1. Frank W.G. Leebeek, MD PhD Dept of Hematology Erasmus MC Rotterdam, The Netherlands 5 juli 2012 Indicaties voor recombinant factor VIIa (Novoseven) Regionaal Bloedtransfusieoverleg Zuidwest: Kliniek van Bloedtransfusie

2. coagulation NEJM 2001,344:1527

3. Recombinant Factor VIIa  Activated eptacog alpha, Novoseven®  Developed for use in haemophilia patients with inhibitors against FVIII or IX  First clinical use in 1983  Dose: 90 microgram/kg i.v. every 2-3 hours, or continuous infusion  Half-life 2 -3 hours  Excellent efficacy in haemophilia patients with inhibitors  Rarely thrombo-embolic events in these patients

4. Recombinant Factor VIIa  Tissue factor dependent mechanism of action  Activates FX on activated platelets  Inhibits fibrinolysis by upregulating TAFI by generation of thrombin

5. Mannucci, PM.NEJM 2007;356:2301

6. Current indications of rFVIIa  Bleeding (spontaneous and surgical) in patients with congenital and acquired haemophilia A or B with inhibitors against FVIII or FIX  Glanzmann thrombasthenia  Factor VII deficiency

7. rFVIIa in Haemophilia

8. Other possible indications for rFVIIa  Without pre-existing coagulopathy  Excessive, uncontrollable bleeding post-surgery, trauma  Major surgery (prostatectomy, cardiac surgery)  Acute intracerebral hemorrhage  With coagulopathy  Liver surgery, transplantation  Thrombocytopenia  Gastro-intestinal bleeding  Bleeding associated with anticoagulant treatment  Extensive study program has been done

9.  Trauma: reduction in RBC transfusion in severe blunt trauma  Liver transplantation: no reduction in blood loss, number of patients requiring RBC transfusion was lower  Hepatectomy: no reduction in blood loss  Upper gastrointestinal bleeding: rVIIa showed no advantage over standard treatment Randomized-controlled trials rFVIIa: Efficacy Boffard J Trauma 2005;59:8 Planinsic Liver transpl 2005;11:895 Shao Am J Surg 2006;191:245; Lodge Anestesiology 2005;102:269Lodge Liver transpl 2005;11:973, Bosch Gastroenterology 2004;127:1123

11. Recombinant Factor VIIa use in the US O’Connell et al. JAMA 2006;295:293-298

12. Recombinant Factor VIIa for excessive bleeding  Several case series on succesful use of rVIIa in excessive bleeding  rFVIIa not registered for this indication  >90 % of rVIIa use in the US is off-label

13. What is excessive blood loss  Several definitions of massive blood loss  Replacement of total blood volume with RBC in<24 hrs  Blood loss of > 50% within 3 hrs  Blood loss of > 150 ml/min

14. rVIIa in treatment of excessive bleeding  Retrospective, uncontrolled chart audit  196 non-hemophilic individuals in 21 US academic centers  Surgical bleeding37%  Gastro-intestinal 31%  Intra-cranial 13 %  Pulmonary 11 %  Others 8 %  75 % of patients was treated once MacLaren et al Transfusion 2005;45:1434-1442

15. Outcome after rVIIa  52.6 % of patients bleeding stopped  26 % of these rebled  37 % of patient died from bleeding < 48 hrs  Dependent upon acidosis (pH<7.20 neg. predictor, OR 0.2; 0.1-0.51) MacLaren et al Transfusion 2005;45:1434-1442

16. Effectiveness of rFVIIa and acidosis Laffan, NM et al Blood Coagul Fibrinolysis 2003:14(suppl 1): S35-S38

17. Adverse events off-label vs trial patients: O’Connell et al. JAMA 2006;295:293-298

18. Considerations regarding adverse events rFVIIa  Thrombo-embolic events hardly occur in haemophilia patients  Thromboembolic events in studies are low, comparable to controls  rFVIIa might be more thrombogenic in patients predisposing to thrombosis, as is seen in ICU patients  FDA adverse event reporting system does not mention the total number of patients treated. Not all SAE may have been reported  Most patients will also have been treated with other prohaemostatic drugs

20. Deaths due to trauma

21. Pharmacological measures to reduce blood loss Desmopressin Fibrinolysis inhibitors  Plasminogen inhibitorsTranexamic acid Epsilon-amino-caproic acid  Serine protease inhibitors Aprotinin Recombinant factor VIIa Topical agents (thrombin//collagen/fibrin sealants) Coagulation factor concentrates

22. Desmopressin (DDAVP)  Increases VWF and FVIII in plasma  Improves platelet function  Improvement of primary hemostasis  Hardly any randomized trials available  Effect in cardiac surgery (+ aspirin) (several studies)  No effect in scoliosis surgery (Spine 1999)  No effect in hepatectomy(Can J Anaesthesia, 2003)  No effect in variceal bleeding(Hepatology 1993)

23. Antifibrinolytics in excessive bleeding  Tranexamic acid  Epsilon amino caproic acid (EACA)  Aprotinin

25. Tranexamic acid and Epsilon-Amino caproic acid Inhibits binding of plasmin to fibrin by interfering with the lysine binding sites of the proenzyme plasminogen Tranexamic acid is 10 times more active than EACA Dose: 4 times daily 1 gram In cardiac surgery: total dose 3-10 g; loading dose of 3-7 g, followed by continuous infusion of 20-250 mg/hr

26. Mannucci, PM.NEJM 2007;356:2301

27. Fibrinolyis inhibitors and clinical events Significant lower transfusion need for aprotinin and tranexamic acid Mannucci, PM.NEJM 2007;356:2301

28. Fibrinolysis inhibitors do not increase the risk of thrombosis

30. Transfusie protocol massaal bloedverlies

35. Transfusiegids

36. New therapeutic indications for Novoseven

38. Recommendations concerning rFVIIa  Strict transfusion guidelines for each individual hospital (RBC, FFP and platelet concentrates)  Based on laboratory control of APTT, PT, Fbg and platelets  Limit the use of rVIIa to indications and off-label use only in very selected cases (diffuse oozing patient)  No rFVIIa in patients with severe hypothermia or acidosis  Last-ditch use is ineffective