Pharmacology 9c – Haemostasis and Thrombosis
Anil Chopra
1. To understand the terms haemostasis and thrombosis and differentiate between
them.
2. To understand the coagulation cascade and the action of specific anti-coagulant
drugs within this cascade.
3. To understand the process of platelet activation and the action of specific antiplatelet drugs.
4. To understand the process of fibrinolysis and the action of specific fibrinolytic
drugs.
5. To understand which of these classes of drugs can be used in specific clinical
situations.
Haemostasis: the arrest of blood loss from damaged blood vessels. It provides a
localised, rapid and potent response to vascular damage without which you would
bleed to death. It occurs in 3 stages:
1. Vasoconstriction
2. Platelet aggregation
3. Coagulation (producing a fibrin clot).
Drugs are occasionally used to promote haemostasis e.g.
- in haemophilia (treated with factor VIII or IX)
- after anti-coagulant treatment
- stop haemorrhage e.g. after surgery.
Thrombosis: this the formation of a haemostatic plug in a blood vessel (i.e IN VIVO)
without the presence of bleeding. It can occur for a number of reasons:
- Virchow’s triad
- Injury to vessel wall (atherosclerotic plaque rupture)
- Stasis
- Hypercoagulability of blood. (e.g. late stage
pregnancy)
There are 2 types of thrombi
White thrombus: forms in ARTERIES
 Associated with
atherosclerosis
 Forms in heart of patients
with atrial fibrillation
 Consists of platelets and
leukocytes in a fibrin mesh.
 Can result in ischaemic
heart disease and MI.
Red thrombus: forms in
VEINS
 Associated with blood stasis
 Small platelet component
 Mainly composed of fibrin
 Emboli form from broken off parts
Treatment for Thrombosis
Three types of treatment:
 Anti-platelet – used to treat arterial white thrombi
 Anti-coagulation - used to treat venous red thrombi
 Fibrinolytic - used to treat arterial white thrombi
Coagulation: Activation of several inactive enzymes (zymogens / clotting factors)
occurs at the site of injury to finally activate prothrombin to the powerful enzyme
thrombin. There are 2 pathways
 Extrinsic Pathway – short pathway (in vivo) that produces thrombin quicker
 Intrinsic Pathway – longer sustained pathway (contact pathway)
Vitamin K is an important co-factor in the synthesis of a number of clotting factors
(II, VII, IX and X). Once synthesised these clotting factors are modified by the
addition of carboxyglutamic acid. Without this modification these proteins are not
functional.
 Vitamin K is also an important co-factor in this post-translational modification
 Vitamin K is synthesised in the gut by bacteria
 Given to newborns to prevent haemorrhagic disease
 Can be given to stop bleeding due to excessive anti-coagulation therapy
Coagulation Cascade
Intrinsic Pathway
( Contact pathway )
XII
XIIa
XI
Anti-thrombin III
2+
Heparin
Extrinsic Pathway
( in vivo pathway )
Generated by damaged
endothelial cells
Tissue Factor
Ca
XIa
IX
VIIa
IXa
2+
Activated
Platelets can
induce
activation
VII
2+
Ca
Phospholipid
Ca
Phospholipid
X
Xa
Anti-thrombin IIIa
X
2+
Ca
Phospholipid
( Prothrombin ) II
XIII
Ca
(thrombin) IIa
2+
XIIIa
Fibrinogen
(soluble)
Fibrin
(insoluble)
Stabilised
Fibrin
NB: haemophilia is caused by a lack of factor VIII – treated with fresh plasma,
concentrations of factor VIII or IX.
Anti-Coagulants
Natural
1. TFPI – tissue factor pathway inhibitor
2. Protein C – activated by thrombin, inactivates factors VII and V
3. Anti-thrombin III – activated by heparin inactivates thrombin
Drugs
Name – Warfarin
Usage – an orally administered anti-coagulant.
Mechanism of action – prevents activation of vitamin K. Its effects are delayed due to
the slow turnover of clotting factors.
Pharmacokinetics and Side Effects
 binds to plasma albumin.
 metabolised by liver by cytochrome P450.
 haemorrhage (especially into the brain or bowel
 teratogenicity (not given to pregnant mothers)
 Interacts with other drugs e.g.
o Erythromycin & fluconazole – inhibit Cyt P450
o Phenobarbital – induces Cyt P450
o Aspirin – inhibits platelet function and displaces warfarin from plasma proteins.
 Administration:
o Oral, quickly absorbed from the GI tract
o Peak blood concentration in 1 hr
o Pharmacological effects are delayed by 12-16hrs at peak at 48hrs and last 4-5 days
o Delay due to slow turnover of clotting factors
Names – heparin, LMWH (low molecular weigh heparin)
Usage – an anticoagulant. Given intravenously or subcutaneously.
Mode of Action – activates anti-thrombin III which results in the inhibition of factor
Xa and thrombin. Ant-thrombin III binds to serine sites. LMWH has the same effect
on factor Xa but less of an effect on thrombin.
Pharmacokinetics and Side effects
 Administration: poor oral absorption so given either subcutaneously or IV
 Pharmacokinetics:
 Immediate onset when given IV
 Delayed 1hr of given SC (LMWH)
 Short half life, shows saturation kinetics (apparent ½ life increases with
increasing dose)
st
 LMWH has a longer half-life – 1 order kinetics, activity does not require
monitoring (unlike normal heparin)
 Bleeding
 Thrombocytopenia (blood fails to clot properly)
 Osteoporosis (associated with long term therapy over 3 months)
 hypersensitivity
 chills, fever, urticaria and even anaphylaxis
Platelet Clot Formation
1. Platelet adhesion
a. endothelium is damaged
b. vWF (von Willebrand Factor) is
released.
c. Platelets stick to wall via platelet
Gp1b-IX factors.
2. Platelet aggregation
a. Having adhered, the platelets release
mediators and synthesise new
mediators such as TXA2.
b. This causes up-regulation of GpIIbIIIa receptors on platelet and causes
other platelets to be recruited to the
area.
3. Fibrin plug
a. Platelets provide a phospholipid
surface over which the coagulation
cascade can take place.
b. Fibrinogen is formed from thrombin,
and fibrin from fibrinogen.
In the absence of vessel injury, the vascular
endothelium secretes arachidonic acid (AA).
This is converted to PGI2 via COX-1
(cyclooxygenase 1) which prevents platelet
aggregation. This prevents the clot spreading.
Platelets also secrete arachidonic acid (AA) which is converted by COX-1 to TXA2 –
Thromboxane A2.
Antiplatelet Drugs
Name – aspirin
Usage – analgesic, anti-platelet drug. Administered orally.
Mode of Action – irreversibly inhibits COX-1 enzyme stops the production of TXA2
from platelets. It also inhibits the production of PGI2 (which prevents platelet
aggregation) but this can be resynthesised by epithelial cells.
Side Effects – GI sensitivity due to loss of gastro-protective prostacyclins produced
by COX -1
- Given orally
- High plasma protein bound
Name - Clopidogrel
Usage – used primarily as an anti-platelet drug. Administered orally.
Mode of Action - A pro-drug which inhibits fibrinogen binding to glycoprotein IIb/IIIa receptors
resulting in a breakdown of the fibrin mesh. This is a very slow process and the peak effect of the
drug is not seen until 4 days of administration.
Side effects - Bleeding –GI haemorrhage, diarrhea, rash. In some patients neutropoenia is seen.
(low neutrophils in blood).
Name – Abciximab
Usage – acute coronary syndromes, usually with heparin and aspirin. Given to ischaemic patients
with unstable angina. Administered IV.
Mode of Action - Antagonist of the glycoprotein IIb/IIIa receptor (an integrin found on platelets
that is essential for platelet aggregation) It binds rapidly to platelets and its effects persist for 2448hrs.
 Antagonistic actions prevent platelet aggregation
 Hybrid murine/human monoclonal antibody used in acute coronary syndrome
 Immunogenicity limits it to 1 dose
Side effects and Pharmacokinetics – bleeding, can also be immunogenic (provoke immune
response).
- Administered IV
- Binds rapidly to platelets
- Is cleared with platelets
Fibrinolytic Drugs
Name - streptokinase
Usage – acute myocardial infarction, acute thrombotic stroke, Deep vein thrombosis, pulmonary
embolus, acute arterial thromboembolism, local thromboembolism in the anterior chamber of the
eye.
Mode of Action - activates plasminogen (by changing the shape of its active site) and therefore
activating plasmin resulting in a breakdown of the fibrin mesh. It is very rapid and thus rapidly
cleared.
Fibrinolytic drugs
Tissue plasminogen
Activator (tPA)
Side Effects & Pharmacokinetics – Bleeding, can also be antigenic.
- Administered IV short infusion (30-60 Mins) Plasminogen
- Rapidly cleared (t½ = 12-18 mins)
+
( Streptokinase
Plasmin
Fibrin
Name - alteplase
Usage – as streptokinase
Mode of Action – has the same effect as tPA (tissue plasminogen
activator) and hence causes activation of plasmin which breaks down the fibrin clot.
Side Effects – Bleeding.
- Administered IV short infusion (30 Mins)
- Rapidly cleared (t½ = 12-18 mins)
/ Alteplase )
Fibrin degrading
products
Clinical use of fibrinolytic drugs
-
•
Clinical Use of Fibrinolytic (thrombolytic) Drugs:
Acute myocardial infarction
- clinical studies have shown that administration of
fibrinolytic drugs within 12h or onset of symptoms
reduces the mortality rate
•
Acute thrombotic stroke- within 3h
•
Deep vein thrombosis, pulmonary embolus, acute
arterial thromboembolism, local thromboembolism in
the anterior chamber of the eye.