Thrombolytics - Antifibrinolytic Cardiovascular Poison

Thrombolytics

Thrombolytic agents are plasminogen activators which cleave the Arg-Val bond of plasminogen resulting in the formation of plasmin. They are used in the treatment of thromboembolic disorders such as myocardial infarction, peripheral arterial thromboembolism, and venous thromboembolism (deep-vein thrombosis and pulmonary embolism). They are also used to clear blocked cannulas and shunts. Common examples include alteplase, anistreplase, reteplase, streptokinase, tenectoplase, urokinase, and tissue plasminogen activator.

Streptokinase is a 47-kDa protein produced by betahaemolytic streptococci, which forms a stable non-covalent 1 : 1 complex with plasminogen, leading to its conversion to plasmin. It is given intravenously. Plasma half- life varies from 18 to 23 minutes. The effectiveness may be decreased if given within 5 days to 12 months after prior use of strep-tokinase or anistreplase, or after streptococcal infection. This is due to the formation of antistreptokinase antibodies which may result in resistance to thrombolysis. Patients with high antibody titres who are nevertheless given streptokinase are more prone to experience adverse reactions (hypotension; serum sickness).

Urokinase is a two-chain serine protease isolated fromcultured human kidney cells. It is metabolised in the liver and has a half-life of 15 to 20 minutes. Mode of administration is intravenous.

Tissue plasminogen activator (t-PA) is a serine proteasealso referred to as alteplase. Following IV administration it is metabolised in the liver and has a half-life of 3 to 5 minutes.

Bleeding is the most common adverse effect of throm-bolytic therapy. The bleeding associated with thrombolytic therapy can be categorised into 2 groups. The first category is superficial or surface bleeding (primarily observed at disturbed sites including venous cutdowns, and arterial punctures). The second category is the internal bleeding involving the gastrointestinal tract, genitourinary tract, retro-peritoneal sites, or intracranial sites. Minor bleeds include haematuria, haematemesis, haematomas, and oozing from IV puncture sites. Strokes and intracerebral bleeding occur occasionally. Other adverse effects include hypotension, headache, backache, renal dysfunction, hepatic dysfunction, leukocytosis, platelet activation, emboli, arterial occlusions, reperfusion arrhythmias, nausea, vomiting, haemoperi-cardium, hallucinations, agitation, confusion, depression, bronchospasm, cutaneous or allergic reactions, chills, and fever. Streptokinase can cause hypersensitivity reactions, haemolysis, and Guillain-Barre syndrome. A few cases of alteplase-induced anaphylactoid reaction with angioedema have been reported.

Reperfusion arrhythmias are common after the use of thrombolytics in the setting of acute myocardial infarction. A wide variety of atrial and ventricular arhythmias have been documented, including bradycardia, idioventricular rhythm, pre- mature ventricular contractions, ventricular tachycardia, and ventricular fibrillation. These are related to the reperfusion of ischaemic myocardium, rather than a direct arrhythmogenic effect of thrombolytic therapies per se. Haemopericardium causing cardiac tamponade has been observed following intravenous streptokinase for the treatment of pulmonary embolism.

The possible association of streptokinase therapy and Guillain-Barre syndrome has been reported in several patients. Neuralgic amyotrophy with severe pain and pareses in the upper extremities (Parsonage-Turner syndrome) has also been reported.

Concurrent administration of thrombolytic agents with oral anticoagulants is contraindicated when the prothrombin time is greater than 15 seconds. Concurrent use of thrombolytic agents with drugs known to significantly affect platelet integrity (e.g. aspirin, indomethacin, dipyridamole, phenylbutazone) should also be avoided.

Treatment of toxic effects arising from the use of these agents involves the following measures:

·              If bleeding is suspected, monitor patient’s haematocrit, haemoglobin, partial thromboplastin time, prothrombin time/INR, platelet count, and fibrinogen. Monitor vital

·              signs, renal and hepatic functions in symptomatic patients. Discontinue the drug.

·              Replace volume as required.

·              Apply (normal) pressure to (compressible) bleeding sites for 15 to 20 minutes.

·              If bleeding continues, administer transfusion products. Cryoprecipitate (10 U) can be given.

·              If patient continues to bleed, 2 to 6 U of fresh-frozen plasma may be necessary.

·              If the bleeding is persistent in spite of the above measures, 10 U of platelets and antifibrinolytic drugs (e-aminocaproic acid or tranexamic acid) must be given. The use of amino-caproic acid as an antidote for streptokinase has not been documented, but it may be considered in an emergency situation.

·              Aprotinin has been effective in reversing streptokinase- induced bleeding in some patients with acute myocardial infarction who underwent emergency cardiac surgery.