Thrombolytics

Thrombolytics, also known as fibrinolytics, include recombinant tissue plasminogen activator (TPa) (i.e., alteplase, reteplase, and tenecteplase), urokinase, and streptokinase. The agents promote the breakdown of a blood clot by converting plasminogen to plasmin, which then degrades fibrin. Thrombolytics are particularly helpful for conditions related to vascular obstruction by a blood clot (e.g., acute STEMI, pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism (PE), deep venous thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis), and acute ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke). Efficacy declines the longer tissue ischemia persists; therefore, timing of therapy is particularly important in myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction and stroke. Life-threatening bleeding and allergic reactions are potentially serious complications. Weighing the risks and benefits of thrombolytics and evaluating individuals for contraindications/bleeding risk before initiating therapy is important.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Chemistry and Pharmacodynamics

Chemistry

  • Recombinant tissue plasminogen activator (TPa):
    • Alteplase
    • Reteplase
    • Tenecteplase
  • Urokinase: a physiologic enzyme produced in renal parenchymal cells 
  • Streptokinase: a protein (not enzyme) synthesized by beta-hemolytic streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus

Mechanism of action

Normal physiology:

  • The function of the fibrinolytic system is to remove clots. 
  • Plasminogen is activated and cleaved to plasmin by:
    • TPa
    • Urine plasminogen activator (UPa), also known as urokinase
  • Plasmin cleaves fibrin polymers (fibrinolysis): 
    • Forms fibrin degradation products (e.g., D-dimer)
    • Generates new plasmin binding sites on partially degraded fibrin

Thrombolytics (also known as fibrinolytics):

  • Recombinant TPa: 
    • Catalyzes the cleavage of plasminogen → plasmin
    • Fibrin specific → activates clot-bound plasminogen (tenecteplase is the most specific agent)
  • Urokinase: 
    • Directly cleaves and converts plasminogen → plasmin
    • Not fibrin specific → activates free circulating and clot-bound plasminogen
  • Streptokinase:
    • Binds plasminogen → forms a complex 
    • Conformational change of bound plasminogen allows cleavage of other plasminogen → plasmin
    • Not fibrin specific → binds and activates free and clot-bound plasminogen
Normal physiology relating to thrombolysis

Normal physiology relating to thrombolysis:
Endogenous tissue plasminogen activator (TPa) and urokinase cleave plasminogen into plasmin, resulting in the degradation of fibrin.

Image by Lecturio.

Indications

Administration

  • Formulation: bolus and/or infusion IV
  • Half-life:
    • Alteplase: approximately 5 minutes
    • Reteplase: 13–16 minutes
    • Tenecteplase: 20–24 minutes (final clearance approximately 90–130 minutes)
    • Urokinase: approximately 20 minutes
    • Streptokinase: approximately 18 minutes

Indications

ST elevation myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction (STEMI):

  • Used when percutaneous coronary intervention (PCI) is not readily available
  • Timing:
    • Ideally given within 30 minutes of presentation
    • Can be given up to 12 hours after symptom onset, but efficacy declines with time

Acute ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke:

  • For individuals with persistent neurologic deficits
  • Given within 4.5 hours of symptoms (ideally < 3 hours)
  • Rule out intracranial hemorrhage with CT prior to administration.

Pulmonary embolism (PE):

  • Indicated for:
    • Hemodynamically unstable PE
    • Select individuals with hemodynamically stable PE and right ventricular strain
  • Can be given as:
    • Systemic therapy
    • Catheter-directed therapy

Deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis):

  • May be indicated for:
    • Large, proximal DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis
    • Individuals at risk of limb ischemia
  • Catheter-directed therapy is preferred.

Additional indications:

  • Acute limb ischemia Acute limb ischemia Acute limb ischemia (ALI) is a major vascular emergency because of the rapid decrease in limb perfusion that causes a potential threat to limb viability. The majority of cases are caused by arterial thrombosis due to plaque progression or embolism, but ALI can also be caused by blockage of the venous drainage. Acute Limb Ischemia
  • Indwelling catheter occlusion:
    • Central venous catheters
    • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis catheters

Adverse Effects and Contraindications

Use thrombolytics cautiously. The medications have a significant risk of bleeding, which can be life threatening or fatal.

Adverse effects

  • Bleeding/hemorrhage, including:
    • Intracranial
    • GI
    • Retroperitoneal
    • Epistaxis
    • Ecchymosis
    • Hematoma
  • Cholesterol embolization
  • Allergic reactions:
    • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)
    • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
    • Anaphylaxis
  • Reperfusion arrhythmias (from treatment of STEMI)

Contraindications

Contraindications depend on the medication, dosing, and pathology and may include:

  • Active or recent internal bleeding:
    • Intracranial hemorrhage 
    • GI bleed
  • Bleeding diathesis
  • Intracranial pathology:
    • Cerebral vascular lesions (e.g., arteriovenous malformation or aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms)
    • Neoplasm 
    • Recent ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke
    • Recent significant head injury or facial trauma
  • Possible aortic dissection Aortic dissection Aortic dissection occurs due to shearing stress from pulsatile pressure causing a tear in the tunica intima of the aortic wall. This tear allows blood to flow into the media, creating a "false lumen." Aortic dissection is most commonly caused by uncontrolled hypertension. Aortic Dissection
  • Recent intracranial or spinal surgery
  • Severe, uncontrolled hypertension Uncontrolled hypertension Although hypertension is defined as a blood pressure of > 130/80 mm Hg, individuals can present with comorbidities of severe asymptomatic or "uncontrolled" hypertension (≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic) that carries with it a significant risk of morbidity and mortality. Uncontrolled Hypertension

Drug interactions

An increased risk of bleeding may occur in individuals taking:

  • Antiplatelet agents Antiplatelet agents Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Antiplatelet Agents
  • Anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants
  • Salicylates
  • Prostacyclin analogs

References

  1. Baig, M. U., Bodle, J. (2021). Thrombolytic Therapy. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK557411/
  2. Medscape. (n.a.). Reteplase. Retrieved September 11, 2021, from https://reference.medscape.com/drug/retavase-reteplase-342289
  3. Medscape. (n.a.). Tenecteplase. Retrieved September 11, 2021, from https://reference.medscape.com/drug/tnk-tpa-tnkase-tenecteplase-342291
  4. Medscape. (n.a.). Alteplase. Retrieved September 11, 2021, from https://reference.medscape.com/drug/activase-tpa-alteplase-342287
  5. Rivera-Bou, W. L. (2021). Thrombolytic therapy. In Schraga, E.D., et al. (Ed.), Medscape. Retrieved September 11, 2021, from https://emedicine.medscape.com/article/811234-overview#a2
  6. Kumar, A., et al. (2011). Evolutionary trend of thrombolytics: Their significance. ResearchGate. https://www.researchgate.net/publication/266286698_Evolutionary_Trend_of_Thrombolytic_-_Their_Significance
  7. Weinberg, A. S., & Tapson, V. F. (2021). Catheter-directed thrombolytic therapy in deep venous thrombosis of the lower extremity: Patient selection and administration. In Finlay, G. (Ed.), UpToDate. Retrieved September 29, 2021, from https://www.uptodate.com/contents/catheter-directed-thrombolytic-therapy-in-deep-venous-thrombosis-of-the-lower-extremity-patient-selection-and-administration
  8. Tapson, V. F., & Weinberg, A. S. (2021). Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration. In Finlay, G. (Ed.), UpToDate. Retrieved September 29, 2021, from https://www.uptodate.com/contents/approach-to-thrombolytic-fibrinolytic-therapy-in-acute-pulmonary-embolism-patient-selection-and-administration
  9. Gibson, C. M., Corbalan, R., & Alexander, T. (2020). Acute ST-elevation myocardial infarction: The use of fibrinolytic therapy. In Dardas, T. F. (Ed.), UpToDate. Retrieved September 29, 2021, from https://www.uptodate.com/contents/acute-st-elevation-myocardial-infarction-the-use-of-fibrinolytic-therapy
  10. Oliveira-Filho, J., & Samuels, O. B. (2020). Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use. In Dashe, J. F. (2020). UpToDate. Retrieved September 29, 2021, from https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use
  11. Runge, M. S., Quertermous, T., & Haber, E. (1989). Plasminogen activators: The old and the new. Circulation. 79(2), pp. 217–224. https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.79.2.217

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