The document discusses various drugs affecting haemostasis and thrombosis, including anticoagulants, antiplatelet agents, and thrombolytics, along with their mechanisms of action, clinical uses, and side effects. It outlines the importance of vitamin K in coagulation and categorizes anticoagulants, describing their pharmacokinetics and monitoring requirements. The document also addresses specific agents such as warfarin, heparin, direct thrombin inhibitors, and their roles in preventing and treating thrombotic disorders.

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DRUGS THAT AFFECT
HAEMOSTASIS AND
THROMBOSIS
Dr Sindwa Kanyimba
Lecturer, Pharmacology

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The term 'haemostasis' refers to the normal response of the
vessel to injury by forming a clot that serves to limit
haemorrhage
Thrombosis is pathological clot formation that results when
haemostasis is excessively activated in the absence of bleeding
Drugs can be used to modify haemostasis and thrombosis in
three ways: (1) By modifying coagulation (2) By modifying
platelet aggregation (3) By modifying fibrinolysis
INTRODUCTION

3. 3
Anticoagulants prevent thrombus formation or extension of an
existing thrombus in the slower moving venous side of the
circulation
Anti-platelet agents inhibit adhesion, activation and
aggregation of platelets and therefore prevent thrombosis.
They are mostly used for prevention of arterial thrombosis.
Thrombolytic drugs are used to lyse thrombi in blood vessels
in arterial and venous thrombosis, and are useful in conditions
such as acute myocardial infarction occurring due to coronary
thrombosis
INTRODUCTION …. CONT’D

4. 4
Anti-thrombolytic drugs inhibit thrombolysis and are used
in conditions where there is need to inhibit excessive
thrombolysis e.g. treatment of excessive effect of
thrombolytic drugs
INTRODUCTION …. CONT’D

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ANTI-COAGULANT DRUGS

6. 6
LEARNING OBJECTIVES
1. Describe the role of vitamin K in coagulation and list
the clinical uses of vitamin K
2. Classify anticoagulant drugs based on route of
administration and mechanism of action
3. Describe the mechanisms of action, clinical uses and
adverse effects of the various categories of
anticoagulant drugs
4. Explain the pharmacotherapeutic implications of the
pharmacokinetics and time course of action of warfarin
and heparin

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VITAMIN K
Forms of vitamin K
• K1 (Phytomenadione) – found in plants
• K2 (Menaquinone) – synthesized by bacteria e.g. E.coli
in the mammalian gut
• K3 (Menadiol) – synthetic and water soluble
Vitamin K1 and K2 are fat soluble and require bile for
absorption while vitamin K3 does not require bile for
absorption

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ROLE OF VITAMIN K IN COAGULATION
• Vitamin K in the reduced form is required as a co-factor
for the final stages of the synthesis of clotting factors II,
VII, IX and X (gamma carboxylation of the glutamate
residues on these proteins)
• When vitamin K is deficient or inhibited, the clotting
factors formed are not functional

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CLINICAL USES OF VITAMIN K
1. Bleeding resulting from vitamin K antagonists such as
warfarin (phytomenadione is preferred as it has a rapid
action)
2. Haemorrhagic disease of the newborn
3. Vitamin K deficiency: e.g. caused by obstructive
jaundice, mal-absorption syndromes and reduced gut
flora (as in neonates and use of broad spectrum
antibiotics)
Use the water soluble vitamin K3 for deficiency arising
from biliary obstruction and mal-absorption syndromes

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ANTI-COAGULANTS
There are four categories of anti-coagulants:
1. Oral: Vitamin K antagonists e.g. warfarin
2. Oral: Direct thrombin inhibitors and direct Xa
inhibitors
3. Parenteral: Heparin and low molecular weight heparins
4. Parenteral: Hirudin and its analogues

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USES OF ANTI-COAGULANTS
• Anticoagulants are used in the prevention and treatment
of deep vein thrombosis in the legs and pulmonary
embolism
• They are of less use in preventing thrombus formation in
arteries

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GOALS OF ANTI-COAGULANT THERAPY
1. To stop expansion of established clots
2. To prevent thromboembolism complications
3. To prevent formation of new thrombi
NB: Anticoagulants do not lyse established thrombi

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ORAL ANTICOAGULANTS: WARFARIN
The first oral anticoagulant to be used clinically and is the
most widely used
Mechanism of action
• Warfarin is an antagonist of vitamin K (structurally
similar)
• It inhibits vitamin K reductase, the enzyme that reduces
vitamin K. This impairs the gamma carboxylation of
clotting clotting factors II, VII, IX and X and thus the
clotting factors formed are not functional

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WARFARIN: PHARMACOKINETICS
• Well absorbed from the GIT
• 99% protein bound to albumin
• Unbound warfarin readily crosses membranes including
the placenta
• Metabolised in the liver
• Half-life is 2 days

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WARFARIN: TIME COURSE OF EFFECTS
• Initial response starts at 8-12 hours
• It takes about 72 hours for the full anticoagulant effect to
be seen (warfarin has no effect on clotting factors
already present prior to the time of drug administration)
• On discontinuation of treatment, coagulation remains
inhibited for 2-5 days due to the long half-life

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WARFARIN: CLINICAL USES
• Prophylaxis against venous thrombosis
• Prevention of thromboembolism in patients with
prosthetic valves
• Prophylaxis against thrombosis in the atria in atrial
fibrillation
• Due to slow onset of action, warfarin is not used in
emergency situations (heparin is used instead)
• Warfarin is the drug of choice for long-term
anticoagulation for all patients except pregnant women
who should be treated with heparin

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WARFARIN: MONITORING THERAPY
1. Monitored by measuring prothrombin time (expressed
as INR). The therapeutic target is INR 2-3.
2. Warfarin has a narrow therapeutic index thus close
monitoring is required

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WARFARIN …. CONT’D
Adverse effects: (1) Haemorrhage (2) Cutaneous
reactions: purpura, dermatitis, alopecia, pruritic lesions (3)
Fetotoxic and teratogenic
Treatment of warfarin overdose: Vitamin K
Contra-indications: (1) Vitamin K deficiency (2) Liver
disease (3) Alcoholism (4) Pregnancy (5) Lactation

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WARFARIN: DRUG INTERACTIONS
Drugs that increase anticoagulant effect of
warfarin
• Drugs that displace warfarin from albumin: aspirin,
salicylates, phenylbutazone, sulfonamides
• Drugs that inhibit metabolism of warfarin: cimetidine,
disulfiram, phenylbutazone, metronidazole, imipramine,
ciprofloxacin
• Drugs that reduce synthesis of clotting factors: broad
spectrum antibiotics e.g. ampicillin (inhibit bacterial
synthesis of vitamin K)

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WARFARIN: DRUG INTERACTIONS ….
CONT’D
Drugs whose effects on bleeding are enhanced by
warfarin
• Other anti-thrombotic drugs
Drugs that reduce the effects of warfarin
• Inducers of drug metabolizing enzymes e.g. barbiturates,
carbamazepine, phenytoin, rifampicin, griseofulvin
• Drugs that promote synthesis of clotting factors: vitamin
K, hormonal contraceptives
• Drugs that decrease absorption of warfarin:
cholestyramine, colestipol

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ORAL DIRECT THROMBIN INHBITORS &
ORAL DIRECT Xa INHIBITORS
In comparison with warfarin, these drugs:
• Have equivalent anticoagulant efficacy
• Have lower bleeding rates
• Have a rapid onset of action
• Have a wider therapeutic window
• Do not require monitoring for dosage optimization
• Have fewer drug interactions

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ORAL DIRECT Xa INHIBITORS
• Include rivaroxaban and apixaban
• Inhibit factor Xa, in the final common pathway of
clotting
• They are given as fixed doses and do not require
monitoring for dosage optimization
• They have a rapid onset of action and shorter half-lives
than warfarin
• The main toxicity is bleeding

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ORAL DIRECT Xa INHIBITORS …. CONT’D
Clinical uses
• Prevention of embolic stroke in patients with atrial
fibrillation without valvular heart disease
• Prevention of venous thromboembolism following hip or
knee surgery
• Treatment of venous thromboembolic disease

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ORAL DIRECT THROMBIN INHBITORS
• Include dabigatran
• Dabigatran is a direct thrombin inhibitor
• Advantages of oral direct thrombin inhibitors include
1. Predictable pharmacokinetics and bioavailability,
which allow for fixed dosing and predictable
anticoagulant response, thus routine coagulation
monitoring not necessary
2. Rapid onset and offset of action allowing for
immediate anticoagulation

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DABIGATRAN …. CONT’D
Clinical uses
• Prevention of embolic stroke and systemic embolism
with non-valvular atrial fibrillation
• Treatment of venous thromboembolism following 5–7
days of initial heparin or LMWH therapy
• Venous thromboembolism prophylaxis following hip or
knee replacement surgery
Adverse effects
The primary toxicity of dabigatran is bleeding

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HEPARIN
Standard heparin (unfractionated heparin)
• A large polymer composed of repeating units of two
disaccharides with a molecular weight of 3000-40,000
daltons
• An acidic molecule
• Has many negatively charged groups and is therefore
highly polar
• In the body, heparin is found in mast cells, plasma and
endothelial cells

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STANDARD HEPARIN …. CONT’D
Mechanism of action and time course of action
• Heparin augments the effects of anti-thrombin III
• Anti-thrombin III is a naturally occurring inhibitor of
clotting factors IIa, IXa, Xa and XIIa and thereby
suppresses fibrin formation
• Heparin binds to anti-thrombin III and accelerates its
rate of activity making it instantaneous
• Effects occur quickly (within minutes) because it acts
directly to inhibit clotting factor activity

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STANDARD HEPARIN …. CONT’D
Pharmacokinetics
• Heparin is not absorbed from the GIT due to its large size and
polarity
• Administered IV or SC (not given IM because of the potential
for haematoma formation)
• Metabolized in the liver and the metabolites are excreted in
urine
• Half-life is 40-90 minutes, and is dose dependent
Duration of activity
Several hours (varies with dosage, and is prolonged in hepatic
and renal disease)

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STANDARD HEPARIN: CLINICAL USES
• Anticoagulant of choice in pregnancy and in situations
that require rapid onset of anticoagulant effects
• Used in the management of pulmonary embolism,
massive deep vein thrombosis, evolving stroke
• Used in open heart surgery and renal dialysis to prevent
coagulation in the extracorporeal circulation device
• Used for prevention of post-operative veno-thrombosis
• Used in the management of disseminated intravascular
coagulation

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STANDARD HEPARIN …. CONT’D
Adverse effects: (1) Haemorrhage (2)
Thrombocytopaenia (3) Hypersensitivity reactions: chills,
fever, urticaria (4) Osteoporosis (with long term therapy)
Treatment of heparin overdose: Treated with
protamine sulphate a strong basic protein that forms an
inactive complex with heparin
Contra-indications: (1) Thrombocytopaenia (2) Surgery
of the eye, brain and spinal cord (3) Lumbar puncture

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STANDARD HEPARIN: MONITORING THERAPY
• Heparin therapy is monitored by measuring activated
partial thromboplastin time (APTT) [target: 1.5x the
normal APTT]
• Monitoring is required because of the unpredictable
pharmacokinetics of standard heparin

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LOW MOLECULAR WEIGHT HEPARINS
(LMWHs)
Include enoxaparin and dalteparin
• LMW heparins act on anti-thrombin III to inhibit factors
X and XI, and they have little effect on thrombin (factor
II)
• As effective as standard heparin
• Associated with lower risk of haemorrhage
• Less likely to produce hypersensitivity reactions,
thrombocytopaenia and osteoporosis

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LMWHs …. CONT’D
• Have longer half-lives compared to standard heparin
and have more predictable pharmacokinetics
• Do not require APTT monitoring
• Can be used on an outpatient basis
• Given subcutaneously

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HIRUDIN AND ITS ANALOGUES
• Hirudin and its analogues (bivalirudin, desirudin and
lepirudin) directly bind to and inhibit thrombin (they do
not require anti-thrombin III)
• All are administered parenterally (IV or SC, and not IM)
• They are used in patients with unstable angina
undergoing angioplasty and percutaneous coronary
interventions
• Lepirudin is used as an alternative to heparin in patients
who develop heparin induced thrombocytopaenia

35. END
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36. 36
ANTI-PLATELET AGENTS
THROMBOLYTIC AGENTS
ANTI-THROMBOLYTIC AGENTS
HAEMOSTATIC AGENTS

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LEARNING OBJECTIVES
Describe the mechanisms of actions, clinical uses and
adverse effects of the drugs that affect haemostasis and
thrombosis:
• Platelet aggregation inhibitors
• Thrombolytic drugs
• Anti-thrombolytic and haemostatic drugs

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PLATELET AGGREGATION INHIBITORS
These drugs decrease the formation or the action of chemical
signals that promote platelet aggregation
They inhibit thrombus formation in arteries
Include:
• Aspirin: inhibits the rate limiting step (inhibits the enzyme
cyclo-oxygenase) in the synthetic pathway for thromboxane
A2
• Adenosine diphosphate (ADP) receptor inhibitors:
clopidogrel, ticlopidine, prasugrel and ticagrelor
• Glycoprotein IIb/IIIa receptor inhibitors: abciximab,
eptifibatide and tirofiban

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ASPIRIN
• MOA: Inhibits the synthesis of thromboxane A2 (TXA2)
in platelets by irreversible inhibition of cyclo-oxygenase,
a key enzyme in TXA2 synthesis pathway. TXA2 is one of
the factors required in platelet aggregation.
• Because platelets lack nuclei, they cannot synthesize new
enzyme. Thus the lack of TXA2 persists for the lifetime of
the platelet (7-10 days).
• Given orally

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ASPIRIN …. CONT’D
When used to inhibit platelet aggregation, aspirin is used at
much lower doses than those required for anti-
inflammatory action
• At higher doses (> 325mg/day), aspirin will have
reduced anti-thrombotic action by decreasing
endothelial synthesis of prostacyclin
• Low doses impair prostaglandin synthesis in platelets
more than in endothelial cells and thus the anti-
thrombotic effect is preserved

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ASPIRIN …. CONT’D
Uses of aspirin as a platelet aggregation inhibitor
• Prophylactic treatment of transient cerebral ischaemia
• Primary and secondary prophylaxis of myocardial
infarction
• In the management of acute myocardial infarction
• In the management of unstable angina
Adverse effects
• Increased incidence of haemorrhagic stroke
• Gastro-intestinal bleeding (hence contraindicated in peptic
ulcer disease)

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ADP RECEPTOR INHIBITORS
Include ticlopidine, clopidogrel, prasugrel and ticagrelor
MOA: These drugs reduce platelet aggregation by
irreversibly inhibiting the platelet ADP receptor (P2Y12
receptor) (except ticagrelor is a reversible inhibitor) thus
blocking ADP binding to platelets ADP is one of the main
platelet-activating factors and is required for binding of
platelets to fibrinogen and to each other
Adverse effects: Haemorrhage, dyspepsia, nausea

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ADP RECEPTOR INHIBITORS …. CONT’D
Clinical uses
• Management of unstable angina
• Primary and secondary prophylaxis of myocardial
infarction
• Prophylaxis of transient cerebral ischaemia and
ischaemic stroke
• Prevention of atherosclerotic events in peripheral
arterial disease

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ADP RECEPTOR INHIBITORS …. CONT’D
• ADP receptor inhibitors can be used as alternatives to
aspirin or in combination with aspirin
• Clopidogrel is the most widely used ADP receptor inhibitor
• Ticlopidine causes leukopenia and thrombocytopaenia; it is
therefore no longer used
• Prasugrel and ticagrelor are approved for patients with acute
coronary syndromes (in combination with aspirin)
• Prasugrel is contraindicated in patients with history of
cerebrovascular accident because of increased bleeding risk

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PLATELET GLYCOPROTEIN IIb/IIIa
RECEPTOR INHIBITORS
Include abciximab (monoclonal antibody), eptifibatide
(peptide) and tirofiban (non-peptide). They are all given
intravenously.
MOA: The glycoprotein IIb/IIIa receptor complex on
platelets acts as a receptor for fibrinogen. Activation of the
glycoprotein IIb/IIIa receptor complex is the final common
pathway for platelet aggregation. Inhibition of the receptor
prevents platelet aggregation by blocking the binding of
fibrinogen to platelets.

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PLATELET GLYCOPROTEIN IIb/IIIa
RECEPTOR INHIBITORS …. CONT’D
Clinical uses
• Management of acute coronary syndromes (unstable
angina and myocardial infarction)
• To prevent thrombosis in patients undergoing
percutaneous coronary intervention
Adverse effects
• Bleeding
• Abciximab also causes hypersensitivity reactions

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THROMBOLYTIC (FIBRINOLYTIC) DRUGS
Include streptokinase, alteplase, reteplase, tenecteplase and
urokinase
Promote lysis of thrombi (clots)
All are given intravenously
MOA: Convert plasminogen to plasmin. Plasmin digests
the fibrin meshwork of clots
Major adverse effect of thrombolytic drugs is haemorrhage

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STREPTOKINASE
• A protein derived from beta-haemolytic streptococci
• Acts on both circulating plasminogen and fibrin-bound
plasminogen
• Causes allergic reactions (anaphylaxis, urticaria, fever,
bronchospasm). Thus avoid re-use between 5 days and
12 months.

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ALTEPLASE, RETEPLASE & TENECTEPLASE
• Alteplase is recombinant tissue type plasminogen
activator (tPA), which is selective for plasminogen bound
to fibrin in thrombi. Hence the incidence of bleeding is
less than with streptokinase. Alteplase is not antigenic
and therefore can be re-used within 1 year.
• Reteplase and tenecteplase are genetically engineered
forms of human tPA and have a longer half-life, higher
specificity for fibrin and greater resistance to
plasminogen activator inhibitor than naturally occurring
tPA. They are not antigenic.

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UROKINASE
• Prepared from cultured kidney cells using recombinant
technology
• Activates both circulating and fibrin-bound plasminogen
• Used in the treatment of pulmonary embolism
• Less antigenic than streptokinase and so it is indicated in
patients sensitive to streptokinase

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THROMBOLYTIC DRUGS: CLINICAL USES
• Lysis of coronary artery thrombi associated with acute
myocardial infarction
• Deep vein thrombosis
• Pulmonary embolism
• Acute ischaemic stroke (thrombotic stroke)

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THROMBOLYTIC DRUGS:
CONTRAINDICATIONS
Recent haemorrhage, trauma or surgery, coagulation
defects, bleeding diathesis, severe uncontrolled
hypertension, recent stroke, recent symptoms of peptic
ulcer disease, severe liver disease, oesophageal varices,
acute pancreatitis, heavy vaginal bleeding and coma

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ANTI-FIBRINOLYTIC AGENTS
AMINOCAPROIC ACID
Aminocaproic acid, which is chemically similar to the amino
acid lysine, is a synthetic inhibitor of fibrinolysis
It competitively inhibits plasminogen activator
Given orally or IV
Adverse effects: Intravascular thrombosis, hypotension,
myopathy, abdominal discomfort, diarrhea, and nasal
stuffiness
Contraindications: Disseminated intravascular
coagulation

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AMINOCAPROIC ACID …. CONT’D
Clinical indications
• Haemophilia
• Bleeding from fibrinolytic therapy
• Prophylaxis for re-bleeding from intracranial aneurysms
• Post-surgical gastrointestinal bleeding
• Post-prostatectomy bleeding
• Bladder hemorrhage secondary to radiation- and drug-
induced cystitis

55. 55
ANTI-FIBRINOLYTIC AGENTS:
TRANEXAMIC ACID
Tranexamic acid is an analog of aminocaproic acid and also acts
by inhibiting plasminogen activator
Given intravenously
Adverse effects: Nausea, diarrhoea, orthostatic hypotension
and intravascular thrombosis
Indications: (1) To prevent hyper-plasminaemic bleeding
states that result from damage to tissues rich in plasminogen
activator e.g. after prostatic surgery, tonsillectomy (2) In
haemophiliacs after dental extraction (3) To reduce bleeding
after ocular trauma (4) Overdosage with thrombolytic agents
(5) Thrombocytopaenia (6) Upper GIT haemorrhage

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HAEMOSTATIC AGENT: DESMOPRESSIN
Desmopressin is a longer acting analogue of vasopressin
• Stimulates the release of factor VIII and von Willebrand
factor
• Indications: (1) Haemophilia A (2) von Willebrand’s
disease (mild disease)
• Routes of administration: Intranasal, oral, sublingual
and IV

57. END
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