Use of rFactor VII in Trauma

1. Use of rFactor VII in Trauma Steven C. Bharadwaj

2. Introduction Major trauma- massive hemorrhage is the second most common cause of death in the prehospital setting leading cause of death in the acute hospital setting.

3. Introduction Patients with isolated systolic hypotension (< 90 mm Hg) have up to 54% mortality, and 50% require an urgent operation to control hemorrhage. Transfusion of > 20 units of PRBCs mortality of 50%.

4. Introduction Uncontrolled hypothermia secondary to hemorrhagic shock is an independent risk factor for mortality. Hypothermia has been shown to be the most predictive element of the SIRS criteria for developing MODS.

5. Introduction Hypothermia Found in patients after significant injury requiring massive resuscitation. Perpetuates coagulopathic bleeding. Re-warming these patients is time-consuming. Acidosis both results from and contributes to coagulopathy- difficult to reverse while patients are still bleeding.

6. Introduction Dilution of clotting factors occurs with massive transfusion worsens coagulopathy

7. Introduction Therefore: Coagulopathy of trauma is multifactorial. Laboratory values resemble those found in sepsis- induced DIC.

8. Introduction Treatment of sepsis-induced DIC is focused on elimination of the source of sepsis. The treatment of trauma-induced DIC is focused primarily on hemorrhage control, re-warming, factor replacement, and resuscitation.

9. Introduction takes hours to accomplish this. Must accomplish definitive control of ongoing bleeding. Cycle of hypothermia, coagulopathy ad acidosis usually fatal.

10. Introduction rFactor VII used as an attempt to stop the cycle at the level of acquired coagulopathy in trauma. Thereby controlling bloodloss that cannot be controlled surgically (microvascular).

11. Factor VII FVIIa When bound to exposed TF , activates the extrinsic clotting system at the site of injury without causing systemic hypercoagulability. good candidate as therapy for coagulopathy bypasses intrinsic coagulation system, is active only in the presence of exposed TF, has a rapid onset and a short half-life.

12. Factor VII

13. Factor VII The resulting hemostasis generally occurs only at the site of injury for two reasons: (1) factor VII is not biologically active unless it is bound to TF (2) thrombin generation occurs on the surface of activated platelets localized to the site of injury.

14. Animal Studies Lynn et al. 2002 Pig liver-injury model (Grade IV) was utilized to evaluate the hemostatic efficacy of rFVIIa as the sole agent for hemostasis. mimics a prehospital situation in which a patient suffers a truncal injury.

15. Animal Studies Grade I – Hematoma  Subcapsular, <10% surface area Laceration   Capsular tear, <1cm parenchymal depth   

16. Animal Studies Grade II- Hematoma-  Subcapsular, 10-50% surface area   <10cm diameter Laceration -1-3cm parenchymal depth, <10cm length

17. Animal Studies Grade III Hematoma Subcapsular, >50% surface area or expanding. Ruptured subcapsular or parenchymal Hematoma   Intraparenchymal Hematoma >10cm or expanding Laceration   >3cm parenchymal depth

18. Animal Studies Grade IV Laceration   Parenchymal disruption involving 25-75% of hepatic lobe or 1-3 Coinaud's segments in a single lobe

19. Animal Studies Grade V Laceration- Parenchymal disruption involving >75% of hepatic lobe or >3 Coinaud's segments within a single lobe Vascular- Juxtahepatic venous injuries i.e.. retrohepatic vena cava/central major hepatic veins.

20. Animal Studies Grade VI Vascular- Hepatic Avulsion

23. Animal Studies rFVIIa (180 µg/kg) was given 30 seconds after injury, and no other hemostatic interventions were applied to the liver. The animals were normothermic, not resuscitated, and followed for 60 minutes after injury.

24. Animal Studies rFVIIa when utilized as a single agent for hemostasis, preserved blood pressure and shortened PT but by itself did not significantly decrease blood loss or improve survival.

25. Animal Studies Jeroukhimov et al. 2002 two different doses of rFVIIa (180 µg/kg and 720 µg/kg) were evaluated in the same prehospital liver-injury model. The higher-dose group demonstrated improved length of survival and decreased blood loss (p < 0.05) 60 minutes after injury.

26. Animal Studies Schreiber et al. 2003 rFVIIa (150 µg/kg) in a grade V liver-injury model, injecting the drug 30 seconds after injury. The pigs were normothermic, fluid resuscitated 15 minutes after injury, and followed for 120 minutes. the amount of blood in the peritoneal cavity was 397 mL in the rFVIIa group and 437 mL in the placebo group. MAP did not differ between groups.

27. Animal Studies Normothermic grade V liver-injury model with early drug delivery and rapid resuscitation: utilizing rFVIIa as sole therapy did not alter blood loss or blood pressure.

28. Animal Studies Schreiber et al. 2002 hypothermic (33°C), dilutionally coagulopathic pigs with grade V liver injuries treated with rFVIIa and gauze packing. treated with resuscitation and gauze packing instituted 30 seconds after injury, followed by intravenous injection of rFVIIa.

29. Animal Studies no difference in blood loss between the two treated groups (1,086 ± 227 mL and 1085 ± 289 mL) But there was a decrease in blood loss between the rFVIIa-treated and control group (2,187 ± 577 mL in control; p < 0.05).

30. Animal Studies Summary: Warm-grade IV injury: preserved blood pressure decreased blood loss and improved time of survival.

31. Animal Studies Study in cold, dilutionally coagulopathic animals with grade V liver injuries: used rFVIIa as an adjunct to gauze packing. The laboratory changes of coagulopathy were corrected within minutes of administration. demonstrated a 46% decrease in blood loss in the rFVIIa-treated animals. none of the animals demonstrated any evidence of thrombotic complications.

32. Human Data Kenet et al. 1999 described the first use of rFVIIa in a trauma. young soldier with a gun shot wound to the abdomen, injuring, among other structures, the IVC. rFVIIa- desperate attempt to control the massive coagulopathic bleeding. intervention was successful and the patient ultimately survived.

33. Human Data O’Neil et al. 2002 first use of rFVIIa for trauma in the United States. numerous stab wounds 3 operative explorations and 2 angiographic embolizations, the patient continued to bleed 45 hours after injury.

34. Human Data 105 U of PRBCs administered 90 µg/kg of rFVIIa. The patient stopped bleeding immediately but ultimately died of sepsis 5 weeks after injury. autopsy revealed no evidence of thrombi.

35. Human Data Martinowitz et al. 2001 7 trauma patients who received rFVIIa. Both blunt and penetrating trauma and received 25–49 U of PRBCs before receiving rFVIIa. The dose in this group of patients ranged from 120 to 212 µg/kg.

36. Human Data 3/7 patients died, but the surgeons describe how the coagulopathic bleeding ceased. allowing the surgical bleeding to become obvious and therefore be easily controlled by conventional means.

37. Human Data Freiderich et al. 2003 prospective, randomized, double-blinded, placebo-controlled trial, describing use of rFVIIa in radical prostate surgical patients. placebo treatment arm was compared with two treatment groups receiving either 20 or 40 µg/kg of rFVIIa.

38. Human Data Blood loss was decreased in the rFVIIa groups (p < 0.01), and transfusions were eliminated in the higher-dose group. Operative time decreased in the rFVIIa group (120 versus 180 minutes; p < 0.05). No complications associated with hypercoagulopathy noted.

39. Human Data Boffard et al. 2005 multicenter prospective, randomized, placebo-controlled, double-blind trial of the efficacy and safety of rFVIIa as adjunctive therapy for hemostasis in trauma patients. 237 patients, equally divided between blunt and penetrating injuries, were enrolled.

40. Human Data Patients received the first dose of rFVIIa following the 8th unit of PRBCs additional doses 1 and 3 hours later (200 + 100 + 100 µg/kg). The primary endpoint was transfusion requirements or the number of PRBC U within 48 hours of the first dose.

41. Human Data Blunt trauma PRBC transfusions were reduced by 2.6 units (p = 0.02) need for massive transfusion (> 20 PRBCs) was reduced (14% versus 33% of patients; p = 0.03).

42. Human Data Penetrating trauma, trend toward a reduction of PRBCs and massive transfusion (7% versus 19%; p = 0.08).

43. Human Data No safety concerns identified: including thromboembolic events.

44. Human data Grounds et al. 2006 Retrospective analysis of rFVIIa use in trauma and surgery in an international registry. Evaluate efficacy and safety of rFVIIa in pts with massive bleeding (>14 U PRBCs). 43 patients. Very heterogeneous population- trauma (blunt and penetrating) and post-surgical.

45. Human data Blood loss significantly reduced in 40/43. Transfusion requirements also reduced. Mortality in trauma patients was significantly reduced compared to predictions using a standard scoring system. No improvement was seen in post-surgical bleeding.

46. Conclusion Preclinical and human data indicate usefulness of rFVIIa in patients with acquired coagulopathies from both blunt and penetrating injuries. Multiple trauma centers around the United States are routinely utilizing rFVIIa for coagulopathic trauma patients.

47. Conclusion Questions about the optimal dosing regimen and safety continue to be unanswered. Price- $10,000US for 4.8 mg vial Newer, more potent formulations of the drug are under investigation. Studies are now looking into about utilizing the drug as a temporizing hemostatic agent in prehospital scenarios.

48. Conclusion Further prospective, randomized, blinded human trauma trials are required.