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CARDIOVASCULAR ANESTHESIA

An Effective Treatment of Severe Intractable Bleeding After Valve Repair by One Single Dose of Activated Recombinant Factor VII

Herman G. D. Hendriks, MD^*, Joost M. A. A. van der Maaten, MD^*, Joost de Wolf, MD, PhD, Tjalling W. Waterbolk, MD, Maarten J. H. Slooff, MD, PhD, and Jan van der Meer, MD, PhD^||||

Departments of *Anesthesiology, Hematology, Thoracic Surgery, Hepatobiliary Surgery and Liver Transplantation, and the ||||Division of Hemostasis, Thrombosis and Rheology, University Hospital, Groningen, The Netherlands

Address correspondence and reprint requests to H. G. D. Hendriks, MD, Groningen University Hospital, Department of Anesthesiology, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands. Address e-mail to h.g.d.hendriks{at}anest.azg.nl

	Abstract

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IMPLICATIONS: The successful treatment with recombinant factor VIIa of a patient experiencing intractable bleeding after cardiac surgery is described.

	Introduction

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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.

	Case Report

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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 x 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 x 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 x 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 x 10⁹/L). Apart from another 2 U FFP, he did not require further transfusion and made a good recovery.

View larger version (29K): [in this window] [in a new window]   Figure 1. Transfusion requirements and cumulative blood loss (L) during and after cardiac surgery. After administration of recombinant factor VIIa infusion, bleeding stopped immediately. Normal values are shown between brackets.

View larger version (38K): [in this window] [in a new window]   Figure 2. Coagulation analysis monitoring 30 min before (A) and 30 min after (B) a bolus injection of 90 µg/kg rFVIIa with corresponding clotting variables and platelet count. The reaction time (r) is measured from the start of the tracing to the point where the curve is 1 mm wide. The coagulation time (k) is the distance from the 1 mm wide point to the 20 mm wide point. The angle (0) is formed between the midline of the tracing and the line tangential to the curve. The r, k, and 0 angle values shortened after administration of rFVIIa, indicating a faster fibrin formation (r) and faster clot formation (k and 0 angle). The maximum amplitude (MA) normalized, representing a normal clot strength. Normal values are shown between brackets.

	Discussion

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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.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999