In 2003, a seventy-six-year-old man had major bleeding after a
primary right total hip replacement that had been done without any form of
factor-VII support. The surgery was complicated by a hematoma requiring
evacuation and prolonged antibiotic treatment for a wound infection.
Additional medical problems included chronic obstructive pulmonary disease,
coronary artery disease, hypertension, chronic anemia, and atrial
fibrillation.
Eight days prior to transfer to Barnes-Jewish Hospital, the patient was
admitted to the referring hospital with hip pain, changes in mental status,
and fever. Enterococcus faecalis grew on culture of fluid obtained by
arthrocentesis of the right hip, confirming a deep hip infection. Following
clinical improvement with antibiotic therapy, correction of the patient's
inherited coagulopathy was attempted. Baseline coagulation tests showed
factor-VII activity of 4% (normal range, 60% to 160%), a prothrombin time of
27.2 sec (normal range, 10 to 13 sec), and an international normalized ratio
of 4.1 (normal range, 0.9 to 1.2). Following the administration of 10 mg of
subcutaneous vitamin K and 8 U of fresh-frozen plasma over a twenty-four-hour
period, the international normalized ratio only partially corrected from 3.9
to 2.0, necessitating transfer to our tertiary hospital.
On admission, coagulation testing confirmed the diagnosis of inherited
factor-VII deficiency, and hematology consultants recommended perioperative
correction of the factor-VII deficiency with recombinant factor VIIa to reduce
the risk of bleeding complications.
As a result of the patient's multiple medical problems, factor-VII
deficiency, and Enterococcus infection, we recommended resection arthroplasty
without reimplantation as definitive treatment. Immediately before the
surgery, the patient received 3.6 mg (38 µg/kg) of recombinant factor VIIa
(Fig. 1). Intraoperatively,
gross infection was evident. The cementless acetabular component was loose and
was removed without difficulty. The cementless femoral component was well
fixed and required an extended trochanteric osteotomy for explantation. The
osteotomy site was fixed with cerclage wires, and an antibiotic spacer was not
placed since this was the definitive procedure. The estimated blood loss was
700 mL. A second 3.6-mg dose of recombinant factor VIIa was administered
toward the end of the procedure. Postoperatively, intermittent pneumatic
compression devices were used for prophylaxis against deep vein
thrombosis.
A postoperative infusion of 3.6 mg of recombinant factor VIIa was given
approximately every five hours for the first twenty-four hours
(Fig. 1). On the second
postoperative day, the dose of recombinant factor VIIa was reduced to 2.4 mg
(25 µg/kg) every six hours and was alternated with 1 U of fresh-frozen
plasma every six hours to conserve NovoSeven until the blood bank was
resupplied. During the third and fourth postoperative days, wound drainage
averaged 200 mL/day of serosanguineous fluid. There was no evidence of
bleeding or hematoma formation. Two units of red blood cells were transfused
to treat a hemoglobin level of 95 g/L, administration of the fresh-frozen
plasma was stopped, and use of recombinant factor VIIa was continued at a dose
of 2.4 mg every six hours (Fig.
1). On the sixth day, the incision remained dry, the drain was
removed, and the dose of recombinant factor VIIa was reduced to 1.2 mg every
six hours. On the eighth postoperative day, surveillance Doppler studies of
the lower extremity were negative for deep vein thrombosis. The patient was
transferred to a skilled nursing facility for additional rehabilitation on the
ninth postoperative day.
Findings at the outpatient follow-up visit seven months postoperatively
showed no evidence of active infection. The patient primarily used a
wheelchair and was able to transfer from bed to chair.
Recombinant factor VIIa has been used successfully to prevent or
stop bleeding in patients with a variety of inherited and acquired hemostasis
disorders including congenital factor-VII
deficiency5,6.
Published case reports describe the use of recombinant factor VIIa during
orthopaedic operations in hemophiliacs with
inhibitors7,8,
in a patient with cirrhosis and
thrombocytopenia9
and factor VII-deficient patients undergoing
synovectomy6,10,
and in patients treated with primary total hip
arthroplasty11.
In this report, we described the use of recombinant factor VIIa during
explantation of a hip prosthesis associated with infection. The patient was at
high risk for perioperative bleeding complications as a result of moderate
factor-VII deficiency, hypervascularity associated with the infected hip, and
the magnitude of the surgery required for explantation of a cementless femoral
stem.
Anecdotal experience indicates that, during invasive procedures in
factor-VII-deficient patients, adequate hemostasis is achieved with lower
doses of recombinant factor VIIa infused at longer intervals than is
recommended for hemophiliacs with
inhibitors6,12.
We are aware of one report of a successful primary hip replacement performed
with 29 µg/kg of recombinant factor VIIa given every eight
hours11.
In July 2005, the FDA extended the indications for use of NovoSeven to
include treatment and prevention of bleeding complications in patients with
congenital factor-VII deficiency. Dosing guidelines are 15 to 30 µg/kg
every four to six hours until hemostasis is achieved. A dose of 30 µg/kg
was recommended for our patient, who weighed 95 kg. Since recombinant factor
VIIa (NovoSeven) is supplied in 1.2, 2.4, and 4.8-mg lyophilized vials, he
initially received 3.6 mg (38 µg/kg).
Thrombotic complications associated with the use of recombinant factor VIIa
in hemophiliacs are
uncommon13.
However, in a recent study of patients with acute intracerebral hemorrhage and
no congenital or acquired coagulopathies, those who received recombinant
factor VIIa had significantly more arterial thromboembolic complications than
did controls (p =
0.01)14. These
adverse events led to recent revisions of the NovoSeven package-insert
warnings and adverse-reaction labeling.
Currently, recombinant-factor-VIIa dosage is not based on laboratory
monitoring. During our patient's postoperative period, the prothrombin time
and international normalized ratio were within the normal reference ranges
except for one time on the sixth day (Fig.
1). However, dosing decisions were based on clinical evaluation of
bleeding rather than on normalization of the international normalized
ratio.
NovoSeven is an expensive recombinant protein with a 2005 wholesale price
(in United States dollars) of $1540/mg or $5852 for a 3.6-mg dose. However,
the financial consequences of inadequate control of surgical bleeding in
patients with inherited factor-VII deficiency are also costly as demonstrated
by this patient's unsuccessful primary total hip replacement.
On the basis of the successful outcome described in this case and the
recommendations of Goodnough et
al.15, we suggest
consideration of the following approach for patients with moderate or severe
factor-VII deficiency who are undergoing a major orthopaedic procedure: (1)
initial treatment with approximately 30 µg/kg of recombinant factor VIIa
every six hours for twenty-four hours, (2) subsequent tapering of the dose of
recombinant factor VIIa and substitution of the factor VIIa with fresh-frozen
plasma on the basis of the clinical assessment of bleeding, and the use of
mechanical prophylaxis against deep venous thrombosis. We do not believe that
normalization of the prothrombin time or the international normalized ratio
should be the primary end point of treatment.