1. Done by : Ali Al-Thubyani, Pharm D Candidate Supervised by : Hend Metwali, Associate Clinical Pharmacist

2. Background  Pulmonary embolism (PE), is a sudden blockage in a lung artery. The blockage usually is caused by a blood clot that travels to the lung from a vein in the leg.  A clot that forms in one part of the body and travels in the bloodstream to another part of the body is called an embolus.  If a blood clot is large, or if there are many clots, PE can cause death

3. Background  PE is a serious condition that can: Damage part of your lung because of a lack of blood flow to your lung tissue. This damage may lead to pulmonary hypertension (increased pressure in the pulmonary arteries). Cause low oxygen levels in your blood. Damage other organs in your body because of a lack of oxygen

4. Etiology of PE 1) Stagnation of blood flow.  Stagnation of blood may be related to:  Bed rest, paralysis, varicose veins, surgery  Reduced cardiac output, e.g. in heart failure

5. Etiology of PE 2) Increasing the risk of hyper-coagulability include:  Surgery  Pregnancy, estrogen administration  Malignancy, myocardial infarction  Several acquired or inherited disorders of coagulation e.g, (antithrombin III, ptn C&Sdeficiency)

6. Etiology of PE  DVT : it is the most common cause of PE.  Deep vein clots are not like clots in veins close to the skin's surface. Those clots remain in place and do not cause PE.

7. Clinical presentation of PE  Symptoms :  Cough, chest pain/tightness, dyspnea, palpitation, hemoptysis.  Dizziness with large PE.  Symptoms often confused with MI.  Patients may die suddenly before TTT can be initiated.

8. Clinical presentation of PE  Signs :  Tachypnea, tachycardia, diaphoresis, distended neck veins.  Cyanosis or hypotension if large PE.  Cardiovascular collapse (shock, oliguria).  Laboratory tests  ↑ESR & leukocyte count

9. of PE Diagnosis  Diagnostic Test :  Pulmonary angiography (gold standard) difficult & expensive  Ultrasonography.  CT.  Ventilation-perfusion (V/Q)  D-dimer test (good negative) help exclude PE.  Wells Criteria

10. Treatment of PE  Treatment of PE involves the use of anticoagulants and, in severe cases, thrombolytic drugs.  Warfarin should begin concurrently with UFH or LMWH therapy. For patients with acute PE, heparin and warfarin therapy should be overlapped for at least 4 to 5 days. The UFH or LMWH can then be discontinued once the INR is within the desired range for 2 days.

11. Warfarin  Warfarin is the most widely used coumarin because of potency, reliable bioavailability and an intermediate half life of elimination (36 h).  It Inhibits vitamin K–dependent clotting factors II, VII, IX, and X, ptn C&S.  Full antithrombotic effect achieved 8 to 15 days after initiation of Therapy.

12. Indications of Warfarin Duration of treatmentEvent 3 months for first eventsVenous thrombosis Lifelong for recurrent attacks 3 months for first eventsPulmonary Embolism Life long for recurrent attacks Life longAtrial Fibrillation Life longMechanical heart valve

13. Dosage And Resistance  Begin warfarin on day 1 of heparin  initiate at 5–10 mg/day.  In case of resistance to warfarin try to : May increase warfarin dosage to 10-mg. Monitor INR and plasma concentrations of Warfarin. Alternative: low-molecular-weight heparin (LMWH).

14. Special Population  Specific patient populations may need starting dose of 5 mg/day or less.  Elderly  Malnourished patients  Debilitated patients  Major surgery  Heart failure  Hepatic impairment

15. Adverse effects of warfarin  Bleeding.  Epistaxis, hematuria, gastrointestinal (GI) hemorrhage, bleeding gums.  Skin Necrosis.  Extensive thrombosis of venules and capillaries Caused by protein C or protein S deficiency  If occurs, discontinue warfarin and initiate heparin.  Restart warfarin at low dose (e.g. 2 mg/dose) and increase gradually over several weeks

16. Adverse effects of warfarin  Purple toe syndrome.  It is rare but if it occurs discontinue warfarin, it may takes several weeks to months till discoloration disappear.  Teratogenicity  If pregnant, Unfractionated heparin or LMWH is safe to use.  Breastfeeding: can use warfarin because not excreted in breast milk

17. Monitoring Parameter  Signs and symptoms of bleeding: a. Nose bleeds, bleeding gums, hematuria, unusual bruising, prolonged bleeding from cuts b. Purple toes  International normalized ratio

18. Monitoring Parameter  Usually, goal INR is 2.0–3.0  In patients with mechanical heart valve the targeted INR is 2.5-3.5  Mildly elevated INR (3.5 to 5.0): reduce dose or hold 1 or 2 doses.  INR 5 to 9: hold warfarin ± low dose vitamin K.  Serious/life-threatening bleeding  IV vitamin K  fresh frozen plasma  clotting factor concentrates  recombinant factor VII

19. Bridge anticoagulation  Bridge anticoagulants is recommended During invasive procedures.  Discontinue warfarin 5 days preoperatively and perform procedure when the INR has normalized.

20. Bridge anticoagulation  Start LMWH after 4 days preoperatively and hold it 24-hours before surgery.  Resume both warfarin and LMWH 12-24 hours after surgery.  NO need to change anticoagulation therapy for dental procedures, cataract surgery, or dermatologic procedures

21. Heparin  There are two forms of heparin : UFH and LMWH (enoxparin, dalteparin and tinazaparin )  Advantages of LMWH over UFH:  Predictable anticoagulation dose response.  Improved subcutaneous bioavailability  Longer biologic t½.  Lower incidence of thrombocytopenia.  Reduced need for laboratory monitoring.

22. Indications of LMWH  Deep vein thrombosis treatment (with or without PE )  Hip-replacement surgery (prophylaxis)  Knee-replacement surgery (prophylaxis  Abdominal surgery (prophylaxis)  Dose : 1 mg/kg SC /12 h or 1.5  mg/kg SC / 24 h of Enoxaparin

23. Adverse effects of LMWH :  Most common: bleeding  Thrombocytopenia, avoid with HIT history  If CrCl < 30 mL/min :  Reduce enoxaparin dose Or use UFH.  Dalteparin & tinzaparin less accumulation in renal insufficiency which could be a good alternatives.

24. Monitoring Parameter  Monitoring by aPTT but not necessary due to predictable anticoagulant response with SC administration.  Monitor CBC.  Monitor platelets count every 2-4 days from day 4 to 14.  Monitor Serum creatinine.

25. Factor Xa Inhibitors  Fondaparinux  FDA-approved indications : VTE prophylaxis following orthopedic surgery DVT/PE treatment  HIT in pregnancy

26. Dosage and monitoring  VTE prevention: 2.5 mg SC once daily 6 to 8 hr after surgery < 50 kg: not indicated  DVT or PE treatment: 7.5 mg SC once daily ◦ > 100 kg: 10 mg once daily ◦ < 50 kg: 5 mg daily  Monitor for bleeding : CBC and Kidney function test, if CrCl less than 30 discontinue.

27. Direct Thrombin Inhibitors  Four parenteral agents:  Lepirudin,  Desirudin,  Bivalirudin,  Argatroban Oral agent : dabigatran.

28. Dose adjustment MonitoringIndicationDrug ↓ renal function PTTHITlepirudin ↓ renal function PTTVTE prophylaxis in hip surgery desirudin ↓ renal function ACT and a PTT unstable angina undergoing PTCA Bivalirudin ↓ liver function ACT and a PTT HITArgatroban

29. Adverse effects of DTIs  serious hemorrhage  minor bleeding  no agents to reverse DTI activity  Concurrent use of DTIs & thrombolytic agents increases bleeding risk

30. Special population Pregnancy : Warfarin is contraindicated. LMWH is more preferred than UFH. Cancer patients :  VTE is frequent complication of Malignancy.  LMWH has lower incidence of bleeding.  warfarin often not used.

31. Heparin Induced Thrombocytopenia (HIT)  Serious adverse effect  Severe thrombotic complications  High morbidity & mortality  ↑ incidence with UFH than LMWH  Typically begins at days 4 to 14 but can be delayed up to 20 days.

32. Heparin Induced Thrombocytopenia (HIT)  Diagnosis:  +ve heparin antibody  drop in platelet count > 50% from Baseline  platelet activation & thrombin generation

33. Heparin Induced Thrombocytopenia (HIT) Treatment :  Once HIT is diagnosed:  discontinue all sources of heparin  DTIs: drug of choice for HIT + thrombosis  Only lepirudin & argatroban are FDA approved  both considered equally suitable for initial TTT  administered IV infusion  titrated based on aPTT.

34. Heparin Induced Thrombocytopenia (HIT)  For warfarin :  initial rapid reduction of protein C ↑ risk of thrombosis in patients with HIT.  can be used for long-term anticoagulation.  Avoid heparin for at least 3 to 6 months.

35. Reference  Joseph T. Dipiro, Robert L. Talbert & Gary C. Yee. (2008) Pharmacotherapy A pathophysiologic Approach. Seventh Edition  Adam C. et al.HIT Pocket Guide (2009).American society of hematology.