Fibrinolytics

Topics:- 

• Introduction 

• Historical story of Fibrinolytics

• When is fibrinolytic therapy indicated?

• How is fibrinolytic therapy given?

• Types of Fibrinolytics

• Drugs available in the Egyptian market

• Mechanism of action

• Clinical use 

• Dose and administration 

• Interactions

• Pharmacokinetics

• Side Effect

• Who is a candidate for thrombolytic therapy?

• When To Call the Doctor?

• Monographs

The discovery and characterisation of the components of fibrinolysis as we know them today were made in the 1900s; thus, our knowledge of the fibrinolytic system is relatively new and is still expanding. A major breakthrough was the discovery of exogenous plasminogen activators in the 1930’s , which led to the development of thrombolytic agents, initially used for treatment of pleural adhesions and later for treating coronary artery thrombosis. Recombinant plasminogen activators were approved for use in the 1980’s and are still used worldwide for the treatment of myocardial infarction, pulmonary embolism, and ischemic stroke. Simultaneously, antifibrinolytic agents are increasingly used to prevent and treat major blood loss in trauma, postpartum bleeding, and surgery, and prehospital administration of antifibrinolytic drugs is now standard care for major trauma worldwide .Over the years, the process of fibrinolysis has been subject to a multitude of studies in the laboratory, but in vivo fibrinolytic capacity can be challenging to quantify in an accurate and timely fashion, since fibrin clot degradation occurs slowly compared with other enzymatic processes due to the presence of endogenous inhibitors in plasma, and since total fibrinolytic capacity is determined not only by plasmin activity in plasma but also by fibrin clot structure and interactions with blood cells and endothelium. While a plethora of fibrinolysis assays have been developed and are in use for research, very few options currently exist for measuring fibrinolysis in the clinical setting. Viscoelastic tests may provide clinically relevant information on the patient’s fibrinolytic capacity, especially with modifications to existing standard protocols, but remain to be validated further in clinical settings.

Fibrinolytic therapy is most often used to treat heart attack (blocked arteries of your heart) and stroke (blocked arteries of your brain). But it can also treat:

1.  Pulmonary embolism (blocked arteries of your lung).

2.   Acute deep vein thrombosis (blocked arteries of your leg).

3.   Acute arterial thrombosis (blocked arteries of your leg).

4.   Blocked catheters, dialysis ,fistulas or surgical bypasses .  

First-Generation Fibrinolytics

 • Streptokinase:

 • Derived from beta-hemolytic streptococci bacteria, streptokinase was the first fibrinolytic to be widely used in clinical practice. It activates plasminogen indirectly by forming a complex with it, leading to plasmin formation. However, it can cause allergic reactions and may lead to the formation of antibodies with repeated use.

Second-Generation Fibrinolytics

 • Urokinase:

 • A human-derived enzyme, urokinase was isolated from urine and later produced from human cell cultures. It directly activates plasminogen to form plasmin. Urokinase has a reduced risk of allergic reactions compared to streptokinase and is used for various applications, including clearing blocked catheters.

 • Alteplase (tPA - tissue plasminogen activator):

 • A recombinant form of tissue plasminogen activator, alteplase is produced using genetic engineering. It has higher specificity for plasminogen bound to fibrin, reducing the risk of systemic fibrinolysis. This specificity makes alteplase a preferred choice for treating acute ischemic strokes, myocardial infarctions, and pulmonary embolisms.

Third-Generation Fibrinolytics

 • Reteplase:

 • A modified form of alteplase, reteplase has a longer half-life, allowing for bolus administration rather than continuous infusion. It is used primarily in the treatment of acute myocardial infarctions.

 • Tenecteplase:

 • Another recombinant variant of tPA, tenecteplase is engineered for greater resistance to degradation and a longer half-life. Like reteplase, it can be administered as a single bolus injection. It is used for similar indications as alteplase, including myocardial infarctions and acute ischemic strokes.

Drug-Drug interaction: 

Anticoagulants: The concurrent use of anticoagulants like warfarin, heparin, or direct oral anticoagulants (DOACs) with fibrinolytics can significantly increase the risk of bleeding. This requires careful consideration and close monitoring.

 • Antiplatelet Agents: Medications like aspirin, clopidogrel, or other platelet inhibitors can also increase bleeding risk when used with fibrinolytics. While these combinations might be necessary in certain medical scenarios (like acute coronary syndrome), the risk must be carefully managed.

 • Non-Steroid Anti-Inflammatory Drugs (NSAIDs): NSAIDs like ibuprofen, naproxen, or aspirin (at higher doses) can increase the risk of gastrointestinal bleeding when combined with fibrinolytics. It’s essential to monitor for signs of gastrointestinal bleeding if this combination is necessary.

 • Selective Serotonin Reuptake Inhibitors (SSRIs): Some SSRIs (like sertraline, fluoxetine, or paroxetine) can slightly increase bleeding risk due to their effects on platelet function. When used with fibrinolytics, there could be a heightened bleeding risk, though the degree of risk might vary.

 • Antihypertensives: While not a direct interaction, managing blood pressure is critical when using fibrinolytics, especially in ischemic stroke. High blood pressure increases the risk of intracranial hemorrhage during fibrinolytic therapy, so it’s crucial to monitor and manage blood pressure carefully.

Drug-Food interaction: 

Vitamin K-Rich Foods: Although fibrinolytics are not directly affected by vitamin K (which affects blood clotting), patients who are receiving anticoagulants (like warfarin) in conjunction with fibrinolytics should maintain a consistent intake of vitamin K-rich foods. Sudden changes in dietary vitamin K can affect anticoagulant activity and bleeding risk. Examples of vitamin K-rich foods include leafy greens (such as spinach and kale), broccoli, and Brussels sprouts.

 • Alcohol: Alcohol can increase the risk of bleeding and gastrointestinal irritation. Patients who have received fibrinolytics should limit or avoid alcohol, especially if they are also on other medications that affect blood clotting, like anticoagulants or antiplatelet agents.

 • Foods That May Affect Blood Pressure: High blood pressure is a risk factor for complications during fibrinolytic therapy, especially in cases of ischemic stroke. Certain foods, like those high in sodium, can raise blood pressure and should be consumed with caution. Patients on fibrinolytics should be mindful of their sodium intake and follow any dietary recommendations provided by healthcare professionals.

Absorption

 • Intravenous Administration: Fibrinolytics are usually administered intravenously (IV), ensuring rapid entry into the bloodstream. This is essential for their immediate action in emergency situations like heart attacks or strokes.

Distribution

 • Rapid Distribution: Once in the bloodstream, fibrinolytics quickly distribute to areas with clots. Tissue plasminogen activator (tPA), for example, has high affinity for plasminogen bound to fibrin, leading to targeted distribution at clot sites.

 • Plasma Protein Binding: Some fibrinolytics, such as tPA, have a relatively low plasma protein binding, allowing them to remain active in the bloodstream.

Metabolism

 • Rapid Inactivation: Fibrinolytics are rapidly metabolized and inactivated in the body, primarily by the liver and other proteolytic enzymes. This quick inactivation is a safety feature, as it reduces the risk of systemic bleeding.

 • Half-Life: Fibrinolytics generally have short half-lives due to rapid metabolism. For instance, alteplase (tPA) has a half-life of 3-6 minutes, with a terminal half-life of 40-50 minutes due to hepatic clearance. Reteplase and tenecteplase, which are modified forms of tPA, have longer half-lives (around 20 minutes for reteplase and up to 90 minutes for tenecteplase), allowing for bolus administration instead of continuous infusion.

Excretion

 • Elimination by the Liver: The primary route of excretion for fibrinolytics is through the liver, where they are metabolized into inactive byproducts. These byproducts are then excreted in the urine.

Common Side Effects:

 1. Bleeding:

 • The most significant risk with fibrinolytics is bleeding. This can range from minor bleeding, like bruising or nosebleeds, to more severe or life-threatening bleeding, such as gastrointestinal bleeding or hemorrhagic stroke. Because fibrinolytics dissolve clots, they can impair the body’s ability to control bleeding.

 2. Allergic Reactions:

 • Some fibrinolytics, like streptokinase, can cause allergic reactions because they are derived from bacterial sources. Symptoms may include rash, itching, hives, swelling, or, in severe cases, anaphylaxis.

 3. Fever and Chills:

 • Some patients may experience fever or chills after receiving fibrinolytics. This can be related to the body’s immune response or the breakdown of blood clots.

 4. Low Blood Pressure (Hypotension):

 • Fibrinolytics can lead to a drop in blood pressure, causing dizziness or lightheadedness. This may occur due to the rapid dissolution of blood clots or a reaction to the medication.

 5. Nausea and Vomiting:

 • Gastrointestinal symptoms such as nausea and vomiting can occur with fibrinolytic therapy.

Serious Side Effects:

 1. Intracranial Hemorrhage:

 • A rare but severe risk is intracranial hemorrhage, or bleeding in the brain. This is a critical concern when using fibrinolytics, particularly in the treatment of ischemic strokes.

 2. Major Hemorrhage:

 • Severe bleeding in other areas, such as the gastrointestinal tract, urinary tract, or surgical sites, can occur with fibrinolytics, requiring prompt medical intervention.

 3. Arrhythmias:

 • In the context of thrombolysis for myocardial infarction, rapid reperfusion can lead to cardiac arrhythmias, such as ventricular fibrillation or ventricular tachycardia.

Precautions must be taken when considering thrombolytic therapy, and there are several situations in which this treatment can’t be used. You’re probably not a candidate for thrombolytic therapy if you:

 • Are over the age of 75.

 • Had prior bleeding into your brain.

 • Are currently on blood-thinning medications.

 • Have a history of stroke in the past three months.

 • Have active bleeding or recent trauma or surgery.

 • Have a known brain tumor.

 • Are currently pregnant.

 • Have uncontrolled high blood pressure .

 • Have eye diseases related to diabetes.

 • Have a severely low platelet count.

If you’ve received thrombolytic therapy and develop complications — like excessive bleeding, pain or fever call your healthcare provider right away. They can determine the cause of your symptoms and adjust your treatment accordingly.