Excessive bleeding (>2 L) after cardiac surgery is encountered in 5% to 7% of patients (1), and necessitates reexploration in 3.6%(2) to 4.2%(3) of cases. A variety of hemostatic defects may contribute and are probably induced by cardiopulmonary bypass (CPB), i.e., impaired platelet function, thrombocytopenia, hyperfibrinolysis, heparin effect, protamine excess, and deficiencies of coagulation factors (4,5). Platelet concentrates and plasma products, as well as drugs such as aprotinin and desmopressin, are administered to improve hemostasis. Nevertheless, excessive bleeding persists in some patients.
Recombinant factor VIIa (rFVIIa, NovoSeven®; NovoNordisk, Copenhagen, Denmark) is a potentially effective hemostatic drug. Its beneficial effect was demonstrated in hemophilia patients with inhibitors to factor VIII or IX (6), and it has been suggested in a growing variety of hemostatic disorders such as thrombocytopenia, thrombocytopathia (7), and disorders related to liver disease (8). We describe a patient who experienced intractable bleeding after heart valve repair with successful treatment using rFVIIa.
A 65-yr-old man underwent cardiac surgery because of severe mitral and tricuspid regurgitation. Preoperative liver function tests revealed no abnormalities. Oral anticoagulant therapy (acenocoumarol in a dose adjusted to maintain the international normalized ratio (INR) between 2.5 and 3.5) because of atrial fibrillation was discontinued 3 days before surgery, when perioperative venous thromboprophylaxis by once daily subcutaneously administered low molecular weight heparin (nadroparine 2850 IU anti-Xa) was started. The last dose was administered 12 h before surgery. Neither aspirin nor other platelet-inhibiting drugs were administered before surgery. Tricuspid and mitral valve repair were performed using CPB with moderate hypothermia during a pump run of 140 min. Aprotinin (2 × 106 KIU) was added to the colloid/crystalloid priming solution. Activated clotting time was maintained at >400 s during CPB with an initial dose of 300 IU/kg heparin and a subsequent increment of 100 IU/kg. After weaning from CPB, residual heparin was neutralized by administering 3 mg/kg protamine sulfate, resulting in an activated clotting time of 147 s, which was comparable with the pre-CPB value. An intraaortic balloon pump was inserted, in addition to inotropic support with 15 μg · kg−1 · min−1 dopamine and 5 μg · kg−1 · min−1 enoximone, to enable discontinuation of CPB. The patient received 2 U of red blood cell concentrate (RBC) during surgery. Oozing responded to the administration of 3 U fresh frozen plasma (FFP) and 5 U platelet concentrate (PC). Postoperative blood loss via chest drains approached 750 mL/h and persisted despite the administration of PC and FFP (Fig. 1). A rethoracotomy performed 3 h after surgery provided no evidence of a surgical cause of bleeding. During this procedure the patient received tranexamic acid (2 g) by IV infusion in addition to RBC, PC, and FFP. Blood loss via chest drains was >400 mL/h over the next 18 h, and did not respond to FFP and PC transfusions and an IV bolus of 1 × 106 KIU aprotinin. At a second rethoracotomy, no surgical cause of bleeding could be demonstrated, and hemostasis was not obtained. Overall the patient had received 30 U RBC, 20 U FFP, and 30 U PC (Fig. 1). Coagulation studies at that time revealed a prolonged prothrombin time (PT, 27.2 s) and an activated partial thromboplastin time (APTT, 49.7 s), a decreased fibrinogen plasma level (1.0 g/L) and a decreased platelet count (52 × 109/L) (Fig. 1). Coagulation analysis showed an obviously abnormal recording (Fig. 2A). As a last attempt to stop the life-threatening bleeding, we administered rFVIIa. After a single IV dose of 90 μg/kg rFVIIa, blood loss promptly declined to 350 mL over the next 12 h. Coagulation variables (PT, 12.0 s; APTT, 41.8 s; fibrinogen, 1.5 g/L) and the coagulation analyzer recording improved (Fig. 1, 2B) at 30 min, whereas platelet count decreased (42 × 109/L). Apart from another 2 U FFP, he did not require further transfusion and made a good recovery.
This patient experienced excessive blood loss after heart valve repair that persisted for more than 24 hours and did not respond to massive transfusions. The treatment with acenocoumarol and a small dose of low molecular weight heparin was discontinued 3 days and 12 hours before surgery, respectively, making its contribution to the postoperative bleeding unlikely. Heparin was properly antagonized by protamine at the end of CPB. Neither the remaining CPB-circuit blood nor shed mediastinal blood were retransfused. Although not measured, hyperfibrinolysis was considered to explain the excessive blood loss. For this reason, attempts were made to stop the bleeding by administering tranexamic acid and subsequently aprotinin without success. When there were no options left, rFVIIa was administered to obtain sufficient hemostasis, and bleeding promptly stopped.
Our observation is in agreement with a similar effect of rFVIIa in a few reported patients with uncontrollable and life-threatening bleeding resulting from other conditions (9). The potency of rFVIIa as a hemostatic drug is also supported by our experience in liver transplant patients who received a single dose of rFVIIa before surgery. The latter patients required fewer transfusions of RBC (0–5 U; median, 3 U) as compared to a matched control group (4–40 U; median, 9 U) (8). In cardiac surgery, experience with rFVIIa is limited. We are aware of only one publication in which five patients were successfully treated with rFVIIa (10). In this open pilot study, one 2.5-year-old child undergoing an arterial switch procedure and four adults undergoing valve replacement were treated with rFVIIa because of excessive and uncontrollable bleeding or oozing. Satisfactory hemostasis was reported in all patients with a 30-μg/kg dose of rFVIIa without clinically relevant adverse events. We administered a larger dose (90 μg/kg) of rFVIIa because it was effective and safe in our liver transplant patients.
The exact working mechanism of rFVIIa remains to be established. Activated factor VII (FVIIa) initiates thrombin formation by interacting with tissue factor (11). Normally only trace levels of FVIIa (0.5 μg/L), about 1% of the total amount of FVII, are present. In large doses (80–100 μg/kg) rFVIIa also activates factor X bound to activate platelets in the absence of tissue factor, leading to thrombin formation (9,12). Thrombin is not only responsible for the formation of fibrin but also for stabilization of fibrin by activating factor XIII and for inhibition of fibrin degradation by thrombin-activated fibrinolytic inhibitor. rFVIIa might be useful in all bleeding conditions that result from insufficient thrombin generation, including a deficiency of the clotting factors VII, VIII, or IX and thrombocytopathia or thrombocytopenia (9,13). rFVIIa is not exclusively used as replenishment therapy in FVII-deficient patients, but it is primarily used to generate thrombin at sites where this is needed. As tissue factor or activated platelets are required, it is assumed that rFVIIa will produce a localized effect without systemic activation of coagulation.
In conclusion, this case suggests that a bolus injection of 90 μg/kg recombinant FVIIa may be effective in some instances to treat massive intractable bleeding after cardiac surgery.
1. Despotis GJ, Filos KS, Zoys TN, et al. Factors associated with excessive post operative blood loss and hemostatic transfusion requirements: a multivariate analysis in cardiac surgical patients. Anesth Analg 1996; 82: 13–21.
2. Dacey LJ, Munoz JJ, Baribeau YR, et al. Reexploration for hemorrhage following coronary artery bypass grafting: incidence and risk factors. Arch Surg 1998; 133: 442–7.
3. Moulton MJ, Creswell LL, Mackey ME, et al. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg 1996; 111: 1037–46.
4. Despotis GJ, Goodnough LT. Management approaches to platelet-related microvascular bleeding in cardiothoracic surgery. Ann Thorac Surg 2000; 70: S20–32.
5. Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiol 1999; 91: 1122–51.
6. Lusher J, Ingerslev J, Roberts H, Hedner U. Clinical experience with recombinant factor VIIa. Blood Coagul Fibrinolysis 1998; 9: S119–28.
7. Hedner U. Recombinant activated factor VII as a universal haemostatic agent. Blood Coagul Fibrinolysis 1998; 9: S147–52.
8. Hendriks HGD, Meijer K, de Wolf JTHM, et al. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation, a pilot study. Transplantation 2001; 71: 402–5.
9. Négrier C, Lienhart A. Overall experience with NovoSeven®
. Blood Coagul Fibrinolysis 2000; 11: S19–24.
10. Al Douri M, Shafi T, Al Khudairi D, et al. Effect of the administration of recombinant activated factor VII (rFVIIa; Novo- Seven®
) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrin 2000; 11 (suppl 1): S121–7.
11. Ten Cate H, Bauer K, Levi M. The activation of factor X and prothrombin by recombinant factor VIIa in vivo
is mediated by tissue factor. J Clin Invest 1993; 92: 1207–12.
12. Monroe DM, Hoffmann M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99: 542–7.
13. Poon MC, d’Orion R. Recombinant activated factor VII (Novo- Seven) treatment of platelet-related bleeding disorders. Blood Coalgul Fibrin 2000; 11: S55–S68.