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Recombinant activated factor VII for intractable intraoperative hemorrhage

Recombinant activated factor VII for intractable intraoperative hemorrhage. Panthila Rujirojindakul, MD. Prince of Songkla University. 1. Initiation phase. Injury of vessels wall leads to contact between blood and subendothelial cells.

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Recombinant activated factor VII for intractable intraoperative hemorrhage

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  1. Recombinant activated factor VII for intractable intraoperative hemorrhage Panthila Rujirojindakul, MD. Prince of Songkla University

  2. 1. Initiation phase Injury of vessels wallleads to contact between blood and subendothelial cells Tissue factor (TF) isexposed and binds toFVIIa or FVII which is subsequently converted to FVIIa The complex between TF and FVIIa activates FIX and FX FXa binds to FVa on thecell surface

  3. The FXa/FVa complexconverts small amountsof prothrombin into thrombin The small amount ofthrombin generatedactivates FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa 2. Amplification phase Activated platelets bind FVa, FVIIIa and FIXa

  4. The FVIIIa/FIXa complexactivates FX on thesurfaces of activatedplatelets FXa in association withFVa converts largeamounts of prothrombininto thrombin creating a “thrombin burst”. The “thrombin burst”leads to the formationof a stable fibrin clot. 3. Propagation phase

  5. Recombinant activated factor VII (NovoSeven) • Ulla Hedner (1980) activated factor VII concentrate (plasma) - Hemophilia A with inhibitor to coagulation factor VIII • Novo Nordisk, Denmark (1988)- transfected baby hamster kidney cells • FDA (1999) – label/licensed • 2005- off-label/off-licensed

  6. Recombinant activated factor VII (NovoSeven) • Vitamin K-dependent glycoprotein • Structurally similar to human plasma-derived factor VIIa • Molecular weight 50,00 dalton

  7. Tissue factor (TF)/FVIIa, or TF/rFVIIa interaction,is necessary to initiatiate haemostasis At pharmacological concentrations rFVIIa directly activates FX on the surface of locally activated platelets. This activation will initiatethe ”thrombin burst” independently of FVIII and FIX. This step is independent of TF. Mechanism The thrombin burst leads to the formation of a stable clot

  8. Definition • Massive blood loss • Massive bleeding/hemorrhage • Massive transfusion • Ineffectiveness of standard replacement therapy

  9. Definition • Massive blood loss • Loss of 1 blood volume within a 24 h period • 50% blood volume loss within 3 hr BV: adult 7%IBW, child 8-9% • Rate of loss 150 mL/min Guidelines on the management of massive blood loss. BJH; 135: 634-41.

  10. Definition • Massive bleeding/hemorrhage • Bleed > 3 L (150 mL/min) within > 20 min • Bleed > 30 mL/kg (1.5 mL/kg/min) within > 20 min

  11. Definition • Massive transfusion • PRC/whole blood 10 U • > 3000 mL • > 1 blood volume within 24 hr • > 5 U (0.5 blood volume) within 3 hr

  12. Definition • Ineffectiveness of standard replacement therapy • FFP 10-20 mL/kg • Platelet concentrate 1-2 U/ 10 kg or 0.2-0.4 U/kg • Cryoprecipitate 1-2 U/ 10 kg or 0.2 U/kg

  13. Indications (Label) • Treatment and prophylaxis bleeding in hemophilia A or B with inhibitors to factor VIII or IX • Acquired hemophilia due to auto-antibodies 90 µg/kg

  14. Indications (Label) • Factor VIII inhibitor with active bleeding or require surgery • Glanzmann’s thromboasthenia (with platelet antibodies or refractoriness) • Congenital factor VII deficiency

  15. Indications (Label) • Pedriatric patients • Hemophilia with inhibitors to FVIII and FIX • Joint, muscle and musculocutaneous bleeding with inhibitors • Severe hemophilia bleeding with inhibitors 90 µg/kg every 2 hr • Hemophilia with CNS bleeding 60-135 µg/kg every 2-4 hr Hemophilia 2006; 12: 457-72.

  16. Indications (off-label) • Life threatening bleeding +specific platelet or coagulation defect • Multiple trauma • Diffuse microvascular hemorrhage after major surgery • Uncontrolled obstetric hemorrhage: PPH

  17. Postpartum hemorrhage Aust N Z J Obstet Gynaecol 2008; 48(1): 12-6.

  18. Major bleeding • Major bleeding in blunt trauma patient 200µg/kg then 100 µg/kg every 1-3 hr x 2 doses Management of bleeding following major trauma: a European guideline. Crit Care 2007; 11(2): 1-22.

  19. Crit Care 2007; 11(2): 2-22.

  20. Indications (off-label) • Cardiac surgery: CABG (On/Off-pump), Re-do surgery, valve surgery, aortic arch+root surgery, ASD,VSD, heart+lung transplant 30-90 µg/kg

  21. Criteria allowed for earlier use rFVIIa (Cardiac surgery) • refractory blood loss > 2000 mL • Requiring PRC > 4 U precluded sternal closure in OR • Caused postoperative bleeding > 100 mL/h from chest drains despite administration antifibrinolytic drugs, FFP and platelet. Transfusion 2005; 45: 26-34.

  22. Indiactions (off-label) • Urological surgery: retropubic prostatectomy • General surgery: partial hepatectomy 20-80 µg/kg

  23. Indications (off-label) • Bleeding associated with liver disease 15-30 µg/kg every 4-6 hr

  24. Indications (off-label): Pediatric • Non-hemophilia bleeding • Liver disorders • Cardiac surgery • Qualitative platelet disorders 90 µg/kg • Trauma 50-100µg/kg Hemophilia 2006; 12: 457-72.

  25. Indications (off-label): Pediatric • Non-hemophilia bleeding • Preterm/term infants 50 µg/kg every 3 hr • Bone marrow transplantation 90-270 µg/kg every 4-24 hr Hemophilia 2006; 12: 457-72.

  26. Indications (off-label) • Severe thrombocytopenia, which is refractory to platelet transfusion • Reversal of warfarin toxicity • Controlled bleeding associated with intracerebral hemorrhage (ICH) 15 – 200 µg/kg

  27. Most Efficacy • Fibrinogen level > 50 mg/dl (preferably > 100 mg/dl)(Cryoprecipitate 1 U/10 kg) • Platelet count > 50,000 (Preferably 100,000) • Acid-base balance > pH 7.2 • Normothermia Thromb J 2004; 2(1): 9-15

  28. Contraindication • Hypersensitivity to mouse, hamster or bovine proteins

  29. Contraindications (relatively) • Known thrombotic tendency • History of recent thromboembolic event e.g. pulmonary embolism, myocardial infarction, thrombotic cerebrovascular event, deep vein thrombosis (within previous 6 mo) • Liver disease

  30. Contraindications (relatively) • Recently undergone coronary angioplasty and/or stent insertion • Severe peripheral vascular disease • Disseminated intravascular coagulation (DIC)

  31. Dosage • Treatment of massive bleeding 120 (100-140) g/kg then 100 g/kg 2 hr (30 min, persist hemorrhage)

  32. Administration • BOLUS IV injection over 2-5 min • NOT infusion

  33. Half-life • 3-4 hr in hemophilia • Shortened in bleeding episode (unknown) • Adult > pediatric (rapid clearance)

  34. Cost • 1.2 mg/vial • Cost/ 1.2 mg • PSU 32,300 bath • UK 660 pounds

  35. Monitoring • Clinical response • NO predictive laboratory parameters

  36. Adverse effects • Fever • Rash, angioneurotic edema • Nausea • Vomiting • Pain on injection

  37. Adverse effects • Thrombo-embolic (arterial and venous) complication 1-2% • Myocardial infarction • Cerebrovascular infarction • Deep venous thrombosis • Pulmonary embolism • Disseminated intravascular coagulopathy (DIC) Crit Care Med 2005: 33(4): 883-90. BJA 2004; 93(6): 842-58.

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