lec 6_ Fibrinolytic
“Thrombolytic” drugs
**Hemostasis refers to the finely regulated dynamic process of maintaining fluidity of the
blood, repairing vascular injury, and limiting blood loss & avoiding vessel occlusion
Hemostasis refers to the prevention of blood loss, and is accomplished by vasoconstriction
and coagulation by cellular and coagulation factors. Undue bleeding is controlled and the
fluidity of the blood is maintained by counterbalances within the coagulation and fibrinolytic
systems. Blood vessel injury or disruption, platelet defects, abnormalities of the normally
circulating anticoagulants and fibrinolytic mechanisms may upset the balance between
fibrinolysis and coagulation.
Blood normally circulates through endothelium-lined vessels without coagulation or platelet
activation occurring and without appreciable hemorrhage. Injury to the endothelial cells
triggers the hemostatic process, which typically begins with the attachment of platelets
(“Adhesion”) to the damaged endothelium or exposed subendothelial proteins such as
collagen and von Willebrand factor (vWf).
The platelets then change form (“Activate”) and release factors that stimulate the clotting
process. They also bind together (“Aggregate”). At the same time, plasma proteins may react
with elements in the subendothelium, activating the “contact” phase of coagulation.
Exposed fibroblasts and macrophages present tissue factor, a membrane protein, to the
blood at the injured site, thereby triggering the “Extrinsic “phase of blood coagulation.
Under normal conditions, hemostasis protects the individual from massive bleeding
secondary to trauma. In abnormal states, life-threatening bleeding can occur or thrombosis
can occlude the vascular tree. Hemostasis is influenced by a number of different factors
including: (a) vascular extracellular matrix and alterations in endothelial reactivity, (b)
platelets, (c) coagulation proteins, (d) inhibitors of coagulation, and (e) fibrinolysis.
Hemostasis
Platelets
Hemostatic plug
Fibrin
Hemostasis means
finely regulated
dynamic process of
maintaining fluidity
of the blood,
repairing vascular
injury, and limiting
blood loss &
avoiding vessel
occlusion
After the formation of a thrombus, flow must be restored by lysis of the clot “fibrinolysis”
that means fibrin digestion by the fibrin-specific protease, plasmin
During plug formation
thefibrinolytic pathway is locally activated. Plasminogen is converted to plasmin ( fibrinolysin
by plasminogen activators in the tissue. Plasmin dissolves the fibrin network as wound heal
A fibrinolytic cascade is initiated concomitantly with the coagulation cascade, resulting in the
formation of plasmin, which digests fibrin.
Thrombosis:
•
Occlusion of an artery or a vein caused by a thrombus or embolus - results in
ischemia & necrosis of the tissues
•
When they occur in coronary, cerebral or pulmonary vessels, they can be
immediately life-threatening
•
Coronary thrombi are the cause of MI, cerebrovascular thrombi produce strokes
**, and pulmonary thromboemboli can lead to respiratory and cardiac failure
Aim of Therapy:
•
It takes about 1 to 2 weeks for the blood clot to disintegrate by natural fibrinolytic
mechanisms
•
If the thrombus is dissolved quicker damage will be minimized & blood flow
restored faster  purpose of therapy
•
Therefore, it is important to rapidly diagnose and treat blood clots
Thrombolytic drugs:
•
Thrombolytic drugs dissolve blood clots by activating plasminogen, which forms
plasmin , a proteolytic enzyme capable of breaking cross-links between fibrin
molecules
•
Because of these actions, thrombolytic drugs are also called "plasminogen
activators" and "fibrinolytic drugs"
•
Thrombolytic drugs are used in the acute stage of thromboembolic events to
dissolve thrombi (e.g. acute MI)
•
It is important to note that the efficacy of thrombolytic drugs depends on the age
of the clot. Older clots have more fibrin cross-linking and are more compacted;
therefore, older clots are more difficult to dissolve
**It is important to note that the efficacy of thrombolytic drugs depends on the age of
the clot. Older clots have more fibrin cross-linking and are more compacted; therefore,
older clots are more difficult to dissolve
Thrombolytic drugs – Indications:




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The advantage of therapy is highest within the first few hours
They are administered by IV infusion
To dissolve thrombi in case of :
Acute myocardial infarction (MI)
Deep vein thrombosis (DVT)
Pulmonary embolism (PE)
**Clearing thrombosed shunts and cannulae
Thrombolytic drugs
mechanism of action
**Thrombolytic drugs catalyse the conversion of the proenzyme plasminogen to
plasmin, which, when in proximity to a thrombus or embolus…
Thrombolytic drugs –
mechanism of action
…degrades fibrin into soluble peptides
**Plasmin itself cannot be used because naturally occurring inhibitors in plasma
prevent its effects…degrades fibrin into soluble peptides, known as fibrin
degradation products (FDPs) and D-dimers, thus dissolving the main body of the clot.
These drugs are therefore often referred to as ‘clot busters’.
Examples of Fibrinolytic drugs:
1- Streptokinase (SK) the first thrombolytic
drug and Urokinase
2- Tissue plasminogen activator (t-PA) is
naturally occurring but is manufactured
using recombinant DNA technology
“ Alteplase”
3-Recombinant mutant variants of t-PA,
“Reteplase
***1- Streptokinase (SK) the first thrombolytic
drug and urokinase have now been replaced by the
2nd generation agent
Streptokinase (Streptase:

It is a bacterial protein obtained from cultures of ß-haemolytic streptococci
•
Streptokinase activates plasminogen, catalyses the conversion of plasminogen to
plasmin
•
Infused intravenously, it reduces mortality in acute myocardial infarction, and this
beneficial effect is additive with aspirin
**is a protein extracted from cultures of streptococci. As a bacterial product continuous use - immune reaction
It activates plasminogen. Infused intravenously, it reduces mortality in acute
myocardial infarction, and this beneficial effect is additive with aspirin (Fig. 21.8). Its
action is blocked by anti bodies, which appear about 4 days or more after the initial
dose. At least 1 year must elapse before it is used again.
, it still activates circulating plasminogen thereby releasing plasmin, which can lead
to the breakdown of circulating fibrinogen and cause an unwanted systemic
fibrinolytic state.
Streptokinase : Side Effects:
•
High incidence of bleeding (GI bleeding, cerebral hemorrhage) as plasmin lysis
fibrin haemostatic plugs and degrades fibrinogen and factor V and VII, causing
systemic fibrinolytic state.
•
Hypersenstivity: Patients with antistreptococcal antibodies can develop fever, rash,
and therapeutic failure
Hypotension (due to formation of plasmin and generation of kinins
**High incidence of bleeding (GI bleeding ,cerebral hemorrhage) as plasmin lysis
fibrin haemostatic plugs and degrades fibrinogen and factor V and VIIcause an
unwanted systemic fibrinolytic state.
. Streptokinase causes a burst of plasmin formation, generating kinins (see Ch. 13),
and can cause hypotension by this mechanism.
Urokinase:
•
Urokinase (UK) is a human enzyme synthesized by the kidney that directly
converts plasminogen to active plasmin
•
It has limited clinical use because, like SK, it produces considerable fibrinogenolysis
•
One benefit over SK is that UK is non-antigenic but it is expensive
**Urokinase (Abbokinase®; UK) is sometimes referred to as urinary-type plasminogen
activator (uPA) because it is formed by kidneys and is found in urine. It has limited
clinical use because, like SK, it produces considerable fibrinogenolysis; however, it is
used for pulmonary embolism. One benefit over SK is that UK is non-antigenic; however,
this is offset by a much greater cost.
Tissue plasminogen activator (t-PA):

t-PA is an endogenous fibrinolytic protein produced by the endothelium
(important in maintaining the body's own clot-dissolving process)

t-PA is more active on fibrin-bound plasminogen than on plasma
plasminogen, and is therefore a 'clot-selective
**This family of thrombolytic drugs is used in acute myocardial infarction,
cerebrovascular thrombotic stroke and pulmonary embolism. For acute myocardial
infarctions, tissue plasminogen activators are generally preferred over
streptokinase.
This family of thrombolytic drugs is used in acute myocardial infarction,
cerebrovascular thrombotic stroke and pulmonary embolism. For acute myocardial
infarctions, tissue plasminogen activators are generally preferred over
streptokinase.
But because of the relative fibrin specificity of tPA, clot dissolution occurs with less
breakdown of circulating fibrinogen than occurs with SK and UK
•
This family of thrombolytic drugs is used in acute MI, cerebrovascular thrombotic
stroke and pulmonary embolism
•
For acute MI, t-PAs are generally preferred over streptokinase
Alteplase (Activase):
 t-PA , alteplase is a recombinant form of human tPA

Alteplase has the following advantages:
i- it is not allergic
ii-It is clot selective
 Therefore can be given in:
i. Severe life threatening clot
ii. Known recent streptococcal infection
iii. Previous exposure to streptokinase
 It has a very short duration of action (5 min)
**Alteplase (Activase®; rtPA) is a recombinant form of human tPA. It has a short half-life
(~5 min) and therefore is usually administered as an intravenous bolus followed by an
infusion.
Third-generation thrombolytic drugs:
•
Third-generation thrombolytic drugs are recombinant mutant variants of t-PA and
have comparable efficacy with that of t-PA
•
They differ from native t-PA by having increased plasma half-lives that allow more
convenient dosing
•
These agents are similar to t-PA in efficacy and toxicity
•
Examples: Reteplase
Contraindications to
Thrombolytic Therapy:
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Active bleeding
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Pregnancy
•
General surgery within the previous
10 days
Thrombolytic Therapy: Drawbacks:
•
A single course of fibrinolytic drugs is expensive: hundreds of dollars for
streptokinase and thousands for urokinase and t-PA
•
Additional disadvantage of current thrombolytic drugs is that they can only be
administered by injection
Toxicity of Thrombolytic Therapy:
The major toxicity of all thrombolytic agents is hemorrhage
which results from two factors:
(1) The lysis of fibrin in "physiological thrombi" at sites of vascular injury
(2) A systemic lytic state that results from systemic formation of plasmin, which degrades
fibrinogen and other coagulation factors (esp. factors V and VIII).
Treatment of bleeding during use of thrombolytic drugs:

Stop the drug

Fresh frozen blood / fibrinogen
concentrate
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Aminocaproic acid / tranexamic acid
Inhibition of Fibrinolysis Aminocaproic
Acid & Tranexamic acid
•
Aminocaproic Acid & Tranexamic acid are potent inhibitor of fibrinolysis which
inhibit activation of plasminogen
•
They can be given by IV or oral routes
•
Side effects: intravascular thrombosis
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