Thrombolytic

therapy
OBJECTIVES:
• To know mechanism of action of thrombolytic therapy.
• To differentiate between different types of thrombolytic drugs.
• To describe indications, side effects and contraindications of
thrombolytic drugs.
Titles • To recognize the mechanism, uses and side effects of anti-plasmins.
Very important
Extra information
Doctor’s notes
 Thrombolytic drugs: Plasmin:
Drugs used to lyse already formed blood clot in clinical sittings Non-specific protease capable of breaking down:
where ischemia may be fatal.  Fibrin.
 Other circulating factors including:
• Fibrinogen.
• Clotting factor V.
Mechanism of action: • Clotting factor VIII.
They have common mechanism of action by stimulating
activation of plasminogen via converting plasminogen to “pro-
enzyme” to plasmin ”active enzyme” which leads to lysis of the
Plasminogen is inactive and found into two forms:
insoluble fibrin into soluble derivatives.
• Bound with fibrin. (forms the thrombus)
• In plasma.
Plasminogen
Lippincott’s corner  Thrombolytics (Plasminogen activators)
All thrombolytic agents act either directly or or indirectly to convert
Plasmin
plasminogen, which in turn cleaves fibrin, thus lysing thrombi.
Clot dissolution and reperfusion occur with a higher frequency Plasmin is the active
when therapy is initiated early after clot formation because clots form of plasminogen.
become more resistant to lysis as they age. Unfortunately, increased
local thrombi may occur as the clot dissolves, leading to enhanced Insoluble fibrin Soluble degradation
platelet aggregation and thrombosis. Strategies to prevent this
include administration of anti-platelet drugs such as aspirin, or anti-
products
thrombotics such as heparin. Plasmin lysis the insoluble Fibrin into soluble degradation products.

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 Types of Thrombolytic drugs

Fibrin specific
(also called tissue plasminogen Non-fibrin specific
activators)(t-PA)
‫)الفن‬t-PA( ‫تبغى‬
‫) ؟‬ART(

Alteplase Reteplase Tenecteplase Anistreplase Streptokinase Urokinase

‫دكتور أنس ترى لقينا ستربتو‬

”‫يا الطيب رتب وراك ال تنسى “بليز‬
‫باليورن‬

Fibrin specific plasminogen activators activate Activate both plasminogen bound to clot surface and circulating
mainly plasminogen bound to clot surface and have plasminogen in blood leading to extensive systemic plasminogen
less effect on circulating plasminogen. activation, with degradation of several plasma proteins including
fibrinogen, factor V, and factor VIII.

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 Fibrin-specific thrombolytic drugs Non fibrin-specific thrombolytic drugs

 Fibrin-specific drugs (clot specific).

Activate plasminogen bound to clot surface and circulating
 Reduced risk of bleeding. .plasminogen in blood
 Not-antigenic.

Degrade mainly fibrin clots.

Degrade fibrin clots as well as fibrinogen and other plasma proteins.
)Once they bind to fibrin, their activity is enhanced(

More selective in action (clot or fibrin specific). Less selective in action.

Less systemic plasminogen activation. Extensive systemic plasminogen activation.

Less risk of bleeding. .More risk of bleeding

Alteplase Streptokinase
Reteplase Anistreplase
Tenecteplase Urokinase

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 Streptokinase

• Streptokinase is a bacterial protein produced by Beta-hemolytic Pharmacokinetics:

streptococci. • T ½ is less than 20 minutes.
• Streptokinase is non-fibrin specific. • Given as intravenous infusion (250,000 U then 100,000 U*/h for 24-72 hours)
• Can degrade fibrin clots as well as fibrinogen and other plasma *U=unit.
proteins.  It is the least expensive among others.
Which depends on the patient
 Used for venous or arterial thrombosis.
without a standard doses of ml.

Mechanism of action:
Acts indirectly by forming plasminogen-streptokinase complex
“active complex” which converts plasminogen into active plasmin. Side effects:
• Antigenicity*: high-titer antibodies develop 1 to 2 weeks after use,
*Antigenicity means that the precluding retreatment until the titer declines.
immune system will produce an • Allergic reaction: rashes, fever, hypotension.
antibodies for this drug so that: • Bleeding: due to activation of circulating plasminogen.
• The effectiveness of the drug
will be decreased after the 1st Not used in patients with:
dose. • Recent streptococcal infections.
• The drug can cause allergic • Previous administration of the drug.
reactions that can be serious.  These patients may develop fever, allergic reactions and resistance
upon treatment with streptokinase due to antistreptococcal
antibodies.

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 Antistreplase (APSAC) Urokinase

• Anisoylated Plasminogen Streptokinase Activator Complex (APSAC) • Human enzyme synthesized by the kidney that can be Obtained
“acylated plasminogen combined with streptokinase”. from either urine or cultures of human embryonic kidney cells.
• It is a prodrug, de-acylated in circulation into the active plasminogen-
streptokinase complex. • Is a direct plasminogen activator.
• T ½ is longer 70/120 min.
• Given by intravenous infusion (300.000 U over 10 min, then
Advantages: 300,000 U/h for 12h).
• Given as bolus IV injection. (20 U over 3-5 min.) • Has an elimination half-life of 12-20 minutes.
‫أنس ترى طولت علينا بليز‬
• Longer duration of action than streptokinase. ‫يعني‬ There is relationship
• More thrombolytic activity. • Used for lysis of acute massive pulmonary embolism. between the kidney’s
& lung’s enzymes
• Greater clot selectivity. • Has NO anaphylactic effect. (Because it’s a human enzyme) such as in RAAS

• Disadvantages:
Disadvantages: o Minimal fibrin specificity.
 Similar but less than streptokinase alone in: o Systemic lysis (act upon fibrin-bound and circulating
• Antigenicity.
• Allergic reactions. plasminogen).
• Minimal fibrin specificity. o Expensive and its use now is limited.
• Systemic lysis.
• More expensive than streptokinase.

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 Tissue plasminogen activators (t-PA)
• All are recombinant (combination) of human tissue plasminogen
activator. Alteplase Reteplase Tenecteplase
• Prepared by recombinant DNA Technology.
• Includes the drugs that end with suffix “PLASE”: • Is a recombinant form
o Alteplase. of human t-PA.
o Reteplase. • Has a very short
duration of action ”5 • Another modified
o Tenecteplase. min”. human t-PA.
 Don’t confuse them with Antistreplase. • A variant of
• It’s usually recombinant t-PA. • Prepared by
administered as an • It has longer duration recombinant DNA
intravenous bolus of action (15 min). technology.
Mechanism of action: followed by an • Has enhanced fibrin • Has t ½ of more than
• They activate fibrin-bound plasminogen rather than free infusion. (60 mg IV specificity. 30 min.
plasminogen in blood. bolus then 40 mg • Given as 2 IV bolus • Can be administered
• There action is enhanced by presence of fibrin. infusion over 2 injections of 10 U as a single IV bolus.
hours). each. (NO INFUSION) • More fibrin-specific
• They bind to fibrin in a thrombus and convert the entrapped with longer duration
plasminogen to plasmin followed by activation of local of action.
fibrinolysis with limited systemic fibrinolysis.  Approved only to be
used in acute
Advantages: myocardial infarction.
•
Both (alteplase and reteplase) of them are used in:
Fibrin-specific (clot specific) drugs.
• In ST-elevation (myocardial infarction).
• Limited systemic fibrinolysis.
• Pulmonary embolism.
• Reduced risk of bleeding. (Because of the limitation of systemic fibrinolysis)
Tencete for a long period
• Not-antigenic ( can be used in patient with recent ‫ما شاء الله دايم تنصتي‬
streptococcal infection or even with a previous ‫كثير‬

administration of streptokinase).

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 Indication of thrombolytics
• Acute myocardial infarction. (elevation of ST segment).
• Acute ischemic stroke.
Contraindication of thrombolytic
• Peripheral artery occlusion.
• Deep venous thrombosis.
• Pulmonary embolism. “such as Urokinase / Alteplase / Reteplase”

Rational for use of thrombolytic drugs in acute MI Absolute Relative

• Improvement of ventricular function.
• Reduction in incidence of congestive heart failure.
• Reduction of mortality following AMI. • Active internal bleeding. • Active peptic ulcer
• Cerebral hemorrhagic stroke. • Severe uncontrolled
 Thrombolytic drugs need to be administered immediately after • Recent intracranial trauma. hypertension.
diagnosis of MI, delay of administration will be of no value because • Intra cranial neoplasm.
the clot will be resistant to the drugs and there will be tissue damage • Major surgery within two weeks.

What is the role of thrombolytic therapy in

antithrombotic plan?
• The goal of thrombolytic therapy is rapid restoration of blood flow in an occluded blood vessel by accelerating proteolysis of already formed thrombus.
• Thrombolytic therapy is one part of an over all antithrombotic plan that frequently includes anticoagulants, antiplatelet agents and mechanical approaches
to rapidly restore blood flow and prevent re-occlusion.

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 Fibrinolytic Inhibitors (Antiplasmins)

inhibit plasminogen activation and thus inhibit fibrinolysis and promote clot stabilization.

‫أمين‬ ‫ ترا نقسمك‬.. ‫لحفظ أسماء الدرقز‬

‫هو كبرك‬
Aprotinin Aminocaproic Acid & tranexamic acid Drug

inhibits fibrinolysis by blocking the action of plasmin (Plasmin antagonist). Competitive Inhibition of Plasminogen Activation. Mechanism

Orally or IV. Orally. Administration

 Adjuvant therapy in hemophilia.

 Postsurgical bleeding. Uses
 Antidote for Fibrinolytic therapy-induced bleeding.

These drugs work like antidotes for fibrinolytic drugs. Similar to Protamine (Antidote of the anticoagulant, heparin)
or Vitamin K (Antidote of the oral anticoagulant warfarin).

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 Lippincott’s
Thrombolytic drugs:
Acute thromboembolic disease in selected patients may be treated by
2. Therapeutic use: Originally used for the treatment of DVT and serious
the administration of agents that activate the conversion of
PE, thrombolytic drugs are now being used less frequently for these
plasminogen to plasmin, a serine protease that hydrolyzes fibrin and,
conditions. Their tendency to cause bleeding has also blunted their use
thus, dissolves clots. Streptokinase, one of the first such agents to be
in treating acute peripheral arterial thrombosis or MI. For MI,
approved, causes a systemic fibrinolytic state that can lead to bleeding
intracoronary delivery of the drugs is the most reliable in terms of
problems. Alteplase acts more locally on the thrombotic fibrin to
achieving recanalization. However, cardiac catheterization may not be
produce fibrinolysis. Urokinase is produced naturally in human kidneys
possible in the 2- to 6-hour “therapeutic window,” beyond which
and directly converts plasminogen into active plasmin. compares the
signicant myocardial salvage becomes less likely. Thus, thrombolytic
thrombolytic agents. Fibrinolytic drugs may lyse both normal and
agents are usually administered intravenously. Thrombolytic agents are
pathologic thrombi.
helpful in restoring catheter and shunt function, by lysing clots causing
occlusions. They are also used to dissolve clots that result in strokes.
A. Common characteristics of thrombolytic agents:
1. Mechanism of action: The thrombolytic agents share some 3. Adverse effects: The thrombolytic agents do not distinguish between
common features. All act either directly or indirectly to convert the fibrin of an unwanted thrombus and the fibrin of a beneficial
plasminogen to plasmin, which, in turn, cleaves fibrin, thus lysing hemostatic plug. Thus, hemorrhage is a major side effect. For example, a
thrombi. Clot dissolution and reperfusion occur with a higher previously unsuspected lesion, such as a gastric ulcer, may hemorrhage
frequency when therapy is initiated early after clot formation following injection of a thrombolytic agent. These drugs are
because clots become more resistant to lysis as they age. contraindicated in pregnancy, and in patients with healing wounds, a
Unfortunately, increased local thrombi may occur as the clot history of cerebrovascular accident, brain tumor, head trauma,
dissolves, leading to enhanced platelet aggregation and thrombosis. intracranial bleeding, and metastatic cancer.
Strategies to prevent this include administration of antiplatelet
drugs, such as aspirin, or anti-thrombotics such as heparin.

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 B. Alteplase, reteplase, and tenecteplase: C. Streptokinase:
Alteplase [AL-teh-place] (formerly known as tissue plasminogen Streptokinase [strep-toe-KYE-nase] is an extracellular protein purified
activator or tPA) is a serine protease originally derived from cultured from culture broths of group C β-hemolytic streptococci. It forms an
human melanoma cells. It is now obtained as a product of active one-to-one complex with plasminogen. This enzymatically
recombinant DNA technology. Reteplase [RE-teh-place] is a genetically active complex converts un-complexed plasminogen to the active
engineered, smaller derivative of recombinant tPA. Tenecteplase [ten- enzyme plasmin. In addition to the hydrolysis of fibrin plugs, the
EK-te-place] is another recombinant tPA with a longer half-life and complex also catalyzes the degradation of fibrinogen, as well as
greater binding affinity for fibrin than alteplase. Alteplase has a low clotting factors V and VII. With the advent of newer agents,
affinity for free plasminogen in the plasma, but it rapidly activates streptokinase is rarely used and is no longer available in many
plasminogen that is bound to fibrin in a thrombus or a hemostatic markets.
plug. Thus, alteplase is said to be “fibrin selective” at low doses.
Alteplase is approved for the treatment of MI, massive PE, and acute D. Urokinase:
ischemic stroke. Reteplase and tenecteplase are approved only for use Urokinase [URE-oh-KYE-nase] is produced naturally in the body by the
in acute MI, although reteplase may be used off-label in DVT and kidneys. Therapeutic urokinase is isolated from cultures of human
massive PE. kidney cells and has low antigenicity. Urokinase directly cleaves the
Alteplase has a very short half-life (5 to 30 minutes), and therefore, arginine–valine bond of plasminogen to yield active plasmin. It is only
10% of the total dose is injected intravenously as a bolus and the approved for lysis of pulmonary emboli. Off-label uses include
remaining drug is administered over 60 minutes. Both reteplase and treatment of acute MI, arterial thromboembolism, coronary artery
tenecteplase have longer half-lives and, therefore, may be thrombosis, and DVT. Its use has largely been supplanted by other
administered as an intravenous bolus. Alteplase may cause orolingual agents with a more favorable benefit-to-risk ratio.
angioedema, and there may be an increased risk of this effect when
combined with angiotensin-converting enzyme (ACE) inhibitors.

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Drugs used to treat bleeding: Adverse effects of drug administration include hypersensitivity as well as
Bleeding problems may have their origin in naturally occurring pathologic dyspnea, flushing, bradycardia, and hypotension when rapidly injected.
conditions, such as hemophilia, or as a result of fibrinolytic states that may
arise after GI surgery or prostatectomy. The use of anticoagulants may also C. Vitamin K:
give rise to hemorrhage. Certain natural proteins and vitamin K, as well as Vitamin K1 (phytonadione) administration can stop bleeding problems
synthetic antagonists, are effective in controlling this bleeding. Concentrated due to warfarin by increasing the supply of active vitamin K1, thereby
preparations of coagulation factors are available from human donors. inhibiting the effect of warfarin. Vitamin K1 may be administered via
However, these preparations carry the risk of transferring viral infections. the oral, subcutaneous, or intravenous route. [Note: Intravenous
Blood transfusion is also an option for treating severe hemorrhage. vitamin K should be administered by slow IV infusion to minimize the
risk of hypersensitivity or anaphylactoid reactions.] For the treatment
A. Aminocaproic acid and tranexamic acid: of bleeding, the subcutaneous route of vitamin K1 is not preferred, as
Fibrinolytic states can be controlled by the administration of aminocaproic it is not as effective as oral or IV administration. The response to
[a-mee-noe-ka-PROE-ic] acid or tranexamic [tran-ex-AM-ic] acid. Both vitamin K1 is slow, requiring about 24 hours to reduce INR (time to
agents are synthetic, orally active, excreted in the urine, and inhibit synthesize new coagulation factors). Thus, if immediate hemostasis is
plasminogen activation. Tranexamic acid is 10 times more potent than required, fresh frozen plasma should be infused.
aminocaproic acid. A potential side effect is intravascular thrombosis.

B. Protamine sulfate:
Protamine [PROE-ta-meen] sulfate antagonizes the anticoagulant effects
of heparin. This protein is derived from fish sperm or testes and is high in
arginine content, which explains its basicity. The positively charged
protamine interacts with the negatively charged heparin, forming a stable
complex without anticoagulant activity.

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 Team leaders : Rawan Alqahtani
Alanoud Alsaikhan
Abdulrahman Thekry Allulu Alsulayhim

Editing file
Ghadah Almuhana Anwar Alajmi
Ashwaq Almajed
Team members: Atheer Alrsheed
Jawaher Abanumy
Abdulaziz Redwan Laila Mathkour
Khalid Aleisa Maha Alissa
Omar Turkistani Najd Altheeb
Faris Nafisah Rana Barasain
Contact us : Mohammed Khoja Reem Alshathri
Abdulrahman Alarifi Sama Alharbi
@Pharma436 Shoag Alahmari
Abdulrahman Aljurayyan
Moayed Ahmad Shrooq Alsomali
[email protected]
Faisal Alabbad