Iranian Urology and Renal Transplantation Center

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Recombinant Activated Factor VII as a hemostatic agent after Renal Surgery

Dr,Wadah Ceifo,Dr,Addel al-tawhyed,Dr. Ayscha Fakeir
Endourology Urolaparascopy
Moh in KuwaitAl-Jahra HospitalDepartment of Urology and Haematology
Renal surgeryHemostasisRecombinant activated factor VII (rFVIIa)


Recombinant activated factor VII (rFVIIa) is a well known hemostatic agent licensed for control of bleeding in congenital hemophiliacs with inhibitors to coagulation factors VIII or IX, acquired hemophilia, as well as for treatment and prevention of bleeding in patients with congenital factor VII deficiency and Glanzmann’s thrombasthenia. The Surgical literature increasingly reports the off-license administration of rFVIIa to arrest hemorrhage refractory to other interventions. It has been successfully used to control peri operative bleeding in trauma, cardio-vascular as well as ortho-surgical patients. Here we report three cases of previously healthy males, without pre-existing coagulopathy, who had undergone surgical procedures to treat renal stone disease and despite the administration of red blood cell concentrates the patients were unstable and presented with non-surgical bleeding. Intravenous rFVIIa was given at a dose of 60-90 µg/kg. It was observed that in all the three cases, bleeding was stopped after the administration of rFVIIa and no complications were noted in any of the three cases. We conclude that treatment with rFVIIa for patients who underwent renal surgery complicated with non-surgical and life threatening bleeding, can be effective and safe and additional work is needed to extend the approval of this product.

Main Description


Recombinant activated factor VII (rFVIIa) is a vitamin K-dependent glycoprotein consisting of 406 aminoacid residues (MW 50 K Dalton)[1]. It is structurally similar to human plasma-derived factor VIIa. The gene for human factor VII is cloned and expressed in baby hamster kidney cells [2].. How rFVIIa exerts its prohemostatic effects has been the subject of intense investigation, where it has been shown that the effect of rFVIIa can proceed via Tissue Factor (TF)-dependent [3,4] as well as TF-independent [5,7] pathways, and it has been postulated that both mechanisms are operative in vivo[8] . TF-rFVIIa complexes are formed on the TF-bearing cells at the site of vascular injury, where they activate factor X (FX) to produce activated FX (FXa), leading to the conversion of prothrombin to thrombin. The limited amount of thrombin formed locally activates FV, FVIII, and FXI, as well as platelets [9] . At its pharmacologic concentrations, rFVIIa directly binds to the activated platelet surface and directly activates FX independent to TF producing a thrombin burst which also induces efficient hemostasis at the site of vascular injury. The additional direct activation of FIX on activated platelets in the absence of TF, results in improved thrombin generation and may explain the mechanism of rFVIIa action in acquired coagulopathy following trauma, surgery, or other events [10]. The locally enhanced thrombin generation at also leads to inhibition of fibrinolysis via activation of TAFI [11], and enhances platelet adhesion and aggregation at the site of injury 12 which may also account for the drug activity in conditions with platelet defects.

rFVIIa FDA approved indications are the treatment of acute bleeding episodes and prevention of bleeding during surgical interventions in patients with congenital hemophilia A and B with inhibitors, patients with Acquired hemophilia and patients with congenital FVII deficiency [13], while in addition to these indications, in the European Union, the drug is licensed for the treatment of bleeding episodes and prevention of bleeding during surgical or other invasive procedures in patients with Glanzmann’s Thromasthenia with antibodies to GPIIb-IIIa and/or HLA and with past or present refractoriness to platelet transfusion[14].

Over the last few years, it has been used “off-label” in patients with uncontrolled bleeding due to hemostatic abnormality caused by trauma and/or massive blood loss, thrombocytopenia, platelet dysfunction or liver dysfunction[15] and many other situations characterized by critical bleeding.


Case 1

A 43-years-old male patient admitted with evidence of partial left renal staghorn stone for planned left percutaneous nephrolithotripsy (PCNL). Intravenous urogram (IVU) was done which revealed left renal staghorn stone with evidence of hydronephrosis. His other laboratory investigation reports were non-contributory except for presence of red blood cells and few pus cells in urine. Urine culture and sensitivity study was negative. The patient underwent left PCNL (antegrade approach). On 13th day post PCNL, the patient developed bleeding from PCNL site after nephrostomy tube removal. Hematological investigation exhibited markedly reduced hemoglobin of 8.8 gm/dl. The patient underwent (Packed Red Blood Cells (PRBCs)) transfusion (one unit). But still there was bleeding per nephrostomy site and subsequently two units of (PRBCs) were administered. The patient was vitally stable; however hemoglobin was still going down. Follow up ultrasonography was done which revealed bladder hematoma and left upper and lower calyceal stone with hydronephrosis. Foley catheter was inserted and the hematoma was evacuated. Intravenous (IV) rFVIIa (Novo seven) was given once at a dose of 90 µg/kg. The patient responded dramatically and the bleeding was controlled. On the subsequent day, the Hemoglobin was 11.8 gm/dl.  Patient was discharged after he was clinically improved and vitally stable.  He was advised to follow up in Urology OPD after 6 weeks.

Case 2

A 39-years-old male admitted with gross hematuria of one day duration, he gave us a medical history of right open pyelolithotomy and double-J stent (DJ) application, 10 days prior he visited our OPD . Ultrasound was performed which revealed about 4.5cm3 bladder hematoma. His laboratory investigations were non contributory except for reduced hemoglobin of 8.6 gm/dl. Two units of PRBCs were transfused. Cystoscopy and evacuation of the hematoma was carried out and revealed presence of bleeding from the right ureteric orifice  . So DJ was placed and IV rFVIIa was administered in the average dose (60 µg/kg) once. The response to the rFVIIa was dramatic and the bleeding was stopped. The hemoglobin value was raised to 11g/dl on the next day. Follow up ultrasound examination revealed no blood clot in bladder and DJ tip in right renal pelvis. Patient was discharged one week later, after he clinically improved and became vitally stable. After three weeks, right D J was removed.

Case 3

A 51-years-old, male with known history of type 2 diabetes mellitus admitted with evidence of bilateral renal stone for left PCNL. IVU revealed right and left renal stone of about 3cm and 1.1cm respectively, with no evidence of hydronephrosis. Laboratory investigation exhibited hemoglobin of 12.4g/dl. Urine culture and sensitivity was negative and the patient underwent left PCNL (retrograde approach -Lawson).The patient developed left hemothorax and intercostal tube (ICT) was placed. On Post PCNL day 5, follow up CT scan (chest and abdomen) revealed about 8.6 cm3 pleural collection of blood and left lower calyceal stone around 0.9 cm. Hematological examination  showed reduced hemoglobin of 9g/dl. On post PCNL day 7, we observed that ICT was still draining blood and hemoglobin further dropped to 8.5g/dl. Two units of PRBCs were transfused and IV rFVIIa was given in a dose of (60 µg/kg) once. On the next day hemoglobin raised to 10.3g/dl and subsequently improved to reach 11gm/dl on the following day. Then, patient was discharged after 10 days and advised to follow up in urology OPD after 4 weeks. Patient was readmitted after 3 weeks with gross hematuria. Ultrasound revealed about 10.8cm3 bladder hematoma. Complimentary CT scans revealed same bladder hematoma and pleural empyema. The patient underwent open bladder evacuation of hematoma. Laboratory investigation showed hemoglobin of 9g/dl. Two units of PRBCs were given on next day, however the patient was still hematuric and there was no sign of improvement in his hemoglobin. IV rFVIIa was administered subsequently once at a dose of (60 µg/kg) which stopped the internal bleeding. Three days later  his hemoglobin was 10.1 g/dl and  follow up CT scan revealed residual pleural collection with right renal pelvic stone (3cm) and left lower calyceal stone (0.9cm) with no hydronephrosis. The patient was treated conservatively by chest surgeon. Patient was discharged 3 weeks later, after he clinically improved and became vitally stable for planned left DJ removal and right PCNL after 6 weeks.


Retroperitoneal hemorrhage can occur during open renal surgery due to mobilization of the kidney or retraction of great vessels; homeostasis can be achieved with control of the bleeding vessels[16]. Bleeding during percutaneous renal surgery can be limited with a clamped nephrostomy tube or a tamponade balloon. However if bleeding persists, or sudden hemorrhage occurs on removal of nephrostomy tube, angiography and embolization should be performed [17]. Late postoperative hemorrhage (after seven days) is most often caused by arteriovenous fistulas or ruptured pseudoaneurysm. Initial management is with angiography and embolization, however if embolization fails, the next step is partial or total nephrectomy[17].

rFVIIa has been used in numerous types of surgery to control bleeding due to preexisting conditions or to manage sever surgical bleeding. As there is no previous published data regarding the usage of rFVIIa after renal surgery, we describe in this paper our experience related to the use of rFVIIa in 3 patients, without known history of coagulopathy, who encountered a significant blood loss after an operation for renal stone. The clinical characteristics and treatment response of all the 3 cases are shown in table 1. Despite administration of red blood cell concentrate, in the post-operative period, the patients were unstable and presented with non-surgical bleeding.

Mean post-operative bleeding was about 800-1200 ml. Blood products usage and change in coagulation profile before and 24 hours after administration of rFVIIa is shown in Table 2. The number of doses of rFVIIa given was 1 to 2 doses with individual dose of 60-90 µg/kg.  In all cases, the PT, PTT have been shortened markedly, the response to the treatment was rapid ,and bleeding stopped without adverse events related to rFVIIa administration. All patients were discharged in good general condition and were hematologically and vitally stable.  

A surgery study, aimed to assess the efficacy of rFVIIa for securing hemostasis during surgery, was done. This was a multicenter, double-blind, randomised clinical trial that was conducted in the united State of America[18]. Patients with haemophilia A (n=26, including one acquired) or haemophilia B (n=3), undergoing elective surgical procedures (18 minor and 11 major) were randomized to rFVIIa at dose either 35 μg/kg or 90 μg/kg. Intravenous doses were administered immediately prior to incision, intraoperatively as required, and postoperatively every 2 hours for 48 hours then every 2 to 6 hours for next 3 days [18]. Intra-operative hemostasis was achieved in 28/29 (97%) of patients. In 28/29 (97%) patients, surgical blood loss was less than expected or as expected. In the first 48 hours, satisfactory hemostasis was achieved in 26/29 patients included in the study (100% of patients in the 90 μg/kg group)[9]. For the 90 μg/kg group, 83% patients undergoing major surgery and 100% of patients undergoing minor surgery had satisfactory hemostasis at day 5[18]. In patients undergoing major procedures, the 35μg/kg dose was suboptimal, with efficacy rates dropping from 80% at day 1 to 40% at day 5 [18].

Dose limiting toxicities of rFVIIa have not been investigated in clinical trials. Two cases of accidental overdose by bolus administration have occurred in the clinical program, one hemophilia B patient (16 years of age, 68 kg) who received a single dose of 352 µg/kg and the other being a case of hemophilia A patient (2 years of age, 14 kg) who received doses ranging from 246 µg/kg to 986 µg/kg. On five consecutive days there were no reported complications in either case[19]. The recommended dose schedule should not be intentionally increased, even in the case of lack of effect, due to the absence of information on the additional risk that may be incurred. rFVIIa was also evaluated as a mean of controlling perioperative bleeding in 36 patients with normal coagulation systems who were undergoing retropubic prostatectomy in a double-blind, placebo-controlled, randomized trial[19]. Administration of the study drug by intravenous bolus injection significantly reduced perioperative blood loss and transfusion requirements compared with placebo[19].

The half-life of rFVIIa is approximately 2 hours. It is indeed for intravenous bolus administration only. The recommended dose for patients with hemophilia is 90µg/kg administered every two hours until adequate hemostasis is achieved[20]. Once hemostasis has been achieved in severe hemorrhage cases, the interval for maintained doses is 3 to 6 hours. While generally tolerated in clinical studies, a significant adverse effect is the potential for thrombembolism, which has been associated with disseminated intravascular coagulation, crush injury, advanced atherosclerotic disease, and/or septicemia. The interaction between rFVIIa and coagulation factor concentrates has not been adequately evaluated in clinical studies and the concomitant use of activated prothrombin complex concentrated should be avoided[21].

Coagulation parameters don’t necessarily correlate with or predict the effectiveness of rFVIIa therapy, but the treatment with it has been shown to produce the following characteristics:

-        Prothrombin (PT): In patients with hemophilia A/B with inhibitors.  The PT shortend about a 7-second, plateau at a FVII level of 5u/ml[20]. 

-        Activated partial thromboplastin time (aPTT): Clinical improvement was associated with shortening of aPTT of 15-20 seconds[20].

-        FVII clotting activity: Its levels were measured two hours after, rFVIIa administration of 35μg/kg and 90 μg/kg following two days of dosing at two hours interval. Average steady state levels were 11 and 28u/ml respectively[20].

Patients who receive rFVIIa should be monitored if they develop signs or symptoms of activation of the coagulation system or thrombosis[21]. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, the rFVIIa dosage should be reduced or the treatment stopped, depending on the patient’s symptoms.  The treatment with rFVIIa is contraindicated in patients with known history of hyper sensitivity to it or any of its components or to mouse hamster or bovine proteins.

The appropriate duration of post hemostatic dosing has not been studied. For severe bleeds, dosing should continue at 3-6 hour intervals after hemostasis is achieved, to maintain the hemostatic plug[22]. The biological and clinical effects of prolonged elevated levels of Factor VIIa have not been studied, therefore, the duration of post-hemostatic dosing should be minimized, and the patients should be appropriatly monitored.


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2. Lusher J, Ingerslev J, Robert H, Hedner U. Clinical experience with recombinant Factor VIIa. Blood Coagul Fibrinolysis 1998, 9:119-28.

3. Lisman T, Mosnier LO, Lambert T, et al. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood. 2002;99:175-179.

4. van’t Veer C, Mann KG. The regulation of the factor VII-dependent coagulation pathway: rationale for the effectiveness of recombinant factor VIIa in refractory bleeding disorders. Semin Thromb Hemost. 2000;26:367-372.

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6. Hoffman M, Monroe DM, Roberts HR. Human monocytes support factor X activation by factor VIIa, independent of tissue factor: implications for the therapeutic mechanism of high-dose factor VIIa in hemophilia. Blood. 1994;83:38-42.

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8. Lisman T, de Groot PG. Mechanism of action of recombinant factor VIIa. J Thromb Haemost. 2003;1:1138-1139.

9. ten Cate H, Bauer KA, Levi M, et al.The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest. 1993;92:1207-1212.

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11. Lisman T, Mosnier LO, Lambert T, et al. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood. 2002;99:175-179.

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14. _Product_Information/human/000074/WC500030873.pdf - 2011-05-25 –

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16. Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med 2005; 33:883-90

17. Kevin R Loughlin. Complications of urologic surgery and practice; diagnosis, prevention and managment. New York, Informa healthcare, 2007; p 69-72,320-322

18. Shapiro AD, Gilchrist GS, Hoots WK, Copper HA, Gastineau DA. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998; 80:773-8

19. Friederich PW, Henny CP, Masselink EJ et al. Effect of recombinant factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy : a doule-blind placebo-controlled randomized trail. Lancet 2003; 361:201-205

20. Lindley CM, Sawyer WT, Macik BG et al. Pharmacokinetics and pharmacodynamics of recombinant Factor VIIa. Clin Pharmacol Ther.1994; 55: 638-48.

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22. Moscardo F, Perez F, de la Rubia J et al. Successful treatment of severe intra-abdominal bleeding associated with disseminated intravascular coagulation using recombinant activated factor VII. Br J Haematol 2001; 114:174-6



Table2:   Subset of patients who received replacement therapy before and after treatment with recombinant Factor VIIa

              Before rFVIIa                                                                                                           After rFVIIa

Case       PRBC (U)        FFP(U)       Platelets (U)       Hb%       PT      PTT    INR           PRBC (U)       FFP(U)     Platelets (U)     Hb%     PT     PTT     INR

1               3                         0                    0                   8.8       11.6      34.4     0.0913                   0                    0                   0              10.1      10.2     28.7    0.0767

2               2                         0                    0                   9.6       11         35.1     0.0912                   0                    0                   0              10.6      10.7     27.8    0.0765

3a             2                         0                    0                   9.2       11.2      34.3     0.0911                   0                    0                   0              10.1      10.3     27.8    0.0870

3b             2                         0                    0                   9.1       11.7      34.2     0.0913                   0                    0                   0              10.2      10.1     27.7    0.0760

PRBC= packed red blood cells,  FFP= fresh frozen plasma,   3a = first administration of rFVIIa in case 3,  3b= second administration of rFVIIa in case 3      



Table 1 :    Patient characteristics, diagnosis, rFVIIa dose, complications, and deaths

Case      Age/sex       Primary diagnosis                                   Coagulopathy               Dose (µg/kg)              Clinical  efficacy*/complications                Death 

1           43/M           Partial  right stage horn stone                    No                                      90                                                  Yes/no                                  No

2           39/M           Right  renal  pelvic stone                           No                                      60                                                  Yes/no                                   No

3           51/M           Left lower calyceal stone                           No                                      60 (x 2)a                                        Yes/no                                   No


(x 2)a      Multiple doses administered    

       *            Defined as marked reduction or cessation of post-operative hemorrhage


This study revealed that administration of recombinant activated factor VII (rFVIIa) is a promising treatment for patients undergoing renal surgery complicated with non-surgical life-threatening bleeding. It seems to be both effective and safe. Further research is required to extend the approval of this product in urologic procedures while assessing the consequences