A 57-year-old man presents to the emergency department with his spouse due to right-sided weakness that began 30 minutes ago. According to the patient’s spouse, he had just returned home from work when he suddenly could not move his right arm or leg. Past medical and surgical history are unremarkable. Temperature is 37.2°C (99.0°F), pulse is 101/min, respirations are 21/min, and blood pressure is 172/95 mmHg. On physical examination, he has 0/5 strength in the right upper and right lower extremity with a left gaze preference. A CT-brain without contrast and chest x-ray are unremarkable. Which of the following is the most appropriate next step in managing this patient?

Administer intravenous alteplase

Thrombolytics

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Definitions & Key takeaways

Thrombolytics, also known as clot-busting drugs, are a class of medications that are used to dissolve blood clots. These drugs work by converting plasminogen to plasmin, an enzyme that breaks down fibrin, a protein that forms the backbone of blood clots. By breaking down fibrin, thrombolytics can dissolve blood clots and restore blood flow to the affected area.

Thrombolytics include drugs like alteplase, reteplase, and tenecteplase, typically given for the acute management of pathological blood clots like in embolic or thrombotic strokes. The main side effect of thrombolytics is undue bleeding from other sites, including the injection sites, gastrointestinal bleeds, and hemorrhagic stroke. This is why they are contraindicated in hemorrhagic strokes and head trauma.

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Introduction0:00–0:51

Thrombolytic, also called fibrinolytics, are medications that break up blood clots formed during hemostasis, where hemo means blood, and stasis means to halt or stop.

Hemostasis is divided into primary hemostasis, which involves the formation of a platelet plug at the site of an injured blood vessel, and secondary hemostasis, which involves multiple coagulation factors working together to form a fibrin mesh to stabilize the platelet plug.

Together, these two processes create a blood clot which stops the bleeding. Sometimes blood clots could cause problems, like when they form in a coronary artery to cause a heart attack, or when they break off and travel to the brain and cause a stroke.

In these instances we can use thrombolytics to break up the clot and restore blood flow. Thrombolytic medications were actually derived physiologically--from what is known as the fibrinolytic system.

Pathophysiology0:51–2:42

Approximately two days after an injury occurs to a blood vessel and the blood clot forms, it’s time to for the body to dissolve the blood clot through a process called fibrinolysis, which is the gradual degradation of the fibrin mesh.

To do this, a circulating protein produced by the liver called plasminogen, gets converted by an enzyme called tissue plasminogen activator, or tPA, into its active form called plasmin.

Normally, healthy endothelial cells release only tiny amounts of tPA, but when they’re exposed to coagulation factors produced during 2ndary hemostasis, Factor Xa and thrombin in particular, they start making lots of tPA.

But it’s important that plasmin activity doesn’t get out of hand, either. So the endothelial cells also release plasminogen activator inhibitor 1 and antiplasmin which are proteins that bind and sequester plasminogen and plasmin respectively.

It’s all about always reaching that zen balance of coagulation and anticoagulation. Now, during an injury, more coagulation factors get activated, which causes more tPA to get released by the endothelial cells, and more plasminogen gets converted to plasmin.

Plasmin then acts as a protease and cuts the fibrin into smaller pieces--allowing the trapped red blood cells and platelets to float away, letting the clot dissolve.

Now - although tPA is the main activator of plasmin - a few other proteins activate plasmin as well, including coagulation factors IXa, XIIa, kallikrein, and protein C.

Medicine has taken advantage of tPA, using it clinically as a “clot buster” because it’s used to dissolve pathological blood clots.

Mechanism of Action2:42–4:10

Now common thrombolytics derived from tPA include alteplase, reteplase, and tenecteplase. Streptokinase is derived from beta hemolytic bacteria proteins with a similar mechanism of action.

All thrombolytics are given via IV, usually guided by angiogram to target the blocked blood vessel. Alteplase, reteplase, and tenecteplase work by binding directly to fibrin proteins on the clot.

Next, they bind to nearby fibrin bound plasminogen, convert it to plasmin, which then cuts up the fibrin mesh. Of these medications, tenecteplase has the highest affinity for fibrin.

In contrast, streptokinase works by binding to either circulating or fibrin bound plasminogen. This creates a plasminogen-streptokinase complex that converts other plasminogen to plasmin, which then degrades the fibrin mesh.

The thrombolytics derived forms of tPA are used more frequently than streptokinase because they are clot specific--meaning they will not cause fibrinolysis and unnecessary bleeding outside of the area of the clot unlike streptokinase.

Since these medications activate fibrinolysis and destroys clots while they are forming, they increase the bleeding time, the PT or the prothrombin time, and the PTT or prothromboplastin time.

However, the platelet count will remain unchanged. Thrombolytics are used for the short-term emergency management of pathological thrombosis.

Indications4:10–5:08

They are used to break up clots during myocardial infarctions, deep vein thrombosis, pulmonary embolisms, and ischemic strokes.

For strokes, it’s important to first rule out hemorrhagic strokes with a CT. These strokes are caused by bleeding from damaged arteries, and thrombolytics will make them worse.

The key to using these medications is early administration. For example, it is recommended that if a person suffers a myocardial infarction due to a blood clot in a cardiac vessel, the person should be given thrombolytics within 12 hours from symptom onset.

If a person suffers a stroke, they should be given the medication within 3 hours from symptom onset. This is because after a certain number of hours, the tissue that’s supplied by the blood vessel dies from the lack of oxygen so reperfusion won’t help the necrotic tissue.

Toxicity5:08–6:24

In terms of toxicity, both the recombinant forms of tPA and streptokinase can cause unnecessary bleeding. Thus, they should never be administered when a person has active internal bleeding, before major surgeries, after recent trauma, or in people with any history of intracranial bleeding, bleeding disorders, or severe hypertension.

Thankfully, two antidotes exist to combat this problem called aminocaproic acid and tranexamic acid. Aminocaproic acid works by binding to tPA derivatives, and tranexamic acid binds to plasminogen and prevents its activation.

If these medications fail, other transfusion products can be administered like platelets or coagulation factors in the form of fresh frozen plasma.

Next, Streptokinase is found in bacteria, so it’s immunogenic--meaning it could trigger an immune response. Thus it can cause severe hypersensitivity reactions like anaphylaxis when given.

Also, our antibodies can bind to and disable them, which limits their effect after multiple use. All right, as a quick recap, the thrombolytic medications alteplase, reteplase, tenecteplase, and streptokinase work by converting plasminogen to plasmin to degrade the fibrin mesh.

They are given for the acute management of pathological blood clots. Their primary adverse effect is bleeding, for which aminocaproic acid or tranexamic acid can be given.