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Ann Thorac Surg 2003;76:2094-2097
© 2003 The Society of Thoracic Surgeons

Case report

Use of recombinant factor VIIa as a rescue treatment for intractable bleeding following repeat aortic arch repair

Greg Stratmann, MD, PhDa*, Isobel A. Russell, MD, PhDb, Scott H. Merrick, MDa

a Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA
b Department of Surgery, University of California at San Francisco, San Francisco, California, USA

Accepted for publication April 9, 2003.

* Address reprint requests to Dr Stratmann, Department of Anesthesia and Perioperative Care, Mailbox 0464, Room U 368 P, Moffitt Hospital, 513 Parnassus Ave., San Francisco, CA 94143, USA
e-mail: gstratmann{at}anesthesia.ucsf.edu


   Abstract
Top
 Abstract
Introduction
 Comment
 References
 
Hemorrhage, refractory to aggressive conventional therapy, at a rate of 16 L/hr following separation from cardiopulmonary bypass for aortic arch repair, was controlled with a dose of 90 µg/kg of recombinant factor VIIa, repeated once after 2 hours.


   Introduction
Top
 Abstract
 Introduction
Comment
 References
 
Recombinant factor VIIa (rFVIIa) is a synthetic hemostatic drug that is approved for use in hemophiliacs with antibodies to factor VIII or factor IX. Recent reports of the use of rFVIIa in cases of severe bleeding after trauma and following cardiac surgery [1–6] have suggested its efficacy in patients without preexisting hemorrhagic diatheses and illustrated its potential as a promising new clinical anticoagulant. We present the first case of successful use of rFVIIa in the treatment of life threatening refractory hemorrhage at a rate of 16 L/h after prolonged cardiopulmonary bypass (CPB) and deep hypothermic circulatory rrest (DHCA).

The major theoretical concern regarding the use of this drug, particularly after CPB, is the occurrence of thrombotic complications. RFVIIa requires tissue factor (TF) to develop its procoagulant activity and CPB induces a surge of blood-borne tissue factor (TF) on blood cells [7, 8]. CPB also employs reinfusion of shed blood which has high quantities of TF [9]. Interestingly, complications after the use of rFVIIa following CPB have not been reported [1, 2, 4, 6]. Possible explanations for this fact are proposed.

A 60-year-old male, who had undergone a Bentall aortic root replacement 19 years previously using a porcine-valved conduit for acute type A aortic dissection, was now scheduled for elective aortic valve replacement for severe prosthetic valve insufficiency and aneurysmal enlargement of the remaining ascending aorta. His past medical history was remarkable only for hypertension, which was well controlled by metoprolol and enalapril. The patient was recovering from a lobar pneumonia for which he was taking ciprofloxacin by mouth. He was not receiving any anticoagulants.

Induction of general anesthesia was accomplished with intravenous (IV) midazolam (0.1 mg/kg) and fentanyl (10 µg/kg). After paralysis with IV pancuronium (0.1 mg/kg), endotracheal intubation, and institution of mechanical ventilation, venous and arterial cannulas were placed. Aprotinin, 2 x 106 kallikrein inhibitory units (KIU), was infused over 30 minutes, followed by 5 x 105 KIU/h for 6 hours. Bleeding from an accidental aortotomy upon sternotomy required rapid transfusion of 8 U of packed red blood cells (PRBC) and reinfusion of 550 ml of shed blood while cardiopulmonary bypass (CPB) was being instituted emergently. Sufficient anticoagulation with heparin 400 iU/kg was demonstrated by an activated clotting time of more than 600 seconds and a heparin concentration of 4.5 mg/kg (Hepcon HMS plus; Medtronic, Minneapolis, MN).

The patient's core temperature was reduced to 20°C. A vertical laceration was found in the native, dissected ascending aorta. The previous Bentall aortic root replacement covered only a 3-cm segment of the proximal ascending aorta. The remainder of the aneurysmal ascending aorta and proximal aortic arch was mobilized during the cooling period. At onset of ventricular fibrillation, an aortic cross-clamp was applied. The Dacron valved conduit was then opened and cardioplegia administered directly into the coronary ostia. A degenerated porcine valve was then removed from the base of the Dacron conduit and a St. Jude aortic prosthesis reinserted. At this point, circulation was arrested and the aortic cross clamp was removed. The dissected ascending aorta and proximal arch were removed and the remaining dissection flap was fenestrated. A new Dacron graft was interposed between the arch and original proximal graft. No bioglue or Teflon felt was used, as the residual distal aorta and proximal aortic arch were very fibrotic from chronic dissection. Total circulatory arrest time was 20 minutes. Separation from CPB was complicated by profuse bleeding from the multiple suture sites, which was difficult to control. It was necessary to reinitiate cardiopulmonary bypass three times in order to facilitate exposure of bleeding sites on the pulmonary artery and posterior aortic suture line. Final separation from CPB (total CPB time of almost 6 hours) was accompanied by diffuse bleeding and coagulopathy (Table 1). Inotropic/vasoactive support with dopamine (5 µg · kg-1 · min-1), norepinephrine (0.05 µg · kg-1 · min-1) and phenylephrine at varying doses and vigorous replacement of rapid blood loss prevented the imminent cardiovascular collapse. After protamine was administered, blood loss persisted at a rate of 270 mL/min despite complete reversal of heparin, as evident by a heparin concentration of zero mg/kg (Hepcon HMS plus, Medtronic). Over the next 90 minutes, 25 U of PRBC (6,250 mL), 22 U of fresh frozen plasma (FFP) (4,400 mL), 10 six-packs of platelets (Plt) (2,000 mL), and 8 ten-packs of cryoprecipitate (800 mL), in addition to 11,000 mL of shed mediastinal blood, were administered with no apparent therapeutic effect. We surmised that the replacement of the patient's blood volume 4 to 6 times likely reduced the concentrations of some critical coagulation factors including activated factor VII to levels too low to support thrombin formation.


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  		Table 1. Coagulation Test Results Before and After Administration of rFVIIa

 
It was then decided to administer a dose of 90 µg/kg of recombinant factor VIIa (rFVIIa) intravenously. Three minutes later the bleeding had slowed down, so that rapid resuscitation with blood products was no longer necessary. The patient received no more blood products except for six units of platelet concentrate. The timeline of transfusion events is shown in Figure 1 . Table 1 illustrates the rapid improvement of coagulation test results from 30 minutes before administration of rFVIIa to 10 minutes after. An empiric second dose of rFVIIa was administered 2 hours after the initial dose had been given. This had been suggested in previous reports [3, 6] and is in keeping with the plasma halflife of rFVIIa of 2.3 to 2.9 hours [10]. Hemostasis was permanent. The patient recovered slowly, was extubated on the third postoperative day, and left the hospital six days later without any symptoms or signs of systemic thromboses.



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  		Fig 1. Transfusion timeline: Transfusion events during aortic arch replacement. The initial transfusion event occurred during an episode of torrential bleeding from the aorta during thoracotomy. The following events occurred during initial attempts of separation from CPB and the subsequent CPB period. The final event occurred after administration of protamine. Importantly, although not illustrated in this figure, the infusion of 11,000 mL of "cell saver blood" over the 90 minutes following separation from CPB contributed significantly to meeting this patient's transfusion requirements. (CPB = cardiopulmonary bypass; cryo = cryoprecipitate; ffp= fresh frozen plasma; plt= platelets; prbc= packed red blood cells.)

 

   Comment
Top
 Abstract
 Introduction
 Comment
References
 
Diffuse bleeding and coagulopathy following long or repeated periods of cardiopulmonary bypass can be a difficult and morbid complication [11]. DHCA requires long periods of CPB because cooling to 20°C and subsequent rewarming is required. This can add more than one hour to the CPB period. We present a report of successful treatment of bleeding following a procedure requiring DHCA in adults. Instantaneous hemostasis following administration of rFVIIa in a patient bleeding this rapidly has not been reported in a patient undergoing a surgical procedure. Only one case with a greater rate of blood loss (18 L/h) than that reported herein has been successfully treated with rFVIIa. The patient was a soldier who had been shot in the lower abdomen [5].

Although rFVIIa is licensed only for the treatment of hemophiliacs with inhibitors [3], it has been documented in case reports to control refractory hemorrhage after various types of surgery, including cardiac surgery and transplant surgery [3]. A powerful feature of rFVIIa is the ability to promote localized hemostasis without systemic thromboses [3]. This is because TF [3] or activated platelets [12], which are usually only present at sites of tissue injury, are required for rFVIIa to develop its procoagulant activity.

After CPB, however, TF and activated platelets may be present systemically, raising concerns of systemic thrombosis or disseminated intravascular coagulation (DIC) when rFVIIa is administered in this setting. Interestingly, in the eight reported cases of rFVIIa use after CPB (Table 2), no thrombotic complication or DIC occurred [1, 2, 4, 6].

Indeed, blood cells like neutrophils and monocytes have the ability to express TF [8], which is augmented by CPB [7]. Most of the blood-borne TF is encrypted, that is, bound to FVII and tissue factor pathway inhibitor (TFPI). TFPI is a strong inhibitor of the enzymatic activity of the TF-FVIIa complex and at normal plasma concentrations probably inhibits any blood borne TF-FVIIa activity [8]. The fact that localized hemostasis is nonetheless possible is presumably due to the fact that TF is present at injury sites to a much greater degree than in blood, overwhelming the concentrations of TFPI and allowing coagulation to occur locally [8]. After administration of heparin and again during CPB, the plasma concentration of TFPI increases significantly above baseline, continues to rise as a function of CPB time, and then, although quickly diminishing in response to administration of protamine, remains elevated above baseline [13, 14]. It therefore seems reasonable to speculate that even if CPB had resulted in additional blood borne TF, more TFPI would have been available for its neutralization.

CPB induces a hyperfibrinolytic state. Plasmin cleaves TFPI at 5 different sites, leading to reduced anticoagulant activity of TFPI in vivo [15]. This could potentially result in intravascular coagulation when rFVIIa is administered after CPB because the amount of naturally occurring TFPI may no longer be sufficient to antagonize the amount of blood borne TF. However, this patient had received aprotinin, which prevents the cleavage of TFPI by plasmin [15], and thus may have introduced a margin of safety. Interestingly, in most cases in which rFVIIa was used after CPB, antifibrinolytics were used concomitantly [1, 2, 4, 6].

Endothelial cells express TF in response to activated platelets [16] and cytokines [17]. Cytokine release and platelet activation do occur in response to CPB [18] but it is not known whether endothelial cells express TF after CPB in humans. Hypothermia, as used during this patient's DHCA–CPB period, has been shown to reversibly inhibit the expression of TF on endothelial cells [19] and help prevent thrombotic complications when rFVIIa is used.

Another source of TF is reinfused, shed blood ("cell saver blood"). During the final episode of massive hemorrhage, the majority of this patient's transfusion requirements were met by reinfusion of unwashed, shed blood. There is evidence to suggest that, although the TF antigen concentration is very high in unwashed, shed blood, it is devoid of procoagulant activity, possibly because of inactivation by TFPI or because of proteolysis of TF [9]. Likewise, platelet activation does not occur when blood is collected by an autotransfusion device, and although platelet function after bypass is impaired, the autotransfusion device does not add further to this impairment [20].

In summary, a set of circumstances exists following CPB, which may have protected patients receiving rFVIIa from thrombotic complications.

The more liberal use of rFVIIa in cardiac surgical patients is limited by at least 4 shortcomings. (1) No randomized controlled trial has proven its efficacy and safety in cardiac surgical patients. (2) No dose finding study has been performed in this patient population. (3) The threshold for its administration is not defined. (4) The drug is prohibitively expensive. The acquisition cost of a 4.8-mg vial of rFVIIa is $4,080.

It is, therefore, our opinion that rFVIIa should currently only be used if all reasonable surgical attempts have been made to control bleeding and if a coagulopathy is uncorrected despite aggressive administration of standard blood products.

However, despite all concerns, the lifesaving potential of rFVIIa must not be underestimated.


   References
Top
 Abstract
 Introduction
 Comment
 References
 

  1. 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):S121-127.
  2. Hendriks H.G., van der Maaten J.M., de Wolf J., et al. 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]
  3. Hedner U., Erhardtsen E. Potential role for rFVIIa in transfusion medicine. Transfusion 2002;42:114-124.[Medline]
  4. Sheth S., Dimichele D., Lee M., et al. Heart transplant in a factor VIII-deficient patient with a high-titre inhibitor: perioperative management using high-dose continuous infusion factor VIII and recombinant factor VIIa. Haemophilia 2001;7:227-232.[Medline]
  5. Kenet G., Walden R., Eldad A., Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 1999;354:1879.[Medline]
  6. Von Heymann C., Hotz H., Konertz W., et al. 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]
  7. Ernofsson M., Thelin S., Siegbahn A. Monocyte tissue factor expression, cell activation, and thrombin formation during cardiopulmonary bypass: a clinical study. J Thorac Cardiovasc Surg 1997;113:576-584.[Abstract/Free Full Text]
  8. Giesen P.L., Rauch U., Bohrmann B., et al. Blood-borne tissue factor. Another view of thrombosis. Proc Natl Acad Sci U S A 1999;96:2311-2315.[Abstract/Free Full Text]
  9. Krohn C.D., Reikeras O., Bjornsen S., Brosstad F. Tissue factor antigen and activity in serum of postoperatively shed blood used for autologous transfusion. Blood Coagul Fibrinolysis 2000;11:219-223.[Medline]
  10. Lindley C.M., Sawyer W.T., Macik B.G., et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther 1994;55:638-648.[Medline]
  11. Levy J.H. Pharmacologic preservation of the hemostatic system during cardiac surgery. Ann Thorac Surg 2001;72:S1814-1820.[Abstract/Free Full Text]
  12. Monroe D.M., Hoffman M., Oliver J.A., Roberts H.R. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997;99:542-547.[Medline]
  13. Cardigan R.A., Hamilton-Davies C., McDonald S., et al. Haemostatic changes in the pulmonary blood during cardiopulmonary bypass. Blood Coagul Fibrinolysis 1996;7:567-577.[Medline]
  14. Sun L.B., Utoh J., Kunitomo R., et al. Altered plasma antigen levels of tissue factor pathway inhibitor during open-heart surgery. Surg Today 2000;30:122-126.[Medline]
  15. Li A., Wun T.C. Proteolysis of tissue factor pathway inhibitor (TFPI) by plasmin: effect on TFPI activity. Thromb Haemost 1998;80:423-427.[Medline]
  16. Slupsky J.R., Kalbas M., Willuweit A., et al. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost 1998;80:1008-1014.[Medline]
  17. Lockwood C.J., Krikun G., Koo A.B., et al. Differential effects of thrombin and hypoxia on endometrial stromal and glandular epithelial cell vascular endothelial growth factor expression. J Clin Endocrinol Metab 2002;87:4280-4286.[Abstract/Free Full Text]
  18. Wan S., LeClerc J.L., Vincent J.L. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest 1997;112:676-692.[Abstract/Free Full Text]
  19. Johnson M., Haddix T., Pohlman T., Verrier E.D. Hypothermia reversibly inhibits endothelial cell expression of E-selectin and tissue factor. J Card Surg 1995;10:428-435.[Medline]
  20. Ekback G., Edlund B., Smolowicz A., et al. The effects of platelet apheresis in total hip replacement surgery on platelet activation. Acta Anaesthesiol Scand 2002;46:68-73.[Medline]



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