Thrombolytic agents are proteins that activate a plasma proenzyme, plasminogen, to the active enzyme plasmin. Plasmin then solubilizes fibrin and degrades a number of other plasma proteins, most notably fibrogen.
Agents Available And Indications
Streptokinase (SK)- Derived from group C, ß-hemolytic streptococci. Not fibrin specific. Activates adjacent plasminogen by forming a non-covalent SK-plasminogen activator complex. Plasma half-life 30 min. Stimulates antibody production making retreatment difficult.
Urokinase (UK)- Derived from cultured human cells. Not fibrin specific. Activates plasminogen directly by enzymatic action. Plasma half-life 20 min.
Tissue Plasminogen Activator- Derived by recombinant genetics from human DNA. Fibrin specific. Activates plasminogen associated with fibrin directly by enzymatic action. Short plasma half-life. Two preparations of tPA are available.
- Alteplase (tPA) is the glycosylated protein of 527 amino acids produced by recombinant DNA technology.
- Reteplase (sometimes called rPA) is the 39,571 molecular weight non-glycosylated deletion mutein of tPA. It contains 355 of the 527 amino acids of native tPA and includes the kringle 2 and the protease domains of the parent molecule.
- Tenecteplase is the 527 amino acid protein produced by recombinant DNA technology. It differs from alteplase by 6 amino acids
- Acute myocardial infarction- streptokinase, tPA (Alteplase, Reteplase & Tenecteplase)
- Acute ischemic stroke - tPA (Alteplase)
- Acute pulmonary embolism - SK, UK, tPA (Alteplase)
- Acute deep venous thrombosis - SK
- Clotted AV fistula and shunts - UK
- Bleeding is the major complication of thrombolytic therapy. Consequently, absolute contraindications include dissecting aortic aneurysm, pericarditis, stroke, or neurosurgical procedures within 6 months or known intracranial neoplasm. Relative contraindications include major surgery or bleeding within 6 weeks, known bleeding diathesis, and severe uncontrolled hypertension.
- Allergic reactions: SK and anistreplase are potentially allerogenic. Patients are usually pretreated with intravenous hydrocortisone 100 mg.
- Antibody production: SK and anistreplase induce antibody production, which makes retreatment with either of these agents less effective.
Thrombolytic Therapy In Myocardial Infarction
Intravenous Dosing Of Thrombolytic Agents In Acute MI
|(All patients with acute MI should receive one chewable aspirin 160-325 mg as soon as the diagnosis is suspected)|
|Drug||Loading Dose||Maintenance Dose||Duration Of Infusion||Concurrent Heparin|
|Streptokinase||No||1.5 million IU (45 mL NaCl)||1 hr||No|
|tPA (Alteplase)||15 mg||50 mg over 30 min** and 35 mg over next hr*** (100 mL sterile H2O)||90 min||Yes|
|tPA (Reteplase)||Given by 10 + 10 U double bolus, 10 U bolus over 2 min, wait 30 min and repeat 10 U over 2 min.||34 min||Yes|
|tPA (Tenecteplase)||30-50 mg by single bolus body weight
(see package insert for precise dosing)
|** 0.75 mg/Kg, not to exceed 50 mg over 30 min. *** 0.50 mg/Kg, not to exceed 35 mg over the next hour.|
Other Regimens For Thrombolytic Agents
Peripheral Intra-arterial Infusion
SK: 20,000 IU bolus followed by 2,000 IU/min for 60 min.
UK: 6,000 IU/min for 1-2 hrs. (Both SK and UK should be given with concurrent systemic heparin.)
Clotted IV Catheter Clearance with UK
Inject UK 5,000 IU in 1 mL into catheter. For central venous catheter inject 5,000 IU/mL in volume equal to volume of the catheter. Allow 30-60 min for thrombolysis.
Clotted AV Cannula Clearance with SK
Inject SK 250,000 in 2 mL in each end of cannula. Clamp ends and allow 30-60 min for thrombolysis.
Rapid Evaluation Of Patients With Suspected Acute Myocardial Infarction
|Chest pain or other symptoms suggestive of acute myocardial ischemia|
|ECG shows one of these:
|Give one chewable aspirin 160 mg - 325 mg|
|Confirm absence of contraindications to thrombolytic agents*|
|Symptoms present less than 6 hrs.||Symptoms present between 6 & 12 hrs.||Symptoms present more than 12 hrs.|
|Give thrombolytic agent, therapy most beneficial||Strongly consider thrombolytic agent, therapy moderately beneficial||Therapy less effective, but consider if pain continues or recurs|
* See section on indications. Thrombolytic agents seem to offer less benefits in patients over 75 although age is not a contraindication.
Thrombolytic Therapy In Ischemic Stroke
Dosing tPA (Alteplase) In Acute Ischemic Stroke
- Duration of symptoms and findings less than 3 hours
- CT scan of head shows no intracranial bleeding
- Blood pressure not higher than 185/100 mm Hg (BP must be kept below 185/110 mm Hg during and after therapy)
tPA (Alteplase) Dose
- 0.9 mg/kg IV over one hour (no concurrent heparin or aspirin)
Note: Patients must be carefully selected and treated within 3 hours. Other thrombolytic agents cannot be substituted for tPA. Please refer to the reference given below before using tPA in ischemic stroke.
Clinical debate: should thrombolytic therapy be the first-line treatment of acute ischemic stroke? New England Journal Of Medicine 1997; 337:1309-13
Thrombolytic Therapy In Pulmonary Embolism and Deep Venous Thrombosis
|Dosing Thrombolytic Agents In PE/DVT|
|Drug||Indication||Loading Dose||Maintenance Dose||Duration Of Infusion||Concurrent Heparin|
DVT or arterial thromboembolism
|250,000 IU over 30 min,
250,000 IU over 30 min
|tPA (Alteplase)||PE||None||100 mg||2hrs.||Optional|
|Urokinase||PE||2,000 IU/lb over 10 min||2,000 IU/lb/hr||12 hrs.||NO|
|Interfacing Heparin And Thrombolytic Agents|
|Drug||First Step||Second Step||Third Step||Last Step|
|SK, UK||Stop heparin Infusion||Infuse thrombolytic agent in prescribed fashion||Stop thrombolytic agent infusion||Restart heparin Infusion with or without a loading dose when APTT or thrombin time returns to less than twice normal (usually after 3-4 hours)|
|tPA||If it is elected to discontinue heparin during tPA Infusion for PE, follow directions for the other thrombolytic agents given above.|