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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.

 

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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

Risk Factors

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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.

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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.

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PLASMINOGEN PLASMIN

FIBRIN DEGRADATION PRODUCTS

CLOT DISSOLUTION

PLASMINOGEN ACTIVATOR

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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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Streptokinase Urokinase Anistreplasetissue Plasminogen Activators (t-PA)◦ Alteplase◦ Reteplase◦ Tenecteplase

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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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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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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

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A two chain serine protease containing 411 amino acid 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.

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

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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.

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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.

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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

Alteplase (rt.PA)

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Pharmacokinetics:It has very short t1/2 of 5 minutesSide-Effects:Bleeding including GIT & cerebral hemorrhageAllergic reactions, e.g., anaphylactoid reaction, laryngeal edema, rash, and urticaria have been reported very rarely (<0.02%)

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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 AMIAcute 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 hemorrhagePulmonary Embolism: Treatment of acute massive pulmonary embolism

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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Aminocaproic Acid & tranexamic acidThey have lysine-like structureThey inhibit fibrinolysis by competitive inhibition of plasminogen activationِِِIIIAdjuvant therapy in hemophilia, fibrinolytic therapy-induced bleeding & postsurgical bleedingAprotinin is a serine protease inhibitorIt inhibits fibrinolysis by free plasminUsed to stop bleeding in some surgical procedures

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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 weeksRelative contraindications include: Active peptic ulcer, diabetic retinopathy,

pregnancy, uncontrolled HTN

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By Raman