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Successful treatment with recombinant factor VIIa for intractable bleeding at pelvic surgery
CASE REPORTS
Successful Treatment With Recombinant Factor VIIa for Intractable Bleeding at Pelvic Surgery Jarosław Daniłos´, MD, Andrzej Goral, MD, Piotr Paluszkiewicz, MD, PhD, Krzysztof Przesmycki, MD, PhD, and Jan Kotarski, MD, PhD First Department of Gynecology, Second Department of Anesthesiology and Intensive Therapy, and Department of Traumatic Surgery, Medical University, Lublin, Poland
BACKGROUND: Postoperative bleeding may be complicated by failure to identify the site of bleeding, multiple bleeding points, and persistent hemorrhage despite surgical intervention. CASE: Activated recombinant factor VII was used successfully in a patient with life-threatening postsurgical bleeding after resection of two large extraperitoneal pelvic sarcomas. CONCLUSION: In severe hemorrhage, hemostasis can be achieved with activated recombinant factor VII. (Obstet Gynecol 2003;101:1172–3. © 2003 by The American College of Obstetricians and Gynecologists.)
Mortality can result from postsurgical intraabdominal bleeding if the bleeding site cannot be identified, there are multiple bleeding points, or persistent hemorrhage continues despite surgical intervention.1
CASE A 45-year-old woman with a prior total abdominal hysterectomy with bilateral salpingo-oophorectomy was admitted for surgical excision of a pelvic tumor, confirmed earlier by abdominal computed tomography. She had no personal or family history of bleeding disorder or thromboembolic disease and had a normal platelet count and coagulation screen at the time of admission. At surgery, adhesions between bowel, bladder, and peritoneum were dissected, and two extraperitoneal tumors, one 8 cm in diameter and the other 15 cm and attached to the vaginal wall, were resected. After checking for hemostaAddress reprint requests to: Jarosław Daniłos´, MD, First Department of Gynecology, Medical University, 20-081 Lublin, ul. Staszica 16, Poland; E-mail: [email protected].
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sis, one intraabdominal drain was inserted, and the abdomen was closed. Blood loss was calculated as approximately 1000 mL, and the patient received 2 L of crystalloids (normal saline, Ringer lactate) and 1 L of colloids (6% hetastarch, 5% albumin). The postoperative course was complicated by continued intraabdominal bleeding. Because of her critical condition and profound hypovolemic shock despite the transfusion of 2 U of packed red cells, an emergency laparotomy was performed 5 hours after the initial surgery. Multiple bleeding points were noted with massive oozing at the sites of tumor removal. Ligation of visible bleeding vessels was followed by packing with a hemostatic collagen-coated fibrin-fiber mesh, ligation of both internal iliac arteries, and correction of acidosis and hypovolemia. These failed to achieve hemostasis. The patient received 3 L of crystalloids (normal saline, Ringer solution), 1.5 L of colloids (6% hetastarch, 5% albumin), 10 U of packed red cells and 8 U of fresh frozen plasma. Despite a normal coagulation profile (prothrombin time [PT] 14 seconds [normal range 12–16], partial thromboplastin time [PTT] 37 seconds [normal range 23–37], D-dimers 0.2 g/L [normal values less than 0.5], fibrinogen of 273 g/L, platelet count 40 ⫻ 109/L, and hemoglobin level of 128 g/L), the patient continued to bleed profusely. In a desperate attempt to control the bleeding, a single dose of 80 g/kg of activated recombinant factor VII was given by intravenous bolus. Immediately after the injection, a transient tachycardia (from 80 –90 per minute to 110 per minute) and a decrease of systolic arterial pressure (from 135 mm Hg to 90 mm Hg) were observed. After a few minutes, the hemodynamic parameters spontaneously returned to normal (70 per minute and 120 mm Hg, respectively). Ten minutes later, the oozing resolved and bleeding ceased, enabling surgeons to complete the operation. The abdomen was closed, and two drains were left in the pouch of Douglas. No additional blood transfusions were required. Postoperatively, the patient was hypothermic from massive transfusions, and she required artificial ventilation. The following day she was extubated. Her coagulation profile (PT and PTT) and fibrinogen and hemoglobin levels remained normal, whereas her platelet count during 3 postoperative days increased from 30 ⫻ 109/L to 59 ⫻ 109/L and 64 ⫻ 109/L on the day of discharge. The blood loss after relaparotomy did not exceed 100 mL during the 3 days, and no further transfusions were required. There were no thromboembolic complications, and kidney function and urine output
VOL. 101, NO. 6, JUNE 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(03)00349-1
were normal. The patient had an uneventful recovery and was discharged on postoperative day 9. Both tumors removed were classified as low-grade stromal sarcomas resected with negative surgical margins. One month after the surgery the follow-up examination revealed normal levels of antithrombin III (125%), factor VII (100%), factor VIII (90%), and von Willebrand factor (above 70%). COMMENT Activated recombinant factor VII is a protein that plays a crucial role in initiating the process of blood coagulation. Binding the tissue factor at the site of vascular damage, activated recombinant factor VII forms a complex that activates the intracellular mechanism of coagulation. Activated recombinant factor VII was selected in our case to achieve hemostasis because it provides site-specific thrombin generation by enhancing tissue factor–activated recombinant factor VII complex at the site of vessel injury. This complex has now been recognized as the pivotal activator of the coagulation process and results in local thrombin generation. However, the mode of action of activated recombinant factor VII is not completely clear. Some studies suggest tissue factor– dependent mechanisms, whereas others emphasize the role of factors X and IX on the surface of activated platelets.2 Although activated recombinant factor VII was initially developed for the treatment of bleeding associated with inhibitors to factors VIII and IX, more recently it has been used effectively in the management of thrombocytopenia and blood platelet diseases3 and in the treatment of life-threatening intractable surgical hemorrhage.1,4,5 In our case, the postoperative confirmation of normal levels of coagulation factors excludes the possibility of inherited deficiencies. Other causes of severe bleeding include platelet dysfunction and thrombocytopenia.3,5 In our case, thrombocytopenia was observed at relaparotomy when the patient was bleeding and after surgery when hemostatic control was obtained. The activated recombinant factor VII has been used with incidental reports of thromboembolic disorders. Thromboembolic complications (four of 5522 patients) have been reported with the use of activated recombinant factor VII in patients with a history of ischemic heart disease, stroke, or venous thromboembolism.5,6
VOL. 101, NO. 6, JUNE 2003
Al Douri et al5 successfully used a low dose of activated recombinant factor VII (30 g/kg) in the treatment of five patients with uncontrolled bleeding, but Hedner7 suggested that the dose may be too low to induce reliable hemostasis. The dose of activated recombinant factor VII we used (80 g/kg) was close to the dose of 100 g/kg, recommended by Hedner.7 The higher thrombin concentrations induced by the high dose of activated recombinant factor VII seem to be associated with a different type of clot architecture that is stronger and more resistant to degradation by fibrinolytic enzymes.6 We believe that activated recombinant factor VII has the potential to act as a universal hemostatic agent and warrants further evaluation in surgical and gynecologic cases of intractable intraabdominal hemorrhage that fail to respond to conventional therapy. REFERENCES 1. Hedner U. Recombinant activated factor VII as a universal hemostatic agent. Blood Coagul Fibrinolysis 1998;9: S147–52. 2. Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high dose factor VIIa independents of tissue factor. Br J Haematol 1997;99:542–7. 3. Peters M, Heijboer H. Treatment of a patient with BernardSoulier syndrome and recurrent nosebleeds with recombinant factor VIIa. Thromb Haemost 1998;80:352. 4. White B, McHale J, Ravi N, Reynolds J, Stephens R, Moriarty J, et al. Successful use of recombinant FVIIa (NovoSeven威) in the management of intractable post-surgical intra-abdominal hemorrhage. Br J Haematol 1999;107: 677–8. 5. Al Douri M, Shafi T, Al Khudairi D, Al Bokhari E, Black L, Akinwale N, et al. Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven威) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis 2000;11 Suppl 1:S121–7. 6. Martinowitz U, Kenet G, Segal E, Luboshitz J, Lubetsky A, Ingerslev J, et al. Recombinant activated factor VII for adjunctive haemorrhage control in trauma. J Trauma 2001; 51:431–9. 7. Hedner U. NovoSeven威 as a universal haemostatic agent. Blood Coagul Fibrinolysis 2000;11 Suppl 1:S107–11. Received May 10, 2002. Received in revised form February 21, 2003. Accepted February 27, 2003.
Daniłos´ et al
Use of Recombinant Factor VIIa
1173
Successful Treatment With Recombinant Factor VIIa for Intractable Bleeding at Pelvic Surgery Jarosław Daniłos´, MD, Andrzej Goral, MD, Piotr Paluszkiewicz, MD, PhD, Krzysztof Przesmycki, MD, PhD, and Jan Kotarski, MD, PhD First Department of Gynecology, Second Department of Anesthesiology and Intensive Therapy, and Department of Traumatic Surgery, Medical University, Lublin, Poland
BACKGROUND: Postoperative bleeding may be complicated by failure to identify the site of bleeding, multiple bleeding points, and persistent hemorrhage despite surgical intervention. CASE: Activated recombinant factor VII was used successfully in a patient with life-threatening postsurgical bleeding after resection of two large extraperitoneal pelvic sarcomas. CONCLUSION: In severe hemorrhage, hemostasis can be achieved with activated recombinant factor VII. (Obstet Gynecol 2003;101:1172–3. © 2003 by The American College of Obstetricians and Gynecologists.)
Mortality can result from postsurgical intraabdominal bleeding if the bleeding site cannot be identified, there are multiple bleeding points, or persistent hemorrhage continues despite surgical intervention.1
CASE A 45-year-old woman with a prior total abdominal hysterectomy with bilateral salpingo-oophorectomy was admitted for surgical excision of a pelvic tumor, confirmed earlier by abdominal computed tomography. She had no personal or family history of bleeding disorder or thromboembolic disease and had a normal platelet count and coagulation screen at the time of admission. At surgery, adhesions between bowel, bladder, and peritoneum were dissected, and two extraperitoneal tumors, one 8 cm in diameter and the other 15 cm and attached to the vaginal wall, were resected. After checking for hemostaAddress reprint requests to: Jarosław Daniłos´, MD, First Department of Gynecology, Medical University, 20-081 Lublin, ul. Staszica 16, Poland; E-mail: [email protected].
1172
sis, one intraabdominal drain was inserted, and the abdomen was closed. Blood loss was calculated as approximately 1000 mL, and the patient received 2 L of crystalloids (normal saline, Ringer lactate) and 1 L of colloids (6% hetastarch, 5% albumin). The postoperative course was complicated by continued intraabdominal bleeding. Because of her critical condition and profound hypovolemic shock despite the transfusion of 2 U of packed red cells, an emergency laparotomy was performed 5 hours after the initial surgery. Multiple bleeding points were noted with massive oozing at the sites of tumor removal. Ligation of visible bleeding vessels was followed by packing with a hemostatic collagen-coated fibrin-fiber mesh, ligation of both internal iliac arteries, and correction of acidosis and hypovolemia. These failed to achieve hemostasis. The patient received 3 L of crystalloids (normal saline, Ringer solution), 1.5 L of colloids (6% hetastarch, 5% albumin), 10 U of packed red cells and 8 U of fresh frozen plasma. Despite a normal coagulation profile (prothrombin time [PT] 14 seconds [normal range 12–16], partial thromboplastin time [PTT] 37 seconds [normal range 23–37], D-dimers 0.2 g/L [normal values less than 0.5], fibrinogen of 273 g/L, platelet count 40 ⫻ 109/L, and hemoglobin level of 128 g/L), the patient continued to bleed profusely. In a desperate attempt to control the bleeding, a single dose of 80 g/kg of activated recombinant factor VII was given by intravenous bolus. Immediately after the injection, a transient tachycardia (from 80 –90 per minute to 110 per minute) and a decrease of systolic arterial pressure (from 135 mm Hg to 90 mm Hg) were observed. After a few minutes, the hemodynamic parameters spontaneously returned to normal (70 per minute and 120 mm Hg, respectively). Ten minutes later, the oozing resolved and bleeding ceased, enabling surgeons to complete the operation. The abdomen was closed, and two drains were left in the pouch of Douglas. No additional blood transfusions were required. Postoperatively, the patient was hypothermic from massive transfusions, and she required artificial ventilation. The following day she was extubated. Her coagulation profile (PT and PTT) and fibrinogen and hemoglobin levels remained normal, whereas her platelet count during 3 postoperative days increased from 30 ⫻ 109/L to 59 ⫻ 109/L and 64 ⫻ 109/L on the day of discharge. The blood loss after relaparotomy did not exceed 100 mL during the 3 days, and no further transfusions were required. There were no thromboembolic complications, and kidney function and urine output
VOL. 101, NO. 6, JUNE 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(03)00349-1
were normal. The patient had an uneventful recovery and was discharged on postoperative day 9. Both tumors removed were classified as low-grade stromal sarcomas resected with negative surgical margins. One month after the surgery the follow-up examination revealed normal levels of antithrombin III (125%), factor VII (100%), factor VIII (90%), and von Willebrand factor (above 70%). COMMENT Activated recombinant factor VII is a protein that plays a crucial role in initiating the process of blood coagulation. Binding the tissue factor at the site of vascular damage, activated recombinant factor VII forms a complex that activates the intracellular mechanism of coagulation. Activated recombinant factor VII was selected in our case to achieve hemostasis because it provides site-specific thrombin generation by enhancing tissue factor–activated recombinant factor VII complex at the site of vessel injury. This complex has now been recognized as the pivotal activator of the coagulation process and results in local thrombin generation. However, the mode of action of activated recombinant factor VII is not completely clear. Some studies suggest tissue factor– dependent mechanisms, whereas others emphasize the role of factors X and IX on the surface of activated platelets.2 Although activated recombinant factor VII was initially developed for the treatment of bleeding associated with inhibitors to factors VIII and IX, more recently it has been used effectively in the management of thrombocytopenia and blood platelet diseases3 and in the treatment of life-threatening intractable surgical hemorrhage.1,4,5 In our case, the postoperative confirmation of normal levels of coagulation factors excludes the possibility of inherited deficiencies. Other causes of severe bleeding include platelet dysfunction and thrombocytopenia.3,5 In our case, thrombocytopenia was observed at relaparotomy when the patient was bleeding and after surgery when hemostatic control was obtained. The activated recombinant factor VII has been used with incidental reports of thromboembolic disorders. Thromboembolic complications (four of 5522 patients) have been reported with the use of activated recombinant factor VII in patients with a history of ischemic heart disease, stroke, or venous thromboembolism.5,6
VOL. 101, NO. 6, JUNE 2003
Al Douri et al5 successfully used a low dose of activated recombinant factor VII (30 g/kg) in the treatment of five patients with uncontrolled bleeding, but Hedner7 suggested that the dose may be too low to induce reliable hemostasis. The dose of activated recombinant factor VII we used (80 g/kg) was close to the dose of 100 g/kg, recommended by Hedner.7 The higher thrombin concentrations induced by the high dose of activated recombinant factor VII seem to be associated with a different type of clot architecture that is stronger and more resistant to degradation by fibrinolytic enzymes.6 We believe that activated recombinant factor VII has the potential to act as a universal hemostatic agent and warrants further evaluation in surgical and gynecologic cases of intractable intraabdominal hemorrhage that fail to respond to conventional therapy. REFERENCES 1. Hedner U. Recombinant activated factor VII as a universal hemostatic agent. Blood Coagul Fibrinolysis 1998;9: S147–52. 2. Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high dose factor VIIa independents of tissue factor. Br J Haematol 1997;99:542–7. 3. Peters M, Heijboer H. Treatment of a patient with BernardSoulier syndrome and recurrent nosebleeds with recombinant factor VIIa. Thromb Haemost 1998;80:352. 4. White B, McHale J, Ravi N, Reynolds J, Stephens R, Moriarty J, et al. Successful use of recombinant FVIIa (NovoSeven威) in the management of intractable post-surgical intra-abdominal hemorrhage. Br J Haematol 1999;107: 677–8. 5. Al Douri M, Shafi T, Al Khudairi D, Al Bokhari E, Black L, Akinwale N, et al. Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven威) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis 2000;11 Suppl 1:S121–7. 6. Martinowitz U, Kenet G, Segal E, Luboshitz J, Lubetsky A, Ingerslev J, et al. Recombinant activated factor VII for adjunctive haemorrhage control in trauma. J Trauma 2001; 51:431–9. 7. Hedner U. NovoSeven威 as a universal haemostatic agent. Blood Coagul Fibrinolysis 2000;11 Suppl 1:S107–11. Received May 10, 2002. Received in revised form February 21, 2003. Accepted February 27, 2003.
Daniłos´ et al
Use of Recombinant Factor VIIa
1173