FIBRINOLYTICS (THROMBOLYTICS)

Plasmin: It is the protease enzyme present in our blood which brings about lysis of clot or fibrin Plasminogen: It is the inactive precursor of plasmin On activation it gets converted to active plasmin 2

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Tissue plasminogen activator: It is the enzyme in the body which activates & converts plasminogen to plasmin It is released when there is stasis of blood formation of clots in blood t plasminogen activator Plasminogen Plasmin α 2 Antiplasmin : It terminates the action of t PA after dissolution of pathological clots in our blood. 4

Drugs Affecting Fibrinolytic System 5

Thrombolytic drugs: All these drugs are plasminogen activators - When given in large doses they overcome the action of anti-plasmin and dissolve thrombi The fibrin degradation products also inactivate anti-plasmin When plasminogen activators are administered for thrombolytic therapy massive fibrinolysis is initiated and the inhibitory controls are overwhelmed 6

Streptokinase: It is a protein (protease enzyme) produced by ß hemolytic streptococci It has no intrinsic enzymatic activity But forms a stable non-covalent complex with proactivator plasminogen This produces a conformational change that catalyzes the following conversion plasminogen  plasmin 7

It has to be given in a loading dose of 250,000 units to overcome plasma antibodies (from prior streptococcal infection) ½ life is minutes The streptokinase - plasminogen complex is not inhibited by α 2 antiplasmin ADRs : Allergic reactions Fever Anaphylaxis Prior presence of antistreptococcal antibodies may ↓ efficacy. Hence it cannot be repeated before one year of prior strep. Infection. 8

Urokinase: A protease enzyme isolated from cultured human kidney cells. It is a direct plasminogen activator. ½ life is minutes. It is non antigenic, non pyrogenic, non allergic, does not produce hypotension. It is given in a loading dose of 300,000 U over 10 minutes followed by maintenance dose of 300,000 units/hour over 12 hrs Used instead of streptokinase and in whom streptokinase cannot be repeated. 9

Recombinant tissue plasminogen activator (Alteplase): It is manufactured by recombinant DNA technology. It is a poor plasminogen activator in the absence of fibrin. It preferentially activates bound plasminogen several hundred fold more rapidly than plasminogen in the circulation. It is effective in lysing thrombi during ACUTE MYOCARDIAL INFARCTION. 10

Seems superior to streptokinase and urokinase in dissolving old clots. As effective as streptokinase but safer (more expensive). Minimal antigenicity. It is given as a bolus intravenously 15 mg followed by 0.75 mg/kg over 30 minutes. 11

Anistreplase (APSAC): It consists of a complex of purified human plasminogen and bacterial streptokinase that has been acetylated to protect the active site of plasminogen. When administered the acyl group spontaneously hydrolyses freeing the activated streptokinase proactivator complex to perform fibrinolysis. This allows for rapid IV injection, greater clot selectivity i.e. more active on plasminogen associated with clots than free plasminogen – more thrombolytic activity Dose: 30 units as a single intravenous injection given over 3-5 minutes 12

Therapeutic uses: Myocardial infarction Severe pulmonary embolism Deep vein thrombosis Acute peripheral arterial occlusion 13

ADRs: Bleeding - commonest ADR Less with selective agents – r tPA Allergic reactions: Streptokinase – bacterial protein antigenic Rarely anaphylactic reactions seen Hypotension:  with rapid administration of streptokinase. Hemorrhagic stroke 14

Absolute contraindications to thrombolytic therapy: Prior intracranial hemorrhage Known structural cerebral vascular lesion Known malignant intracranial neoplasm Ischemic stroke within 3 months Suspected aortic dissection Active bleeding or bleeding diathesis Significant head trauma or facial trauma within 3 months. 15

Relative contraindications to thrombolytic therapy: -Major surgery, traumatic or prolonged CPR within 3 weeks. -Recent (within 2-4 weeks)internal bleeding -pregnancy - Non compressible vascular punctures - Severe uncontrolled hypertension (SBP > 180 mmHg or DBP> 110mmHg) -Active pepetic ulcer -Current use of warfarin and INR >

ANTIFIBRINOLYTIC DRUGS

Epsilon aminocaproic acid (EACA): It is chemically similar to the amino acid lysine It is a synthetic inhibitor of fibrinolysis It competitively inhibits plasminogen activation Rapidly absorbed orally Cleared by the kidneys Dosage: 6 g four times daily 18

Tranexamic acid: It is an analog of aminocaproic acid and has the same properties It is administered orally with a 15mg/kg loading dose followed by 30 mg/kg every 6 hours 19

Uses: 1.Adjuvant therapy in hemophilia 2.Treatment of bleeding from fibrinolytic therapy 3.Prophylaxis for re-bleeding from intracranial aneurysms 4.Post surgical GI bleeding 5.Post prostatectomy bleeding 6.Bladder hemorrhages secondary to radiation or drug induced cystitis 20

Aprotinin: (Serine protease inhibitor) It is a serine protease inhibitor It inhibits fibrinolysis by free plasmin It may have other anti-hemorrhagic effects as well It ↓ bleeding by 50% from many types of surgery - heart procedures - liver transplantation It is currently approved for patients undergoing CABG who are at high risk of excessive bleeding ADRs: Recent studies have shown - ↑ risk of MI, stroke & renal damage Association with anaphylaxis also noted - test dose required 21

LOCAL HAEMOSTATICS (STYPTICS) These drugs are used to stop bleeding from oozing locations eg. tooth sockets, open wounds. They are meant only for local application Most of them provide a network of fibrin which promotes coagulation 22

Thrombin: Obtained from bovine plasma. Applied topically it is a good haemostatic Fibrin sealant: Obtained from human plasma Used to stop microbleeding & oozing in dental procedures Gelatin foams: Soaked with saline, fibrin or thrombin to cover or pack bleeding surfaces. Vasoconstrictors: 1% adrenaline soaked gauze effective haemostatic 23