1. Presented by: Passant Mounir Nagy Under the supervision of: Prof. Dr/ Seham Hafez

2. Objectives Goals of therapy Mechanism of Action Indications for thrombolysis therapy Contraindications for thrombolysis therapy Approved thrombolytic gents Differences between thrombolytic agents Outcomes of therapy Heparin versus thrombolytics

3. Goals of therapy The rationale behind thrombolysis is that In conjunction with anticoagulation it may reduce the rate of death, recurrent PE and pulmonary hypertension. The goal is rapid clot lysis hastens reperfusion of lung tissue prevents chronic complications of pulmonary embolism such as pulmonary hypertension.

4. Mechanism of Action

5. Thrombolytics convert plasminogen to plasmin, which in turn breaks down fibrin and promotes clot lysis. These agents also cause systemic plasminogen activation. By cleaving and inactivating fibrinogen and clotting factors II, V and VIII, they interfere with blood coagulation and produce a systemic hypocoagulable state. Furthermore, elevated serum fibrin and fibrinogen degradation products inhibit the conversion of fibrinogen to fibrin by negative feedback; and therefore interfere with fibrin polymerization.

6. Mechanism of Action “Cont’d” There is also a direct neurohormonal effect on pulmonary vasoconstriction and bronchoconstriction. Finally, thrombolysis may cause platelet dysfunction by affecting platelet surface receptors GpIb and GpIIb.

7. Indications for Pulmonary Embolism Thrombolysis Absolute Massive pulmonary embolism with hypotension or systemic hypoperfusion Relative Right ventricular dysfunction Pulmonary hypertension Presence of extensive deep venous thrombosis Prevention of recurrent pulmonary embolism

8. Contraindications Absolute contraindications 1. 1.Hemorrhagic stroke or stroke of unknown origin at anytime 2. 2.Ischemic stroke in preceding 6 months 3. 3.CNS damage or neoplasms 4. 4.Recent major trauma/surgery/head injury (within preceding 3 weeks) 5. 5.GI bleeding within the last month 6. 6.Known bleeding

9. Contraindications “Cont’d” Relative contraindications 1. 1.Transient ischaemic attack in preceding 6 months 2. 2.Oral anticoagulant therapy 3. 3.Pregnancy or within one week post partum 4. 4.Traumatic resuscitation 5. 5.Refractory hypertension (systolic BP > 180 mmHg) 6. 6.Advanced liver disease 7. 7.Infective endocarditis 8. 8.Active peptic ulcer

10. Thrombolytic Agents Approved for the Treatment of Pulmonary Embolism DrugDosageInteractionsNotes Streptokinase (Streptase ® ) (Sedonase ® ) (Kabikinase ® ) 250,000 IU over 30 min then 100,000 IU/ hr for 24 hours Accelerated regimen 1.5 million IU over 2 h Antifibrinolytic agents may decrease effects of streptokinase Heparin, warfarin, and aspirin may increase risk of bleeding Heparin should never be given concurrently with streptokinase Highly antigenic. Highly likely that treatment will be interrupted due to allergic drug reactions. Urokinase (Abbokinase ® ) (Angikinase ® ) 4,400 IU/ kg over 10 min then 4,400 IU/ kg/ hr for 12 or 24 hours Accelerated regimen 3 million IU over 2 h Alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications Heparin should never be given concurrently with urokinase Nonantigenic; however, more expensive than streptokinase and, thus, limits use Alteplase rtPA (Activase ® ) (Actilyse ® ) 100 mg over 2 hours Or 0.6 mg/kg over 15 min (max dose 50 mg) Drugs that alter platelet function (eg, aspirin, dipyridamole, abciximab) causes bleeding May give heparin with and after t-PA infusions to reduce risk of rethrombosis rtPA (recombinant tissue plasminogen activator) Treatment of bleeding involves stopping thrombolysis, compression and transfusion of blood products as needed.

11. Although benefit from thrombolysis for PE may be seen when given up to 14 days after the initial diagnosis of a PE, it is most beneficial when given as early as possible. During administration, laboratory monitoring is unnecessary. However, after the infusion is given, partial thromboplastin time (PTT) should be measured Heparin is started when the thrombin time or PTT is at or below a level that is twice the normal control values

12. Differences Between Thrombolytic Agents In trials comparing two thrombolytic agents: No difference in efficacy between urokinase and streptokinase was apparent. Although rtPA initially produced a faster resolution of the clot, results were the same after 24 hours.

13. Outcomes of Therapy ThrombolyticHeparin Percent improvement in RV function 3917 Percent pulmonary perfusion 141.5 Mortality No evidence suggests that thrombolytic therapy reduces mortality than Heparin Recurrent pulmonary embolism No evidence exists to prove that thrombolysis decreases the rate of recurrent PE than Heparin Only one study provides the most evidence of benefit of thrombolytic therapy for RV dysfunction Unfortunately, other studies failed to confirm these results. Therefore, no evidence at this time supports the efficacy of thrombolysis in these patients

14. Heparin Versus Thrombolytics Anticoagulation remains the standard of treatment for PE and has clearly been shown to reduce mortality and the rate of recurrent PE. Anticoagulation does not directly contribute to clot lysis. It prevents the propagation of the thrombus while allowing endogenous fibrinolytic activity to dissolve the clot. The lytic process may take several days to several months to develop, and in many patients it is incomplete and may lead to the occurrence of pulmonary hypertension. No evidence from clinical trials proves that thrombolytic therapy reduces the recurrence rate of pulmonary embolism or affects mortality in hemodynamically stable patients

15. Heparin Versus Thrombolytics “Cont’d” Although there is a more rapid improvement in pulmonary pressures, and other findings in PE patients receiving thrombolysis than in those receiving heparin, there is no difference in clinical benefit between the two therapies after the first 24 to 48 hours Controlled clinical trials have not demonstrated benefit in terms of reduced mortality rates or earlier resolution of symptoms when currently compared to heparin. Until randomized clinical trials demonstrate a clear morbidity or mortality benefit, the role of thrombolytic therapy in the management of acute PE remains controversial. The currently accepted indications for thrombolytic therapy include hemodynamic instability or right ventricular dysfunction demonstrated on echocardiography.