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Ann Thorac Surg 2005;80:66-71
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

Recombinant Factor VIIa in the Treatment of Postoperative Hemorrhage After Cardiac Surgery

Peter Raivio, MDa,*, Raili Suojaranta-Ylinen, MD, PhDb, Anne H. Kuitunen, MD, PhDb

a Department of Cardiothoracic Surgery, Helsinki University Hospital, Helsinki, Finland
b Department of Anesthesia and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland

Accepted for publication February 15, 2005.

* Address reprint requests to Dr Raivio, Department of Cardiothoracic Surgery, Helsinki University Hospital, Haartmaninkatu 4, FIN-00029 HUS, Helsinki, Finland (Email: peter.raivio{at}hus.fi).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
BACKGROUND: A generalized coagulation disorder after cardiac surgery that is associated with massive postoperative hemorrhage is not completely understood. Recombinant factor VIIa (rFVIIa) has emerged as a possible "salvage" medication. Limited experience reported in the literature and fears of possible thromboembolic complications make the use of rFVIIa in the treatment of bleeding after cardiac surgery controversial.

METHODS: We analyzed retrospectively all consecutive cardiac surgical patients who have received rFVIIa in the Helsinki University Hospital in order to evaluate the safety and efficacy of rFVIIa after cardiac surgery in our institution. Altogether, 16 patients were identified from operating room and intensive care unit (ICU) databases. Patient records and operating room and ICU databases were reviewed.

RESULTS: In this series of high risk patients hospital mortality was high (25%). A definite hemostatic effect was seen after rFVIIa administration in all but three patients (82%). Mean amount of bleeding and amount of platelet and fresh frozen plasma transfusions decreased significantly after rFVIIa administration. Four patients had serious postoperative thromboembolic complications.

CONCLUSIONS: Recombinant factor VIIa was effective in restoring hemostasis, but thromboembolic complications occurred after rFVIIa use. They may be related to the underlying pathologies and surgery performed. It is possible, however, that rFVIIa treatment contributed to their occurrence.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Recombinant factor VIIa (rFVIIa, NovoSeven, NovoNordisk, Bagsvaerd, Denmark) was developed for the treatment of bleeding in patients with hemophilia A and B who have inhibitors against factors VIII and IX, respectively. It has been used for this indication since 1988 and the incidence of treatment-related serious adverse events has been low (under 1%). The use of rFVIIa is approved by the United States Food and Drug Administration solely for this indication and all other use is therefore "off label" [1].

However, successful treatment of bleeding in patients with other coagulopathies, such as congenital and acquired FVII deficiency, von Willebrand's disease, thrombocytopenia, and the platelet function defects Glanzmann's thrombasthenia and Bernard-Soulier syndrome, has also been reported [2]. Recombinant factor VIIa has also been used to treat bleeding in patients with apparently normal hemostasis prior to the bleeding episode [3]. The first report of the use of rFVIIa for the successful treatment of a life-threatening traumatic bleeding after a gunshot injury was published in 1999 [4]. After the report of treatment of two cases of massive intraabdominal postoperative hemorrhage with rFVIIa [5] other anecdotal reports of rFVIIa use for intractable postoperative bleeding have been published [2]. In a single small randomized trial with patients undergoing elective retropubic prostatectomy the prophylactic administration of low-dose rFVIIa reduced bleeding and transfusions [6].

A generalized coagulation disorder after cardiac surgery that is associated with massive postoperative hemorrhage is not completely understood. The use of rFVIIa after cardiac surgery has been controversial because there is a theoretical concern that giving rFVIIa after cardiac surgery and cardiopulmonary bypass in a situation of enhanced thrombin generation and tissue factor expression would be a risk for thrombotic complications [7]. However, rFVIIa has emerged as a possible "salvage" medication to treat intractable postoperative bleeding. The experience reported in the literature is based on a few case reports [8–14] and two small case series in pediatric cardiac surgical patients [15, 16] and two case series in adult cardiac surgical patients, the other of which is in abstract form [17, 18]. Thromboembolic complications have not been reported in any of these reports. However, a single fatal thrombosis after prothrombin complex concentrate and rFVIIa administration to a patient on extracorporeal membrane oxygenation with excessive bleeding after redo lung transplantation has been reported [19]. Because of the limited experience and controversy related to the use of rFVIIa in the treatment of bleeding after cardiac surgery, this study was undertaken to analyze all consecutive cardiac surgical patients who have received rFVIIa in our institution and to evaluate the safety and efficacy of rFVIIa after cardiac surgery in our institution.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
From the operating room and ICU databases we identified retrospectively all consecutive cardiac surgical patients in the Department of Cardiothoracic Surgery of the Helsinki University Hospital, Helsinki, Finland who had received rFVIIa intraoperatively or postoperatively for intractable bleeding. Altogether, 16 such patients who were operated between May 31, 2002 and October 5, 2004 were identified from a total of approximately 2,800 cardiac surgery cases operated during the same time period. Patient records and operating room and ICU databases were reviewed to assess the efficacy and safety of rFVIIa treatment. To assess efficacy hourly bleeding volumes and data of blood products and other hemostatic agents administered 6 hours prior to and 6 hours after rFVIIa administration were registered. The clinical outcome and any reported thromboembolic complications were registered. The study was approved by the Institutional Review Board.

The operative risk was evaluated with the EuroSCORE scoring system, which takes into account several patient, cardiac, and operation related preoperative risk factors such as age, sex, the presence of pulmonary, neurologic, and renal comorbidity, the presence of extracardiac arteriopathy, previous cardiac surgery, active endocarditis, unstable angina, left ventricle dysfunction, recent myocardial infarct, pulmonary hypertension, urgency, and the type of surgery performed [20].

Patient care followed institutional guidelines during the study period. Cardiopulmonary bypass (CPB) was performed using a noncoated circuit and a membrane oxygenator. Heparin (5,000 IU) was added to the CPB priming solution and an initial intravenous dose of 300 IU/ kg of heparin was administered. Heparinization was monitored with kaolin-activated clotting time (ACT) measurements every 30 minutes and ACT was maintained above 480 seconds with additional doses of 5,000 IU of heparin intravenously if needed. Heparinization was neutralized with 1 mg of protamine sulphate per 100 IU of the heparin loading dose. During cardiopulmonary bypass hematocrit was maintained above 0.25. After CPB the cutoff values for postoperative packed red blood cell transfusions were hemoglobin under 80 g/L or hematocrit under 0.30. In case of increased intraoperative or postoperative bleeding (chest tube bleeding > 200 mL/hour) plasma-activated partial thromboplastin time, plasma thromboplastin time, and platelet count were measured. If plasma thromboplastin time was prolonged more than 1.5 fold from the preoperative value or plasma-activated partial thromboplastin time was over 50 seconds, 15 mL/kg of fresh frozen plasma was administered. If the platelet count was under 100 x 109/L, one unit of platelet concentrate/10 kg of weight was administered. Prothrombin complex concentrate, human factor VIII-von Willebrand factor concentrate, human fibrinogen concentrate, and factor XIII concentrate could be used as part of the component therapy administered according to the anesthesiologist's discretion. The use of rFVIIa was reserved for life-threatening bleeding with no identifiable surgical source after adequate, conventional blood component therapy as suggested in the literature [3]. During the study period there were no institutional guidelines for the dosage of rFVIIa.

The data were analyzed with the SPSS for Windows release 11.5.1 software (SPSS Inc, Chicago, IL). Normality of distributions was tested with the Kolmogorov-Smirnov test. The Mann-Whitney U test was used when comparing bleeding and transfusions before and after rFVIIa administration. The p values of 0.05 or less were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Demographic and surgical data of the patients are summarized in Tables 1 and 2. The mean age of the patients was 58 years (range, 27–77 years). None of the patients had a known coagulation defect preoperatively. The majority of cases were emergency operations (10 of 16). The patients operated were high risk patients (mean EuroSCORE 9.3, and mean logistic EuroSCORE expected risk of mortality 19.8%) and the surgery was complex in most of the cases. Six operations involved the use of deep hypothermic circulatory arrest and there were four redo cases. Most commonly a procedure involving either the ascending aorta, aortic arch, or descending thoracic aorta was performed (11/16). Either a dissection or acute rupture of the aorta was the indication for operation in nearly half of the cases (7/16). Reexploration for bleeding was performed in four cases. The clinical results are summarized in Table 3. Hospital mortality of the patients in this series was 25% (4/16). Mean intensive care unit stay was 21 days (range, 1–167 days). Several major complications that are not related to the use of rFVIIa occurred (Table 3).


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  		Table 1. Patient Demographics
 

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  		Table 3. Clinical Outcome
 
The mean dose of rFVIIa used was 65 µg/kg (range, 24–192 µg/kg) (Table 3). A definite hemostatic effect according to either the surgeon's or anesthesiologist's evaluation was seen soon after rFVIIa administration in all but three patients (82%). All of the patients who did not respond to treatment died of multiorgan failure subsequently. The postmortem examinations did not reveal any surgical source of bleeding in any of these three patients. In general rFVIIa administration resulted in a significant decrease in the mean amount of bleeding, when cumulative bleeding in all patients during the 6 hours prior to rFVIIa administration was compared to the cumulative bleeding during the 6 hours after rFVIIa administration (Table 4). The amount of platelet and fresh frozen plasma (FFP) transfusions decreased significantly after rFVIIa administration. There was no significant change in the amount of packed red blood cell (RBC) transfusions. Almost two thirds (10/16) of the patients had received aprotinin and almost a third (five patients) had received tranexamic acid during the 6 hours prior to rFVIIa administration. Only two patients had received no antifibrinolytic medication (Table 2). Five patients had received either human factor VIII-von Willebrand factor concentrate or human fibrinogen or both prior to rFVIIa administration. Only one patient, patient No. 15, who did not respond to rFVIIa treatment, had received human factor VIII-von Willebrand factor concentrate, human fibrinogen, antithrombin III, and prothrombin complex concentrate after rFVIIa administration in a desperate and unsuccessful attempt to restore hemostasis.


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  		Table 4. Bleeding and Transfusions Before and After rFVIIa Administration
 

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  		Table 2. Surgical Data
 
Four patients (25%) had severe postoperative thromboembolic or thrombotic complications (Table 3). Patient No. 5 was operated for acute rupture of an aneurysm of the descending thoracic aorta. He was also diagnosed with an unruptured infrarenal abdominal aortic aneurysm. The aneurysm of the descending thoracic aorta was reconstructed with a Dacron graft from a left thoracotomy under femoro-femoral cardiopulmonary bypass. Because of diffuse bleeding in the operative field, the patient received transfusions of packed RBCs, platelets, FFP, and 30 µg/ kg of rFVIIa. Hemostasis was achieved. Soon thereafter the left femoral artery became pulseless because of a thrombosis of the left iliac artery. A Y-graft reconstruction of the abdominal aortic aneurysm was performed with an aortofemoral anastomosis on the left side and an aortoiliac anastomosis to the left external iliac artery on the right side. Despite adequate heparinization thrombosis of the right graft limb was observed during suturing of the anastomosis. It was treated with thrombectomy of the graft limb. The postoperative course was complicated by paraplegia and acute renal failure that required hemodialysis.

Patient No. 7 was operated for acute type A aortic dissection. The ascending aorta was reconstructed with a Dacron graft leaving the aortic valve intact. The distal anastomosis was sutured under deep hypothermic circulatory arrest. There was increased bleeding into the chest tubes postoperatively and the patient received transfusions of packed RBCs, platelets, and FFP. The bleeding continued and the patient was given 87 µg/ kg of rFVIIa, which resulted in immediate hemostasis. The patient recovered otherwise, but was left with a left-sided paralysis and computed tomography scan of the brain showed multiple embolic infarctions bilaterally.

Patient No. 8 was operated for acute type A aortic dissection. The ascending aorta was reconstructed with a composite aortic mechanical valved graft. The distal anastomosis was sutured under deep hypothermic circulatory arrest. Diffuse bleeding was controlled with transfusions of packed RBCs, platelets, and FFP, and finally 24 µg/ kg of rFVIIa. Postoperatively the patient was diagnosed with acute ischemia of the right lower limb. Computed tomography angiography showed thrombosis of the right iliac artery and a left to right femoro-femoral cross-over was performed. The postoperative course was complicated by transient renal failure, critical illness polyneuropathy, and respiratory insufficiency, but after prolonged intensive care and rehabilitation the patient recovered and was discharged from the hospital.

Patient No. 12 received an orthotopic heart transplantation that was complicated by massive perioperative bleeding due to preoperative right side heart failure and liver failure. Bleeding stopped after transfusions of packed red cells, platelets, FFP, 3 g of human fibrinogen (Hemocomplettan®, Aventis Behring GmbH, Marburg, Germany), 1,000 IU of human factor VIII concentrate-von Willebrand factor concentrate (Haemate®, Aventis Behring GmbH, Marburg, Germany), and finally 43 µg/kg of rFVIIa. The immediate postoperative stage was stable until sudden acute graft dysfunction that led to resuscitation and emergency reinstitution of cardiopulmonary bypass occurred. The patient died despite circulatory support with bilateral centrifugal pumps. Histology of the transplanted heart showed multiple acute myocardial infarctions in multiple areas of the left ventricle.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
In our series rFVIIa was effective in restoring hemostasis. However, several thromboembolic complications occurred after rFVIIa use. They are known complications of, especially, aortic and valve surgery and may be related to the underlying pathologies and the surgery performed. It is possible, however, that rFVIIa treatment contributed to their occurrence. Particularly, the case histories of patients Nos. 5 and 12 raise questions of the role of rFVIIa.

Predisposing factors, such as cardiovascular disease, atherosclerosis, hypertension, diabetes, or advanced age have been present in most of the patients who have suffered from thromboembolic complications after rFVIIa treatment [1, 2]. These risk factors are invariably present in cardiac surgical patients. Cardiopulmonary bypass causes activation of the hemostatic system and increased thrombin generation [21] and rFVIIa further enhances the rate of thrombin formation on activated platelets [2]. Tissue factor is expressed on atherosclerotic plaques and circulating tissue factor is present in patients with acute coronary syndromes [22]. Tissue factor is also expressed in ischemic myocardium [23]. Because, theoretically, rFVIIa acts at sites where tissue factor is exposed to the circulation, the administration of exogenous rFVIIa during tissue factor expression could be the cause of thrombosis.

Recombinant factor VIIa has a possible role in the treatment of otherwise intractable life-threatening bleeding after cardiac surgery, but randomized, controlled trials are required to prove its safety and efficacy. A prospective, randomized, placebo-controlled trial in adult cardiac surgical patients with a high risk of serious hemorrhage has been reported to being ongoing [24]. Based on our experience we recommend caution in the use of rFVIIa after cardiac surgery before the results of randomized trials are published. Furthermore, institutional guidelines to direct the use of rFVIIa after cardiac surgery should be established.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Roberts HR, Monroe DM, Hoffman M. Safety profile of recombinant factor VIIa Semin Hematol 2004;41(suppl 1):101-108.[Medline]
  2. Hedner U, Erhardtson E. Potential role for rFVIIa in transfusion medicine Transfusion 2002;42:114-124.[Medline]
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  6. Friederich PW, Henny CP, Messelink EJ, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomya double-blind placebo-controlled randomised trial. Lancet 2003;361:201-205.[Medline]
  7. Dietrich W, Spannagl M. Caveat against the use of recombinant factor VIIa for intractable bleeding in cardiac surgery(Letter) Anesth Analg 2002;94:1369-1370.[Free Full Text]
  8. Hendriks HG, van der Maaten JM, de Wolf J, Waterbolk TW, Slooff MJ, van der Meer J. An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII Anesth Analg 2001;93:287-289.[Abstract/Free Full Text]
  9. Stratmann G, Russell IA, Merrick SH. Use of recombinant factor VIIa as a rescue treatment for intractable bleeding following repeat aortic arch repair Ann Thorac Surg 2003;76:2094-2097.[Abstract/Free Full Text]
  10. Naik VN, Mazer CD, Latter DA, Teitel JM, Hare GM. Successful treatment using recombinant factor VIIa for severe bleeding post cardiopulmonary bypass Can J Anesth 2003;50:599-602.[Medline]
  11. von Heymann C, Hotz H, Konertz W, Kox WJ, Spies C. Successful treatment of refractory bleeding with recombinant factor VIIa after redo coronary artery bypass graft surgery J Cardiothorac Vasc Anesth 2002;16:615-616.[Medline]
  12. Tobias JD, Berkenbosch JW, Russo P. Recombinant factor VIIa to treat bleeding in an infant Pediatr Crit Care Med 2003;4:49-51.[Medline]
  13. McIlroy DR, Silvers AJ. Recombinant factor VIIa for life-threatening bleeding in high-risk cardiac surgery despite full-dose aprotinin Anesth Analg 2004;99:27-30.[Abstract/Free Full Text]
  14. Tanaka KA, Waly AA, Cooper WA, Levy JH. Treatment of excessive bleeding in Jehovah's witness patients after cardiac surgery with recombinant factor VIIa (NovoSeven®) Anesthesiology 2003;98:1513-1515.[Medline]
  15. Pychynska-Pokorska M, Moll JJ, Krajewski W, Jarosik P. The use of recombinant factor VIIa in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass Pediatr Crit Care Med 2004;5:246-250.[Medline]
  16. Egan JR, Lammi A, Schell DN. Recombinant activated factor VII in paediatric cardiac surgery Intensive Care Med 2004;30:682-685.[Medline]
  17. Al Douri M, Shafi T, Al Khudairi D, et al. Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery Blood Coagul Fibrinolysis 2000;11(suppl 1):S121-S127.
  18. Gill R, Herbertson M, Diprose P. New alternatives for control of severe cardiac surgical bleeding(Abstract) Semin Hematol 2004;41(suppl 1):174.
  19. Bui JD, Despotis GD, Trulock EP, Patterson GA, Goodnough LT. Fatal thrombosis after administration of activated prothrombin complex concentrates in a patient supported by extracorporeal membrane oxygenation who had received activated recombinant factor VII J Thorac Cardiovasc Surg 2002;124:852-854.[Free Full Text]
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