclic AMP activity increased, platelet activity
decreased

3. SULFINPYRAZONE
Uricosuric drug. Cyclooxygenase inhibitor.
Decreases thromboxane and prostacyclin
synthesis
4. TICLOPIDINE
Interacts with the platelet membrane
It is relatively new drug

RECENT ADVANCES
Biochemical manipulation of streptokinase and
plasminogen mixtures have resulted in
therapeutic agents
Eg acetylation of active site serine of streptokinaseplasmin complex forms compound BRL26921
It binds fibrin in inactive form and only becomes
activated slowly due to slow deacylation of the
active site

Isolation and subsequent cloning of tissue

plasminogen activator produces recombinant
plasminogen activator rPA
This compound has a greater specificity for fibrin
allowing fibrinolysis to take place without
development of a systemic hemorrhagic state

MANAGEMENT OF HEMORRHAGE

1.

2.

3.

4.

There are 5 steps in this

PLANNING OF INCISION- avoid large blood
vessels
SECURING OF BLEEDING VESSELS with
HEMOSTATS
Hemostasis through the APPLICATION OF
PRESSURE with swabs
Use of HEMOSTATIC AGENTS

WHITEHEADS VARNISH
Consists of the following
Benzoin
10 parts
Storax
7.5 parts
Balsam of tolu
5 parts
Iodoform
10 parts
Solvent ether up to 100 parts
Half inch ribbon gauze is soaked in whiteheads
varnish. It is remove in 48 hours or it may give to
dry socket

SURGICEL Oxidised regenerated cellulose

bioabsorbable
It dissolves to form acidic products which
coagulate plasma proteins with hemoglobin
producing a black sticky clot
BONE WAX
BEES WAX( yellow) 7 parts by wt
OLIVE OIL
- 2 parts by wt
PHENOL
- 1 part by wt

DRUG INTERACTIONS
Thrombolytic agents + nsaids, sulfinpyrazone,
anticoagulants, platelet inhibitors increases
hemorrhage
Anticoagulants+ ACE inhibitors= hyperkalemia
NSAIDS, ethacrynic acid cephalosporins valproic acid
propylthiuracil + anticoagulant drugs results in
bleeding
Nitroglycerine antagonises the anticoagulant effect of
heparin

 Chlorthalidone, Chlordiazepoxide,Haloperidol,
spirinolactone, Rifampicin decrease anticoagulant
activity
Amiodarone, Disulfiram, Halothane increase warfarin
activity
Various antibiotics affect the anticoagulation of
warfarin by altering bacterial synthesis of vitamin k in
the GI tract eg cephalospoins, Chloramphenicol
,Metronidazole, Tetracyclines
Vitamin E in high doses inhibits vitamin K
Garlic produces antiplatelet effect

INTERNATIONAL NORMALISED RATIO

Usually prothrombin times are assessed during the

treatment.
It is helpful if the labs performing the tests to
control oral anticoagulants have a standardised
approach so that results are comparable between
different centres
INR = PROTHROMBIN TIME OF PATIENT
PROTHROMBIN TIME OF LAB

NORMAL VALUE IS 2-4

IT IS AN ADVANTAGE IF RESULTS ARE
REPORTED AS A RATIO RATHER THAN
A PERCENTAGE OR INDEX

REFERENCES

Clinical Pharmacology by DR Laurence, P N

Bennet, 7th edition
Essentials of medical pharmacology
K D Tripathi 5th edition
De Gruchys Clinical hematology in medical
practice 5th edition
Killey and Kay An outline of oral surgery part 2
Clinicians manual of oral and maxillofacial surgery
3rd edition

THANK YOU