3. Blood clots (thrombus/thrombi)
Vascular bed/Blood vessels
Coronary thrombi cause myocardial infarctions
cerebrovascular thrombi produce strokes
pulmonary thromboemboli can lead to respiratory
and cardiac failure
So it is important to rapidly diagnose and treat blood clots.
3
4. 4
Risk Factors
Major Risk Factors That Cannot Be Changed
Heredity
Gender
Age
Major Risk Factors That Can Be Controlled or Changed
Smoking
High Blood Pressure
Blood Cholesterol Levels
Stress
Contributing Factors
Obesity
Lack of Exercise
Diabetes
5. 5
Plasminogen, an inactive precursor
It is converted to plasmin by cleavage of a single
peptide bond.
Plasmin is a relatively nonspecific protease
it digests fibrin clots and other plasma proteins,
including several coagulation factors.
6. Plasmin is an endogenous fibrinolytic enzyme that
degrades clots by splitting fibrin into fragments
Plasmin itself can not be used because naturally occurring
inhibitors in plasma prevent its effects
Fibrinolytic drugs catalyze the conversion of precursor
plasminogen into active plasmin
Rapidly lyse or break down thrombi
Some drugs are more clot specific as they only act on fibrin
bound plasminogen.
6
9. Thrombolytic drugs dissolve blood clots by activating
plasminogen
which forms a cleaved product called plasmin.
Plasmin is a proteolytic enzyme that is capable of breaking
cross-links between fibrin molecules
which provide the structural integrity of blood clots.
Because of these actions, thrombolytic drugs are also called
"plasminogen activators" and "fibrinolytic drugs.”
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11. Source:
It is a protein produced by beta-hemolytic streptococci.
It has no intrinsic enzymatic activity.
MOA:
It combines with proactivator plasminogen to form a
complex.
This complex catalyzes the conversion of plasminogen
to active plasmin.
So rapid lysis of the clot by plasmin.
This complex also catalyzes the clotting factor V and VII.
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12. Plasma half life: (t ½) 40-80 minutes
◦ The streptokinase-plasminogen complex is not inhibited by natural
alpha 2-antiplasmin
Adverse effects: Not clot specific.
◦ So can create a generalized lytic state when administered I/V.
◦ Thus, both protective haemostatic thrombi and target
thromboemboli are broken down.
◦ Hemorrhage --- most serious cerebral hemorrhage
◦ Allergic reactions, rarely anaphylaxis and fever.
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13. Clinical Uses of streptokinase
Acute Myocardial Infarction: administered by either the
intravenous or the intracoronary route for the reduction of
infarct size & congestive heart failure associated with AMI
Pulmonary Embolism
Deep Vein Thrombosis
Arterial Thrombosis or Embolism: It is not indicated for
arterial emboli originating from the left side of the heart due
to the risk of new embolic phenomena such as cerebral
embolism.
Occlusion of Arteriovenous Cannulae: for clearing totally or
partially occluded arteriovenous cannulae when acceptable
flow cannot be achieved
13
14. A two chain serine protease containing 411 amino acid
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residues isolated from cultured human kidney cells.
It is an enzyme produced by the kidney, and found in
the urine
MOA:
It converts plasminogen to active plasmin.
It is not clot specific:
◦ So can create a generalized lytic state when administered I/V.
◦ Thus, both protective haemostatic thrombi and target
thromboemboli are broken down.
15. Urokinase administered by intravenous infusion is
rapidly cleared by the liver with an elimination half-life
for biologic activity of 12-20 minutes
Clinical Uses:
For the lyses of acute massive pulmonary emboli
15
16. 16
A complex of purified human plasminogen & bacterial
streptokinase that has been acylated to protect the
enzymes active site.
On I/V administration, the acyl group spontaneously
hydrolyzes.
Free activated streptokinase - proactivator complex
produces lysis of clots also degrades fibrinogen.
17. 17
Advantages:
Rapid I/V injection may be given.
Greater clot selectivity .
More thrombolytic activity.
Dose: A single I/V injection of 30 units over 3-5 minutes.
18. 18
Alteplase (rt.PA)
It is a tissue plasminogen activator (t.PA) produced by
recombinant DNA technology of 527 amino acids
Mechanism:
It is an enzyme which has the property of fibrin-enhanced
conversion of plasminogen to plasmin
It produces limited conversion of free plasminogen in the absence
of fibrin
When introduced into the systemic circulation it binds to fibrin in
a thrombus and converts the entrapped plasminogen to plasmin
followed by activated local fibrinolysis with limited systemic
proteolysis
19. 19
Pharmacokinetics:
It has very short t1/2 of 5 minutes
Side-Effects:
Bleeding including GIT & cerebral hemorrhage
Allergic reactions, e.g., anaphylactoid reaction, laryngeal
edema, rash, and urticaria have been reported very rarely
(<0.02%)
20. 20
Acute Myocardial Infarction in adults for the improvement of
ventricular function following AMI the reduction of the
incidence of congestive heart failure, and the reduction of
mortality associated with AMI
Acute Ischemic Stroke for improving neurological recovery
and reducing the incidence of disability. Treatment should only
be initiated within 3 hours after the onset of stroke symptoms,
and after exclusion of intracranial hemorrhage
Pulmonary Embolism: Treatment of acute massive pulmonary
embolism
21. Reteplase:
Recombinant human t-PA. from which several amino
acid sequences have been deleted.
Faster OOA & slighter longer DOA.
Less expensive
Less fibrin specific than t-PA.
Tenecteplase:
Mutant form of t-PA with a longer DOA.
Slightly more fibrin-specific than t-PA.
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22. 22
Aminocaproic Acid & tranexamic acid
They have lysine-like structure
They inhibit fibrinolysis by competitive inhibition of
plasminogen activation
ِ Adjuvant therapy in hemophilia, fibrinolytic
therapy-induced bleeding & postsurgical bleeding
Aprotinin is a serine protease inhibitor
It inhibits fibrinolysis by free plasmin
Used to stop bleeding in some surgical procedures
24. Absolute contraindications include:
Recent head trauma or caranial tumor
Previous hemorrhagic shock
Stroke or cerebro-vascular events 1 year old
Active internal bleeding
Major surgery within two weeks
Relative contraindications include:
Active peptic ulcer, diabetic retinopathy, pregnancy,
uncontrolled HTN
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