U G

D R
IC
AT
O ST
M
HE

ANDI ALFIA MT
PHARMACOLOGY DEPARTMENT
FA C U LT Y O F M E D I C I N E
UNIVERSITAS TADULAKO
DEFINITION OF HEMOSTASIS
• The term comes from the Greek roots heme = blood,
+ stasis = halt  halt of the blood.

Hemostasis is the arrest of bleeding, whether it be by

normal vasoconstriction (the vessel walls closing
temporarily), by an abnormal obstruction (such as a
plaque) or by coagulation or surgical means (such as
ligation).
HEMOSTASIS PHASE
Vascular phase

Platelet phase

Coagulation phase

Fibrinolitic phase
1. VASCULAR PHASE
• Vasoconstriction
• Exposure to tissues activate Tissue factor and
initiate coagulation

Tissue Factor
2. PLATELET PHASE
• Blood vessel wall (endothelial cells) prevent platelet
adhesion and aggregation
• Platelets contain receptors for fibrinogen and von
Willebrand factor
• After vessel injury Platelets adhere and aggregate.
• Release permeability increasing factors (e.g.
vascular permeability factor, VPF)
• Loose their membrane and form a viscous plug
3. COAGULATION PHASE
• Two major pathways
• Intrinsic pathway
• Extrinsic pathway
• Both converge at a common point 13 soluble factors
are involved in clotting
• Biosynthesis of these factors are dependent on vitamin
K1 and K2
• Normally inactive and sequentially activated
• Hereditary lack of clotting factors lead to hemophilia-A
MAJOR PATHWAYS IN COAGULATION PHASE
EXTRINSIC
I N T R I N S I C P AT H WAY P A T H WAY

• All clotting factors are • Initiating factor is

within the blood vessels outside the blood

• Clotting slower vessels - tissue factor

• Activated partial • Clotting - faster - in

thromboplastin test seconds

(aPTT) • Prothrombin test (PT)

 Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury

XII XIIa Tissue Factor

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X
Factors affected
By Heparin Prothrombin Thrombin

Fibrinogen Fribrin monomer

Vit. K dependent Factors
Affected by Oral Anticoagulants XIII Fibrin polymer
4. FIBRINOLYSIS PHASE
• Enhance degradation of clots
• Activation of endogenous protease
• Plasminogen (inactive form) is converted to Plasmin
(active form)
• Plasmin breaks down fibrin clots
 DRUG USED TO REDUCE CLOTTING

Drug Class Prototype Action Effect

1. Anticoagulant
Parenteral Heparin Inactivation of clotting Prevent DVT
factors

Oral Warfarin Decrease synthesis of Prevent DVT

clotting factors

Prevent arterial
2. Antiplatelet Aspirin Decrease platelet
thrombosis
aggregation

3. Thrombolytic Streptokinase Fibinolysis Breakdown of

thrombi
Anticoagulant
Indications of anticoagulant
• Treatment and prevention of Deep Venous Thrombosis
(DVT)
• Pulmonary Emboli
• Prevention of stroke in patients with atrial fibrillation,
artificial heart valves, cardiac thrombus.
• Ischaemic heart disease
• During procedures such as cardiac catheterisation and
apheresis.
 1. HEPARIN

Structure
• Mucopolysaccharide

Pharmacokinetics
• Metabolism partially in the liver by heparinase to
uroheparin, only slight antithrombin activity.
• 20-50 % is excreted unchanged.
• The heparin polysaccharide chain is degraded in the
gastric acid
• Heparin is administered IV or SC.
• Heparin should not be given IM (danger of hematoma
formation)
1.1 UNFRACTIONATED HEPARIN (UFH)

Mol weight
• 3000-30000
Mechanism of action:
• Primarily: interaction with antithrombin III: alters the molecular
configuration of antithrombin III, making it 1,000 to 4,000
times more potent as an inhibitor of thrombin formation, limits
conversion of fibrinogen to fibrin and prolongs aPTT
• Also inhibits the effects of factor Xa on the coagulation
cascade & limits platelet aggregation.
Pharmacokinetics
• Half-life : IV: 1 hr ; SC: 3 hrs.
1.2 UNFRACTIONATED HEPARIN (UFH)

Dosing options
• Preoperative: 5,000U 2 hours before surgery. The
single preoperative dose seems to be as effective
as multiple preoperative doses.
• Postoperative : 8 to 12 hrs after surgery & every 8
to 12 hrs until the patient is fully ambulatory.
Monitor
• aPTT
Use in pregnancy
• does not cross the placenta safe
COMPLICATIONS OF HEPARIN

Haemorrhage

Heparin-induced thrombocytopaenia (HIT)

• Most significant adverse effect of heparin after
haemorrhage
• Most common drug-induced thrombocytopenia
• A large number of patients receive heparin in the hospital
environment.
Osteoporosis (long-term only)
 HEPARIN-INDUCED THROMBOCYTOPAENIA (HIT)
HIT TYPE I
• Benign
• Up to 10% patients
• Rapid decline in platelet
count within first 2 days of
heparin administration
• Platelet count >100 000/ul
• Returns to normal within 5
days despite continued
heparin use (or within 2
days if heparin is stopped).
HIT TYPE 2
• Potentially catastrophic
thrombosis (Heparin-induced
thrombocytopenia and
thrombosis)
• 8% of patients develop
antibody without becoming
thrombocytopenic
• 1-5% patients 
thrombocytopaenia
• Of those with
thrombocytopaenia, 30%
develop venous and/or
arterial thrombosis
• Bleeding uncommon
THREATMENT OF HIT
• Discontinue all heparin
• If need to continue anti-coagulation, use danaparoid
(orgaran)
• Use antidote : protamine sulphate
• Avoid platelet transfusions
• Thrombosis: use danaparoid or thrombin inhibitor
1.2. LOW-MOLECULAR-WEIGHT HEPARIN
Molecular weight
• 1000-10000 Da.
Production
• Produced by concentrating the low molecular
component of UFH. Enzymatic or chemical
controlled hydrolysis of UFH.
Mechanism of action
• Primarily by inhibiting factor Xa, which is higher in
the coagulation cascade than antithrombin
• LMWH is more efficient than UFH: the molecular
configuration of antithrombin III is not altered by
LMWH
• Thrombin conversion is minimally inhibited and
aPTT is not appreciably affected.
1.2. LOW-MOLECULAR-WEIGHT HEPARIN

Pharmacokinatics
• Half-life 4 hrs, by any route: longer dosing interval
• Bioavailability: more consistent than that of UFH:
dosing is based on lean body mass & Less
thrombocytopenia.
Use in pregnancy
• Does not cross the placenta: safe.
Dosing options.
• Prophylaxis: Once a day
• Therapy: Twice-daily.
Advantage
• Decreased need for monitoring
Mol Wt Manufacturer Trade Generic
4500 Rhone-Poulence-Rorer Lovenox, Clexane Enoxaparin
5000 Aspen Pharmacare Fraxiparine Nadroparin
4850 Novo Logiparine Tinzaparin
6370 Kabi Fragmin Dalteparin
LMWH UFH
1000-10000 3000-30000 Mol Wt range
No Yes aPTT monitoring required
No Yes Inactivation by platelet factor 4
Yes No Capable of inactivation of platelet
bound factor Xa
++ ++++ Inhibition of platelet function
No Yes Increase vascular permeability
+ ++++ Protein binding
- +++ Endothelial cell binding
No Yes Dose dependent clearance
2-5 times longer 50-20 min Elimination half life
2. ORAL ANTICOAGULANTS
Coumarins - warfarin, dicumarol

Structure:
• small, lipid-soluble molecules, Structurally related to vitamin K, isolated
from clover leaves
Mechanism:
• Inhibits production of active clotting factors
• blocks the Vitamin K-dependent glutamate carboxylation of precursor
clotting factors e.g. FII, VII, IX , X
Pharmacokinetics
• Absorption: rapid
• Binds to albumin
• Clearance is slow: 36 hrs
• Delayed onset: 8-12 hr (T1/2 of clotting factors in plasma)
Blocks the Vitamin K-dependent glutamate carboxylation of
precursor clotting factors
2. ORAL ANTICOAGULANTS

Use:
• To prevent the formation, recurrence or extension of DVT &
PE
• Not used in pregnant women (cross placenta)
• No effect on platelets
Toxicity
• Bleeding & birth defects
Overdose:
• Reversed by vitamin K infusion
• Recovery needs synthesis of new clotting factors
Warfarin tablets 2 and 1mg
Category Mechanism Representative Drugs
Drugs that Increase Decrease binding to Aspirin
Warfarin Activity Albumin Sulfonamides

Inhibit Degradation Cimetidine, Disulfiram

Decrease synthesis of Antibiotics (oral)

Clotting Factors

Drugs that promote Inhibition of platelets Aspirin

bleeding
Inhibition of clotting Heparin
Factors Antimetabolites

Drugs that decrease Induction of metabolizing Barbiturates

Warfarin activity Enzymes Phenytoin

Promote clotting factor Vitamin K

Synthesis OC
Reduced absorption Cholestyramine
Colestipol
Warfarin Heparin
Oral Parentral only Absorption
7.6-13.9 L Plasma vol (0.07 L/kg) Vol of distribution
Hepatic Hepatic metabolism & uptake by reticulo Metabolism/Clearance
endothelial system
Also by thrombin & other clotting factors
36-42 hr 50-90 min Elimination t1/2
99.4% bound to albumin Bound to antithrombin III & other serine Protein binding
proteases
1.5 mg/L 0.2-0.4 U/ml Plasma concentration
(therapeutic)
Bleeding Bleeding Side effects
Skin necrosis Thrmbocytopenia
Drug interactions Osteoporosis
•Mild: hold 1-2 doses, •Mild: Slow or stop infusion Treatment of bleeding
observe, restart at lower dose •Severe: Protamine 1 mg/100 u of
•Severe: Vit K or fresh frozen
estimated heparin remaining in body
plasma
II. ANTIPLATELET DRUGS

Activation and aggregation of platelets is a major component of

thrombosis especially in arteries

Targets for platelet inhibitory drugs :

• inhibition of prostaglandin metabolism through inhibition of
cyclooxygenase (aspirin)
• inhibition of ADP-induced platelet aggregation (ticlopidine)
Platelet Activation:
• Endothelial damage of vessel: exposes collagen
• Activated platelets release ADP, serotonin (5-HT)& thromboxane A2 (TXA2-) from
arachidonic acid: platelet aggregation by causing the appearance of binding sites for
fibrinogen on platelet membrane
• Fibrinogen is involved: platelet to platelet adhesion (aggregation)
• Thrombin causes further platelet activation by releasing platelet ADP & stimulating PG
synthesis
• Prostacyclin (PGI2) - synthesized within vessel walls inhibits thrombogenesis by
increasing platelet cAMP. Nitric oxide (NO) - released by endothelium - increases cAMP
2.2 ASPIRIN
 
Mechanism:
• inhibits cyclooxygenase (COX).
• COX is a key enzyme involved in the synthesis of
thromboxane 2 (prostaglandins). Inhibits platelet aggregation
long acting because new proteins must be synthesized
• other NSAIDS: shorter duration because of reversible
competitive inhibitory action
• potency varies, e.g. Naproxen, meclofenamic acid, Ibuprofen,
Indomethacin, phenylbutazare
Contraindication:
• Patients with glucose 6-PO4 dehydrogenase deficiency
2.2 ASPIRIN

Dose:
• Low dose daily (180 mg/day): Prevents ischemic attack (ministroke)
and MI
• 325 mg/day: reduced the risk of heart attack in patients over 50

Use:
• Prevention of recurrent infarcts in patients with myocardial
infarction, also reduces the incidence of first infarcts
• low-dose aspirin, compared with placebo, reduces by 36% the risk
of VTE after orthopaedic surgery

Meta-analysis of trials in surgical and medical patients: significant

reduction in DVT and PE with antiplatelet prophylaxis.
II. ANTIPLATELET DRUGS

Ticlopidine
• decrease platelet aggregation by inhibiting ADP pathway of
platelets
• no effect on PG metabolism
• used as alternative for patients intolerant to aspirin
• expensive
Other antiplatelet drugs
• Dipyridamole, sulfinpyrazone
III. THROMBOLYTIC AGENTS

Agents which reduce the formation of arterial platelet thrombi

Mechanism:
• Rapid lysis of thrombi by catalyzing the formation of plasmin from
plasminogen
• Endogenous plasmin breaks down fibrin promoting clot dissolution
Use:
• Emergency treatment of coronary artery thrombonís in M.I.
• IV or intracoronary injection
• DVT: rapid recanalization of occluded vessels  
Toxicity:
• Bleeding (intracranial, G.I.)
• Allergic reactions (i.e. streptokinase)  
III. THROMBOLYTIC AGENTS

Streptokinase:
• Purified from bacteria
• Continuous use: immune reaction
• Forms a complex with plasminogen & catalyzes it: rapid conversion to
plasmin
Urokinase:
• From cultured human kidney cells
• No immune response
• Directly converts plasminogen to plasmin
tPA:
• Produced by recombinant techniques
• No immune reaction - EXPENSIVE
• Promotes conversion of plasminogen (that is found to fibrin) to plasmin
• In theory, selective for formed clots