Emerging Off-Label Uses for Recombinant Activated Factor VII: Grading the Evidence

Crit Care Clin 21 (2005) 611–632

Emerging Off-Label Uses for Recombinant

Activated Factor VII: Grading the Evidence

T. Miko Enomoto, MDa, Per Thorborg, MD, PhD, FCCMb,c,*

aDivision of Surgical Critical Care, Department of Surgery, Oregon Health & Science University,

3181 SW Sam Jackson Park Road, Mail Code L 223, Portland, OR 97201-3098, USAbDivision of Critical Care Medicine, Department of Anesthesiology,

Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USAcSurgical Intensive Care Unit, Oregon Health & Science University,

3181 SW Sam Jackson Park Road, Portland, OR 97239, USA

Recombinant activated factor VII (rFVIIa) (NovoSeven; Novo Nordisk, Bags-

vaerd, Denmark) is currently licensed in the United States for treatment of

bleeding episodes in patients with deficiencies of factor VIII (FVIII) or IX (FIX)

who are refractory to factor replacement because of circulating inhibitors. A 1999

report of its successful use to stop what was deemed to be lethal hemorrhage

after an abdominal gunshot wound in a young soldier without pre-existing

coagulopathy [1] has prompted exploration of other uses for rFVIIa. The virtual

explosion of proposed uses of rFVIIa raises issues not only regarding our

understanding of the coagulation system, but also regarding its efficacy, cost-

effectiveness, and safety.

Recombinant FVIIa is a genetically engineered protein produced in cultured

baby hamster kidney cells that is nearly identical to human plasma-derived

FVIIa in structure and function. Where available, its use is rapidly replacing the

use of activated prothrombin complex concentrates (APCCs) in the treatment

of hemophiliac patients because of the decreased risk of viral transmission and

the virtually absent risks of transfusion reaction, fluid overload, HLA antibody

formation, and anaphylaxis compared with APCCs.

0749-0704/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ccc.2005.04.001 criticalcare.theclinics.com

* Corresponding author. Division of Critical Care Medicine, Department of Anesthesiology,

Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239.

E-mail address: [email protected] (P. Thorborg).

enomoto & thorborg612

Background

In addition to providing a new and highly efficacious treatment for hemo-

philiacs with inhibitors, rFVIIa has prompted a re-evaluation of our under-

standing of the coagulation system. Initially modeled in the 1960s as a cascade,

two sequential series of reactions, the extrinsic (tissue factor/FVIIa-initiated) and

intrinsic (FXII-initiated) pathways, share a common final pathway that cul-

minates in the conversion of prothrombin to thrombin. Although this model

provided an adequate explanation of the standard screening coagulation tests,

prothrombin time (PT, a measure of the extrinsic pathway) and activated par-

tial thromboplastin time (aPTT, a measure of the intrinsic pathway), it fails to

explain some clinically observed problems such as hemophilia [2].

The coagulation cascade remodeled

Hoffman [2] has proposed a cell-based model of coagulation in which the

reactions of the coagulation cascade take place in a cell-specific fashion and in

three distinct but overlapping phases: initiation, amplification, and propaga-

tion. This process requires the participation of a tissue factor (TF)-expressing

cell (usually found outside the vasculature and exposed upon endothelial injury)

and platelets.

The initiation phase requires TF, thereby limiting the initiation of coagula-

tion to the site of endothelial injury. FVII forms a complex with TF. The TF/VIIa

complex cleaves FX to FXa, which binds to FVa on the surface of the TF-bearing

cell. This Xa/Va complex cleaves prothrombin to thrombin, which is crucial in

platelet activation, in releasing circulating FVIII from von Willebrand factor, and

in activating FIX. The presence of inhibitors of FXa (tissue factor pathway in-

hibitor [TFPI]) effectively localizes this reaction to the surface of the TF ex-

pressing cell. However, the TF/FVIIa complex also activates FIX to FIXa, which

is able to diffuse to activated platelets.

The amplification phase occurs on the surface of activated platelets binding

to exposed collagen at the site of injury. Thrombin-activated platelets express

surface binding sites (aka as PF3) for the tenase (FVIIIa/FIXa) and prothrom-

binase (FXa/FVa) complexes. The tenase complex is initially formed in part

from FIXa, which has diffused from the TF-bearing cell in the initiation phase,

but the initiation phase is rapidly inhibited by TFPI. The tenase complex gen-

erates FXa, which moves directly into complex with FVa to form the pro-

thrombinase complex. This complex, in turn, generates the thrombin necessary

to form enough fibrin to stabilize the platelet clot [3]. The clot becomes more

resistant to fibrinolysis with increasing concentrations of fibrin. While TFPI

modulates the activity of the TF/FVIIa complex, antithrombin and the protein

C/S system modulate the activity of factors IIa, Xa, IXa, XIa, and Va and

VIIIa, respectively.

recombinant activated factor vii 613

The role of recombinant activated factor VII

To be effective as a ‘‘bypassing’’ agent in hemophilia, rFVIIa dosing must

achieve blood levels at least 100 times the physiologic FVII level (0.2 nM/L).

A 100 mg/kg dose usually achieves a plasma level 250 times the physiologic FVII

level. The mechanism by which rFVIIa achieves its hemostatic effects is still

under debate. Postulated mechanisms include TF-dependent and -independent

mechanisms. In lower doses, the TF-dependent pathway with FXa production

is predominant, while at higher doses, the TF-independent mechanism where

rFVIIa loosely binds to the activated platelet surface and replaces the tenase

complex. The TF-independent activity has been shown both in a cell-based model

[4], and in healthy volunteers [5]. Recombinant FVIIa does not appear to bind to

resting platelets, which may explain why systemic coagulation activation is

not observed after rFVIIa infusion [6], even if rFVIIa is capable of acting in a

TF-independent manner. The high dose of rFVIIa that attaches to the activated

platelet has the ability to produce a large amount of fibrin, known as a fibrin

burst. The denser clot that results from an increased fibrin burst is more resistant

to fibrinolysis [7].

Purpose

The following is a review of the uses of rFVIIa and an overview of the level of

evidence supporting the use of rFVIIa in each situation. Evidence and recom-

mendations are graded according to the scale presented in Box 1. The graded

recommendations are based on a modified Delphi technology and are used in

several recent major publications [8]. Uses of rFVIIa supported only by case

reports are mentioned, but no graded recommendations are provided.

Off-label uses of recombinant activated factor VII

Coagulation factor deficiency

Single-factor deficiencies (VII, VIII, IX, X, XI)

Approved indication: recombinant activated factor VII for treatment of

hemophilia with inhibitors: grade A recommendation. Recombinant factor VIIa

is currently approved in the United States for the treatment of bleeding episodes

or surgery in patients with hemophilia A (deficiency of factor VIII) or hemophilia

B (factor IX deficiency) with inhibitors. For these indications, rFVIIa has good

efficacy: it is 83% to 95% effective in serious bleeding episodes and 90% to

100% effective in major surgical cases. The best dose is still being studied, with

many early trials using doses of 90 mg/kg, with a range from 20 to 200 mg/kg.

Box 1. Recommendation and evidence grading system

Grading of recommendations

A. Supported by at least two level I investigationsB. Supported by one level I investigationC. Supported by level II investigations onlyD. Supported by at least one level III investigationE. Supported by level IV or V evidence

Grading of evidence

I. Large, randomized trials with clear-cut results; low risk offalse-positive (alpha) error or false-negative (beta) error

II. Small, randomized trials with uncertain results; moderateto high risk of false-positive (alpha) and/or false negative(beta) error

III. Nonrandomized, contemporaneous controlsIV. Nonrandomized, historical controls and expert opinionV. Case series, uncontrolled studies, and expert opinion


There are still unresolved issues regarding parameters for monitoring the rFVIIa

effect, and the relationship between dose, amount of thrombin generated, and the

rFVIIa plasma level. The most common way to monitor rFVIIa is with PT/

international normalized ratio (INR), but this is a poor predictor of the actual

risk of bleeding. Thromboelastographic monitoring has been reported in the

perioperative setting [9] and may be an attractive alternative for monitoring the

effect of rFVIIa on coagulation.

In Europe, rFVIIa has also been approved for use in factor VII deficiency

and in Glanzmann’s thrombasthenia.

Recombinant activated factor VII for treatment of bleeding in factor VII

deficiency: grade E recommendation. Several case reports have suggested that

recombinant factor VIIa can be used to successfully treat bleeding episodes in

patients with congenital deficiency of factor VII. More recently, a case series of

three patients reports the successful use of rFVIIa for therapy of acute bleeding

episodes (n = 3) and for bleeding prophylaxis (n = 2) in these patients (level V

evidence) [10]. Interestingly, the authors noted a decreased incidence of bleed-

ing episodes in the two patients who were receiving prophylactic therapy with

rFVIIa thrice weekly, despite measured half-lives in these patients of less than

1 hour. Recommended dosing has been comparatively low (20 mg/kg every 2 to

3 hours until bleeding stops).


Recombinant activated factor VII for treatment of bleeding in factor X deficiency,

case report. rFVIIa has also been used to successfully manage procedure-

related bleeding in a patient with acquired factor X deficiency resulting from

amyloidosis. The patient was diagnosed after initially presenting with large

and spreading ecchymosis, which resulted in a drop in hemoglobin from 9.6 g/dL

to 6.8 g/dL after minimal physical insults. The patient subsequently underwent

placement of percutaneous internal jugular central venous catheter and later

splenectomy without hemorrhagic or thrombotic complications under the cover

of 90 mg/kg rFVIIa at the time of each procedure and every 3 hours during and

after surgery for a total of 48 hours [11].

In addition to case reports, there is currently an ongoing trial examining

the efficacy of rFVIIa in controlling bleeding in patients who have congenital

FXI deficiency [12].

Multiple factor deficiency

Coagulopathy in liver failure. Coagulopathy associated with liver failure is pri-

marily attributed to poor hepatic synthetic function, especially of the vitamin K–

dependent coagulation factors II, VII, IX, and X, as well as protein C and S.

Additionally, coagulopathy may be contributed to by thrombocytopenia, hyper-

fibrinolysis, and dysfibrinogenemia. The significance of coagulopathy in these

disease processes is demonstrated through the use of coagulation indices in

prognostic scores for both cirrhosis and fulminant hepatic failure. The factor VII

level has been reported to be one of the most significant prognostic indicators

in cirrhosis, perhaps because of its short half-life [13]. Although standard co-

agulation parameters such as PT/INR have been shown to be useful in de-

termining the severity of liver disease, they are, as mentioned above, less useful

as predictors of risk of bleeding. There is no agreement on a value which should

be maintained to prophylax against bleeding (eg, before invasive procedures),

nor is there agreement as to goal values for correction in an actively bleeding

patient with liver disease [14].

There are multiple case reports and case series in the literature that report

the use of rFVIIa for control of [15,16] and prophylaxis against [17,18] bleeding

in the setting of coagulopathy associated with liver failure.

Correction of coagulopathy in hepatic failure: grade D

A retrospective review by Shami and colleagues [19] provides level III evi-

dence in support of using rFVIIa to treat coagulopathy in fulminant hepatic

failure. This study compared eight patients treated with fresh frozen plasma (FFP)

alone versus seven patients treated with FFP and rFVIIa (40 mcg/kg IV bolus),

with outcome measures PT/INR, total plasma transfused, presence of anasarca,

ability to proceed with invasive procedures, bleeding complications, ability to

undergo transplant, and survival. The patients receiving rFVIIa had statistically

significant improvement in their INR, were more often able to have an intra-

cranial pressure monitor placed, had less anasarca, and demonstrated improved

survival (6/8 deaths in the FFP group and 1/7 deaths in the rFVIIa group). Five


of the six deaths in the FFP group were caused by cerebral edema. The

authors suggested that this was partly due to volume load from FFP that the

conventionally treated group received, although there was not a statistically

significant difference in the amount of FFP the two groups received. The FFP

alone group also had fewer ICP monitors placed because of persistently elevated

PT, which may have altered the management of the cerebral edema between the

two groups.

There is also level Vevidence for treatment of coagulopathy secondary to liver

failure with rFVIIa in the pediatric population. In a retrospective review of

15 patients, Brown and colleagues [20] noted improvement in PT at 1 and

6 hours after dosing. There was clinical improvement in 5 of 7 patients with ac-

tive bleeding. The authors felt that 2 patients benefitted from significant im-

provement in their fluid balance attributed to decreased need for FFP transfusion.

Hepatic artery thrombosis occurred in 1 patient, but the authors attributed this

to surgery.

Recombinant activated factor VII for bleeding prophylaxis in liver disease

Prophylactic use of recombinant activated factor VII in patients with cirrhosis

undergoing liver biopsy is safe, but efficacy is unknown: grade C. Life-

threatening bleeding from liver biopsy occurs with a frequency between 1/1000

to 1/10,000 and does not necessarily correlate with the degree of abnormality of

common coagulation laboratory tests. A multicenter, randomized controlled trial

examined the use of different doses (5, 20, 80, and 120 mg/kg) of rFVIIa in

71 coagulopathic patients with liver disease who were undergoing laparoscopic

liver biopsy, to examine the safety and efficacy of rFVIIa in this patient popu-

lation of Child-Turcotte B and C liver disease. PT corrected to normal levels in

the majority of patients. The normalization of PT persisted longer with higher

doses of rFVIIa. Seventy-four percent of patients achieved hemostasis within

10 minutes of laparoscopic liver biopsy without requiring further surgical

intervention or transfusion of blood products, and the time to bleeding cessation

did not appear to correlate with the dose of rFVIIa. Two patients in this study did

experience thrombotic complications, although the authors did not attribute either

to treatment with rFVIIa. One patient experienced portal vein thrombosis 6 days

after therapy, while another patient experienced disseminated intravascular

coagulation shortly after biopsy [21]. This study provides level II evidence of

the safety of using rFVIIa to prevent serious bleeding at the time of laparoscopic

(and presumably open) liver biopsy in coagulopathic patients with liver disease,

but is too small to demonstrate efficacy with decreased incidence of bleed-

ing complications.

Recombinant activated factor VII in major liver resection is safe, but does not

decrease blood loss: grade B. A large randomized trial of 204 patients who did

not have cirrhosis and who had undergone partial hepatectomy was recently

published [22]. Patients received either placebo, 20 mg/kg rFVIIa, or 80 mg/kgrFVIIa, and blood loss and erythrocyte requirements were measured. The pro-


portions of patients who received perioperative blood transfusion were 37%,

41%, and 25%, respectively. Intraoperative blood loss was 1422 mL with pla-

cebo, 1372 mL with 20 mg, and 1073 mL with 80 mg dosing of rFVIIa, respec-

tively, which resulted in transfusion of 1024 mL in the placebo group, 1354 mL

in the 20 mg group and 1073 mL in the 80 mg group. While the reduction of

hematocrit was smallest in the 80 mg group, rFVIIa did not result in a reduction

of either transfusion requirements or number of patients transfused. No safety

issues were identified. An ongoing trial for partial hepatectomy in patients who

have cirrhosis is underway.

Recombinant activated factor VII improves control of upper gastrointestinal

hemorrhage in patients with severe liver failure: grade B. A large randomized,

double-blinded, multicenter trial examining the use of rFVIIa for active upper

gastrointestinal hemorrhage in patients who have cirrhosis provides level II

evidence regarding the use of rFVIIa to treat acute gastrointestinal bleeding in

this population [23]. It demonstrated no overall statistically significant benefit

in a composite end point, including failure to control bleeding within 24 hours

of the first dose, failure to prevent rebleeding between 24 hours and day 5, or

death within 5 days, when compared with conventional therapy. Exploratory analy-

sis, however, suggested that treatment with rFVIIa significantly decreased the

number of failures on the composite end point and the 24-hour bleeding control

end point in the subgroup of patients who had Child-Pugh class B and C disease

and whose bleeding was variceal in origin.

Recombinant activated factor VII normalizes coagulation parameters before liver

transplantation: grade E. Increasing blood loss in orthotopic liver transplan-

tation has been shown to correlate with increased morbidity and mortality [24].

In a case series of eight patients who had coagulopathy indicated by a PT

of 4 or more seconds greater than the normal limit and who underwent ortho-

topic liver transplantation, rFVIIa rapidly brought the PT down into normal

range using a mean dose of 68 mg/kg (level V evidence) [25]. PT was noted

to increase to pre-rFVIIa levels after reperfusion. No thrombotic complications

were observed.

Recombinant activated factor VII may decrease bleeding in liver transplantation:

grade E. Hendriks and colleagues [26] report a series of six adult patients

undergoing orthotopic liver transplantation who received a single dose of

80 mg/kg of rFVIIa at the beginning of orthotopic liver transplantation, with the

option of a second dose being given if operative blood loss exceeded the

patient’s estimated blood volume. Compared with historical controls, the treated

patients required less blood product transfusion (level IV evidence). One patient

experienced hepatic artery thrombosis on postoperative day number one, a com-

plication associated with 5% of liver transplants. A randomized trial of trans-

fusion requirements in patients undergoing liver transplantation using placebo,

60 mg/kg rFVIIa, and 120 mg/kg rFVIIa, is currently underway.


Recombinant activated factor VII for treatment of bleeding in pediatric liver

transplantation: grade E. A pediatric case series has also reported using rFVIIa

for refractory coagulopathy after graft reperfusion in seven children undergoing

orthoptic liver transplantation. Patients received between 37 and 148 mg/kg of

rFVIIa and an antifibrinolytic agent. The authors report clinical decrease in

nonsurgical bleeding in all seven patients. All patients also had a decrease in INR

following rFVIIa dosing, without significant change in aPTT. Two patients

required reoperation, but neither had active bleeding on re-exploration. Five of

the seven patients survived, and no thromboembolic events were noted (level V

evidence) [27].

Reversal of anticoagulation

As our understanding of the in vivo coagulation system evolves, new thera-

peutic anticoagulants are becoming available. One of the main risks of anti-

coagulant therapy is bleeding. For this reason, having antidotes is of great value,

especially for agents with longer half-lives.

Reversal of coumadin anticoagulation: grade C. In a dose-ranging study in

28 healthy volunteers, Erhardtsen showed that rFVIIa can rapidly reverse oral

anticoagulation in a dose-dependent fashion [28]. Deveras and Kessler [29]

reported the use of rFVIIa in a case series of 13 patients with critically prolonged

INR. The indications for rFVIIa use in this latter series included INR greater than

10, clinical hemorrhage, and invasive diagnostic or therapeutic procedures. Doses

ranging from 15 to 90 mg/kg of rFVIIa were used to reverse anticoagulation,

with all patients, regardless of dose, showing a decrease in the INR. Bleeding

ceased immediately in all four patients who presented with hemorrhage. No

thrombotic events were reported (level V evidence).

Central nervous system hemorrhage in coagulopathic patients is associated

with high morbidity and mortality. Intracranial hemorrhage in the anticoagu-

lated patient carries 60% mortality. In a case series of seven patients with supra-

therapeutic levels of warfarin anticoagulation who presented with central

nervous system bleeding (n = 6) or injury with imminent risk of developing

clinically significant hematoma (n = 1), rFVIIa was able to reduce the admission

INR (range 2.9 to N7) to 1.5 or less within 10 minutes of dosing in all seven

patients, facilitating timely neurosurgical decompression. Five of the seven

patients also received vitamin K. Three of the patients had received FFP

transfusion, but without adequate effect. None of the patients died, and there

were no signs of thrombosis. The neurosurgeon assessed intraoperative hemo-

stasis as ‘‘better than expected’’ in all cases. Two of the seven patients required

transfusion of blood products in the postoperative period (level V evidence)

[30]. Similar findings were reported by Lin and colleagues [31] and Park and

colleagues [32]. A series of four warfarin-anticoagulated patients received

FFP and rFVIIa for correction of elevated INR before neurosurgical intervention

for hemorrhage within the spinal canal (n = 2) and subdural hematoma (n = 2)

(level V evidence) [31]. A retrospective review of nine patients with coagu-


lopathy of different origins (coumadin anticoagulation, n = 3, dilutional coagu-

lopathy after trauma, n = 2, and end-stage liver disease, n = 4) requiring urgent

neurosurgical intervention who received between 40 and 80 mg/kg rFVIIa demon-

strated normalization of initially elevated INR and PTT within 20 minutes of

receiving rFVIIa in all cases. No thrombotic or bleeding complications were

noted intra- or postoperatively (level V evidence) [32].

Normalization of prothrombin time and activated partial thromboplastin time

after pentasaccharide anticoagulation: grade C. Fondaparinux is a synthetic

pentasaccharide that selectively inhibits factor Xa. In a randomized, placebo-

controlled study, 16 healthy male volunteers received either 10 mg fondaparinux

subcutaneously or placebo and either 90 mg/kg rFVIIa intravenously or placebo.

Recombinant FVIIa normalized the PT and aPTT and restored thrombin gen-

eration in patients treated with fondaparinux. No thrombotic events were re-

ported; furthermore, no ‘‘overshoot’’ of coagulation or hypercoagulability was

observed in the coagulation assays, including thrombin-generation time, endoge-

nous thrombin potential, prothrombin fragment 1 + 2 (F1 + 2), aPTT, and PT

(level II evidence) [33].

In a similar trial, rFVIIa was evaluated for correction of coagulopathy in-

duced by idraparinux, a longer-acting pentasaccharide with a half-life of 5.5 days,

which only requires once weekly subcutaneous dosing. In a randomized,

controlled trial, 12 healthy male volunteers received a single subcutaneous dose

of 7.5 mg idraparinux, a dose three times higher than that currently recom-

mended. The volunteers were then randomized to receive rFVIIa (90 mg/kgintravenous bolus) at 3 hours after indraparinux administration and placebo at

7 days, or placebo at 3 hours and rFVIIa at 7 days. At 3 hours, administration

of rFVIIa partially reversed the idraparinux-induced inhibition of thrombin,

rapidly decreased the prolonged aPTT, and reversed the prolonged PT. At 1 week

after treatment with idraparinux, rFVIIa infusion resulted in almost complete

reversal of anticoagulation (level II evidence) [34].

Normalization of prothrombin time after anticoagulation with tissue factor

inhibitors: grade C. With the recognition of the importance of the FVII/TF

complex in the initiation of coagulation, efforts to inhibit tissue factor as a means

of anticoagulation have been made. One of these inhibitors is recombinant

nematode anticoagulant protein c2 (rNAPc2), a potent and selective inhibitor of

the TF/FVIIa complex in the presence of factor Xa. In a randomized, controlled

trial, six healthy adult male volunteers were each tested three times in random

order: once with rNAPc2 (3.5 mg/kg subcutaneously) followed after 4 hours

by rFVIIa (90 mg/kg IV), once with RNAPc2 followed by placebo, and once with

rFVIIa alone. Administration of rFVIIa following anticoagulation with rNAPc2

immediately corrected the PT to lower than pre-rNAPc2 levels and restored

thrombin generation as demonstrated by increased plasma levels of F1 + 2 and

thrombin-antithrombin complexes. No thrombotic events were reported (level II

evidence) [5].


It is important to note that although rFVIIa appears to be efficacious in

normalizing laboratory coagulation parameters with various different anticoagu-

lants, no controlled trials have yet been published that demonstrate its ability

to achieve hemostasis in the anticoagulated patient experiencing active hemor-

rhage. A randomized trial of rFVIIa in anticoagulated patients with severe bleed-

ing is underway.

Recombinant activated factor VII for treatment of hemorrhage in the setting

of systemic inflammation and coagulation activation, recommendation

grade E. Because of concerns that rFVIIa could contribute to systemic coagu-

lation, disseminated intravascular coagulation (DIC), and sepsis have been con-

sidered as contraindications to the use of rFVIIa. Despite this, there are numerous

case reports of its successful use to treat hemorrhaging patients in the surgical

[35], obstetrical [36–39], and burn literature [40].

The largest case series of patients with high potential for systemic activation

of coagulation, other than trauma (see later discussion), is a series of 15 children

with life-threatening hemorrhage secondary to dengue hemorrhagic fever, also

known as dengue shock syndrome, which is frequently complicated by DIC.

Nine patients had grade III dengue shock syndrome and received rFVIIa before

receiving platelet concentrates, and six patients had grade IV dengue shock

syndrome and had already been treated unsuccessfully with platelet concentrates.

The patients received 100 mg/kg rFVIIa initially, with doses repeated every

4 hours according to bleeding symptoms. Laboratory values to determine

presence of DIC were not present for all of the patients, but two patients fulfilled

the International Society on Thrombosis and Haemostasis DIC scoring system

criteria for overt DIC, while five others had at least nonovert DIC. Treatment was

considered effective (complete cessation of bleeding with no recurrence for

48 hours) in 53.3% of the patients. The remaining 46.7% of patients had

ineffective responses, which required transfusion of platelet concentrates to

control bleeding. Overall, this series had a 20% case fatality rate. Perhaps the

most significant finding of this study was that no thrombotic complications were

identified in these high-risk patients, although screening mechanisms were not

mentioned (level V evidence) [41].

Platelet disorders

Platelets play a central role in primary hemostasis. There is evidence to

support the role of the FVII/TF dependent coagulation system in providing the

first thrombin necessary for platelet activation to occur. Additionally, there is

likely a tissue factor independent mechanism for FVIIa activation on platelets [4].

This has raised the question of a role for rFVIIa in the treatment of bleeding

in thrombocytopenia and platelet dysfunction. Bleeding episodes occurring in

patients with these conditions have traditionally been treated with platelet

transfusion. This therapy is associated with risks of transfusion reaction, virus

transmission, fluid overload and formation of allo-antibodies.


Recombinant activated factor VII for hemorrhage related to thrombocytopenia:

grade E recommendation. A preliminary phase I/II study demonstrated that

rFVIIa safely reduced bleeding time in 55 of 105 nonbleeding patients who

had thrombocytopenia of differing etiology [42].

Two case series support the use of rFVIIa infusion in patients who have

thrombocytopenia and active bleeding with grade V evidence. This is also

supported by in vitro evidence that addition of rFVIIa to a cell-based model

system containing lower platelet density (20 � 109 and 10 � 109 platelets/L)

shortened the lag phase of thrombin generation as well as the time to half-

maximal platelet activation [43]. In the first clinical series, eight patients were

treated with a total of nine infusions of rFVIIa. Bleeding decreased in all pa-

tients and stopped in six patients (level V evidence) [42]. A smaller case series of

two patients with thrombocytopenia associated with hematologic malignancy

demonstrated the successful cessation of life-threatening hemorrhage unres-

ponsive to platelet transfusion after infusion of rFVIIa. No adverse events were

noted [44].

There is no clear benefit to treatment with recombinant activated factor VII for

hemorrhage associated with thrombocytopenia and allogenic bone marrow

transplant: grade E recommendation. Although there are two case reports of

successful control of diffuse alveolar hemorrhage in patients who have he-

matological malignancy [45,46], larger case series of rFVIIa therapy to treat

bleeding in the setting of thrombocytopenia associated with hematological

malignancy and allogenic bone marrow transplantation demonstrate less im-

pressive results. The largest case series to date reports on the use of rFVIIa to

treat severe hemorrhage in seven patients with hematologic malignancy. Two of

the seven patients had acute myeloid leukemia and presented with severe

bleeding before or during induction chemotherapy. Both of these patients had

complete cessation of their bleeding following the study course of rFVIIa, which

was planned to be 100 mg/kg every 6 hours, for a total of six doses. Of the five

remaining patients, all of whom had undergone bone marrow transplantation,

three patients were partial responders (reduction of bleeding from severe to

moderate), while two patients showed no response to rFVIIa therapy. The authors

concluded that rFVIIa may be more efficacious for patients in the earlier stages of

disease (level V evidence) [47].

In a case series of three pediatric (age 8 years to 19 years) patients who had

hemorrhage and who had undergone bone marrow transplantation for acute

myelogenous leukemia (n = 2) or aplastic anemia (n = 1), rFVIIa was given in

repeated doses of 90 mg/kg every 4 to 24 hours for 3 to 14 days. Bleeding was

evident from pulmonary hemorrhage in one patient, from hemorrhagic cystitis

in three patients, and from gastrointestinal bleeding in two patients. Two patients

were characterized as having a partial response to rFVIIa, with transient decrease

in clinically apparent hemorrhage; however, both of these patients developed

new gastrointestinal hemorrhage during therapy with rFVIIa. The third patient

had no clinical response to rFVIIa. The cost range of rFVIIa therapy in this series


ranged from $10,000 to $200,000 per patient (level V evidence) [48]. A ran-

domized placebo-controlled trial is underway to study the efficacy and safety of

rFVIIa for gastrointestinal bleeding in allogenic stem cell transplantation.

Platelet dysfunction

Recombinant activated factor VII is an effective treatment for bleeding in

Glanzmann’s thrombasthenia: grade E recommendation. The largest series of

the use of rFVIIa for bleeding due to platelet dysfunction is in pediatric pa-

tients. Rather than using rFVIIa in bleeding episodes refractory to platelet

transfusion, both these studies attempted to evaluate the use of rFVIIa to treat

bleeding in place of platelet transfusion. Poon and colleagues [49] reported a

series of 24 bleeding episodes and one surgery in four patients with Glanzmann

thrombasthenia, a congenital, hereditary hemorrhagic disorder caused by quali-

tative or quantitative abnormalities of the platelet glycoprotein IIb/IIIa receptor

leading to excessive bleeding. Doses of rFVIIa ranged from 89 to 116 mg/kg per

injection every 2 hours in addition to antifibrinolytic drugs. Bleeding stopped in

all cases, but additional platelet transfusion was required in one bleeding episode.

Two bleeding episodes recurred within 63 hours after discontinuation of rFVIIa,

but responded to additional doses. No thrombotic events were noted (level V

evidence). A prospective series of pediatric patients with inherited platelet func-

tion disorders (Glanzmann thrombasthenia, Bernard-Soulier syndrome, and

storage pool disease with severe phenotype) reports on a total of 28 episodes of

bleeding and five surgical interventions treated with rFVIIa in seven children.

The protocol for acute bleeding episodes consisted of three doses of a minimum

of 100 mg/kg of rFVIIa at 90-minute intervals. For planned invasive interventions,

the same three-dose regimen was used, with the first dose given 30 to 45 minutes

before surgery. Bleeding ceased in 10 of 28 acute bleeding episodes and recurred

in two of these. Eighteen of the 28 bleeding episodes required blood product

support. Therapy with rFVIIa seemed to be more successful if initiated soon after

the onset of bleeding and in episodes of less severe bleeding. Despite good results

with rFVIIa in 13/15 mild and 1/10 severe bleeding episodes, there was no

significant reduction in transfusion requirements when compared with bleeding

episodes in the same patients treated before the use of rFVIIa. All planned sur-

gical interventions using rFVIIa were successfully completed without bleeding or

thrombotic problems (level IV evidence) [50].

Recombinant activated factor VII for treatment of bleeding related to uremic

platelet dysfunction: case report. Bleeding associated with renal failure is

typically due to uremic platelet dysfunction and is similar in nature to von

Willebrand’s disease. Recombinant FVIIa immediately controlled hemorrhage

in a case report of acute nephrotoxicity complicated by hemorrhagic syndrome

presenting with hematuria, hematemesis, gingival hemorrhage, and hemorrhage

at venipuncture and catheter insertion sites [51], suggesting that there may be a

role for the use of rFVIIa in controlling uremic bleeding. Although the cause of

coagulopathy is not identified in a case report of excessive bleeding during


renal transplant for end stage renal failure from focal glomerulosclerosis, the

massive hemorrhage in this case was controlled after a single dose of 135 mg/kgrFVIIa. The bleeding clinically subsided immediately, and the aPTT decreased

from 43 to 37 seconds, while the PT decreased from 15 to 9 seconds. There was

no evidence of renal vascular thrombosis on Doppler studies. The patient did

experience a subclavian deep venous thrombosis at the site of a central venous

catheter 1 month after surgery [52].

Recombinant activated factor VII as a general hemostatic agent

Perioperative bleeding

Recombinant activated factor VII may be helpful in achieving hemostasis in

cardiac surgery: grade E recommendation. Case reports of the successful use

of rFVIIa to control bleeding in the setting of cardiothoracic surgery include

its use for coagulopathic bleeding associated with use of left ventricular assist

device [53], extracorporeal membrane oxygenation [54], and cardiopulmonary

bypass [55–57]. A case series of 40 patients at the Washington Cancer Institute

who had intractable hemorrhage included 24 patients who received rFVIIa dur-

ing or after cardiac surgery. In this retrospective review, only 50% of the patients

survived 4 hours after rFVIIa dose, while only 25% survived until hospital

discharge. The authors report a statistically significant decrease in transfusion

of all blood products when comparing pre- and post-rFVIIa, including red cells,

platelets, FFP, and cryoprecipitate. The significance of this finding is unclear in

the setting of this high mortality rate. A cardiac ejection fraction of less than 25%

seemed to correlate with fatal outcome in this series. Subclavian vein thrombosis

related to central line placement occurred in one patient (level V evidence) [58].

Results from a prospective, randomized, controlled trial from the United

Kingdom evaluating the use of 90 mg/kg rFVIIa given after coming off bypass in

patients believed to be at high risk for coagulopathic bleeding with cardiovascular

surgery are expected shortly [59].

Two case series in pediatric patients with coagulopathic bleeding unrespon-

sive to conventional transfusion therapy in the setting of cardiac surgery support

the use of rFVIIa in this population (grade E recommendation). The first series,

from Australia, is a retrospective review of six pediatric patients undergoing

cardiac surgery who developed persistent intra- or postoperative coagulopathic

bleeding despite appropriate measures as determined by surgical and medical

staff. These children received 180 mg/kg rFVIIa intravenously, followed by a

repeat dose 2 hours later. There was a reduction in volume of bleeding following

the second dose of rFVIIa, as well as a reduction in INR and aPTT values. All

six patients were reported to have good outcomes, and there were no adverse

events attributed to the use of rFVIIa (level V evidence) [60].

The second series is a prospectively collected series of eight pediatric pa-

tients with excessive bleeding after cardiac surgery with cardiopulmonary bypass

that met criteria for re-exploration and did not respond to conventional trans-

fusion therapy. Recombinant FVIIa was given as an intravenous bolus of 30 or


60 mg/kg if the patient had preoperative coagulopathy, preoperative multiple

organ failure, or indications for an emergent surgery. This was repeated after

15 minutes, and subsequently every 2 hours, to a maximum of four doses, if

the bleeding was not controlled. Return to the operating room was successfully

prevented in all but one patient, for whom there was only a single dose of rFVIIa

available (level V evidence) [61].

Recombinant activated factor VII reduces blood loss and need for transfusion

in elective retropubic prostatectomy: grade B recommendation. In one of

the more rigorous studies of rFVIIa for perioperative hemostasis performed to

date, a randomized, double-blind, placebo-controlled, single-center trial evalu-

ated the safety and efficacy of rFVIIa in reducing blood loss, and thereby

transfusion requirement, in patients without pre-existing coagulopathy under-

going elective retropubic prostatectomy. The study was conducted in phases

to evaluate increasing doses of rFVIIa, beginning with 20 mg/kg, and increasing

to 40 mg/kg. The protocol allowed for a third group to receive 80 mg/kg, butthe dose escalation was stopped after interim analysis revealed significant de-

crease in intraoperative blood loss and transfusion requirement in patients

receiving 40 mg/kg rFVIIa compared with placebo. Perioperative treatment with

rFVIIa resulted in a dose-dependent decrease in total perioperative blood loss

with the placebo, 20 mg/kg rFVIIa, and 40 mg/kg rFVIIa groups having a median

(interquartile range) blood loss of 2688 (1707–3565) mL, 1235 (1025–1407) mL,

and 1089 (928–1320) mL, respectively, with a P value of .001 for each of the

rFVIIa groups compared with placebo. There was also a significant decrease in

units of packed red cells transfused (1.5 versus 0), percentage of patients re-

quiring any transfusion (58% versus 0%), and duration of operation (180 minutes

versus 120 minutes) when comparing the placebo group with the group treated

with 40 mg/kg rFVIIa [62].

Acute bleeding in patients without pre-existing coagulopathy

Recombinant activated factor VII is effective and safe for treatment of

intracerebral hemorrhage: grade B recommendation. Hematoma growth oc-

curs in approximately one third of patients who have intracerebral hemorrhage

and who present within 3 hours of the onset of symptoms, and likely contrib-

utes significantly to the high morbidity and mortality of this disease process. This

appears to be due to continued bleeding or re-bleeding occurring at multiple

sites. Early intervention with a hemostatic agent, which could inhibit or limit this

process, could potentially improve outcome in this group of patients.

A phase II safety trial was recently completed, providing grade II evidence

for the safety of using rFVIIa to treat patients with intracerebral hemorrhage. In

this randomized, double-blinded, placebo-controlled, dose-escalation trial,

48 patients who presented with intracerebral hemorrhage within 3 hours of onset

of symptoms were randomized to receive placebo (n = 12) or rFVIIa (n = 6 for

each dose) at 10, 20, 40, 80, 120, or 160 mg/kg. There were eight adverse eventsclassified as thrombotic or possibly treatment-related. The frequency and sever-


ity of these events did not appear to be dose-related, and in several instances,

seem unlikely to be treatment related. One patient in the placebo group developed

a popliteal vein thrombosis at 72 hours, one patient receiving 10 mg/kg rFVIIa

developed a pruritic rash, one patient receiving 20 mg/kg rFVIIa experienced

vomiting, another a fever, one ECG t-wave inversion without change in cardiac

enzymes, another a peroneal vein thrombosis at 72 hours, one patient receiving

40 mg/kg rFVIIa developed ECG t-wave inversion without cardiac enzyme

change, and another was hospitalized for unstable angina 29 days after treat-

ment. There was no dose-related treatment effect seen in the change in intracra-

nial hematoma volume in this small trial [63]. However, a larger (399 patients)

follow-up trial, in which patients received placebo or 40, 80, or 160 mg/kg rFVIIa,was just published [64]. The primary outcome measure was volume of the in-

tracerebral hemorrhage at 24 hours, and clinical outcome at 90 days. Hematoma

increase was 29% in placebo group, and 16%, 14%, and 11%, respectively, in the

40, 80, and 160 mg/kg groups. Mortality at 90 days was 29% in the placebo group

and 18% in the other groups combined (P = .02). Thromboembolic events

occurred in 7% of the rFVIIa treated patients compared with 2% in placebo, a

notable but not significant difference between the groups. Arterial thrombosis

occurred in 5% of the patients receiving rFVIIa, and none of the placebo group

patients (P = .01).

Recombinant activated factor VII may be an adjunctive hemostatic measure in

hemorrhaging trauma patients with coagulopathic bleeding: grade D. Uncon-

trolled hemorrhage following trauma remains a significant cause of mortality in

both the perioperative and critical care setting, and is the second leading cause of

death from trauma [65]. Definitive repair of bleeding vessels is often complicated

by diffuse, coagulopathic oozing due to what is often referred to as the lethal

triad in trauma: coagulopathy, acidosis, and hypothermia, all of which further

contribute to coagulopathy. For this reason, interest in rFVIIa as a possible

‘‘universal hemostatic agent’’ is high.

To date, there are no published randomized, controlled trials of the use of

rFVIIa in trauma patients who have uncontrolled hemorrhage. There are several

case reports with sometimes fantastic results, including the case report that sparked

much of the interest for using rFVIIa in trauma patients, a case report of a young

soldier who was thought to have fatal hemorrhage secondary to gunshot wound to

the lower abdomen at the level of L5, with resulting injury to the inferior vena

cava and paraspinous muscles. After a single dose of 60 mg/kg, the coagulopathicbleeding slowed significantly, and it stopped completely after a second dose [1].

There are several reported case series which use rFVIIa as an adjunct to

the control of hemorrhage in trauma patients. Dutton, et al, reported on a series of

five patients with what was felt to be life-threatening hemorrhage secondary to

either acute or late-stage trauma. Hemorrhage was controlled in three out of the

five patients after treatment with rFVIIa (level V evidence) [66]. Failure was

attributed to extreme shock and acidosis. Another series of seven massively

bleeding, multitransfused, coagulopathic trauma patients received rFVIIa after


failure of conventional means to achieve hemostasis. In all seven patients ces-

sation of diffuse bleeding was observed, along with decrease in transfusion re-

quirements compared with pre-rFVIIa, and shortening of the PT. Three of the

seven patients died of causes other than bleeding or thromboembolism (level V

evidence) [67]. A series of eight blunt trauma patients treated with rFVIIa for

uncontrolled bleeding reports decreased transfusion requirements after therapy,

and either complete cessation of critical bleeding, or slowing of bleeding enough

to allow some other definitive repair (surgical or angiographic). Three of the

patients died from complications other than bleeding (level V evidence) [68].

The largest-scale study published to date, with the highest grade of evidence,

grade III, fails to show survival advantage to treatment with rFVIIa, possibly

due to the difficulty in identifying an appropriate control population. This study

presents data from 81 coagulopathic trauma patients treated with rFVIIa, com-

pared with control patients matched from a trauma registry for the same time

period [69]. Coagulopathy was reversed in 75% of cases. Forty-two percent of

patients survived to hospital discharge. Twenty-five percent of patients had no

response to therapy. Survival in the rFVIIa cohort was lower than that seen in

the control group matched for coagulopathy and one of the following: specific

anatomic injuries, admission lactate value, and predicted probability of survival.

Survival was similar, with a control group matched for all of these criteria, but the

number of patients in this control group was so small as to prohibit more

meaningful analysis. Three patients in the treatment group with severe mesen-

teric injury developed necrotic bowel on days 5 to 8. The authors were unable

to attribute this to a thrombotic event versus survival of a patient who would

have exsanguinated before the traumatic bowel injury became evident.

A European phase II trauma trial has been conducted, but not yet been pub-

lished. A United States phase II trauma trial is currently underway. Larger trials

are needed to assess the true efficacy of rFVIIa in trauma. Additionally, there are

many associated questions that need an answer; for example, is it better to treat

bleeding early using this medication or to wait until coagulopathy develops,

refractory to traditional blood products?

Our institutional experience

Our institutional experience with rFVIIa is shown in Table 1. Preliminary

analysis of this data indicates that although rFVIIa may be effective in achieving

hemostasis, this does not necessarily contribute significantly to survival in patients

with bleeding due to end-stage liver disease, or when used as a last ditch effort in

severely ill patients. A similar experience has also been noted by others [70].

Safety

Theoretically, the infusion of an activated coagulation factor, such as rFVIIa,

carries a risk of triggering inappropriate thrombosis, possibly even systemic

activation of the coagulation system, which would result in DIC. To date, rFVIIa

has had a surprisingly low incidence of adverse events, although the lack of

controlled trials makes this difficult to evaluate. Recombinant FVIIa use for

Table 1

Use of rFVIIa at Oregon Health Sciences University, 1/2002–12/2004

Diagnosis (n) Mean age Injury type (n)

Average transfusion

requirement before dose

Average

rFVIIa mcg/kg

Hemostasis

improved (%) Survival (%)

Trauma (12) 46 Blunt (9), gunshot wound (1), stab (2) PRBC 25/FFP 12 74 � 1 92 58

Intracranial hemorrhage (22) 65 Traumatic (14), anticoagulated (16) PRBC 4/FFP 12 66 � 1 91 59

Surgery (16) 49 Cardiac (10), other (6) PRBC 8/FFP 11 90 � 1–2 87.5 87.5

Factor deficiency (25) 35 FVIId (6), FVIIIi (11), FIXi (2),

VWD (3), multiple (3), Glanzmann (2)

PRBC 5/FFP 0 90 � 8 100 100

Liver disease (10) 37 NA PRBC 10/FFP 12 66 60 30

Last ditch (9) 36 Bone marrow transplant (3), sepsis (3),

disseminated intravascular coagulation (2),

pulmonary hypertension (1)

Variable 145 � 1 66 0

Abbreviations: FFP, fresh frozen plasma; PRBC, packed red blood cells.

recombinantactivatedfactorvii

627


label and off-label indications appears to have different safety profiles. Until

November 2002, a total of 16 thromboembolic complications after a total of

354,162 doses establishes the frequency at less than 0.007% for label indications,

a very low number (Novo Nordisk data on file). In contrast, in the randomized

controlled trials (RCTs) for off-label indications, thromboembolic events related

to rFVIIa treatment were 3.1% in the treatment arm (n = 1086) versus 2.4% in the

control arm (n = 544) [71]. Deep vein thrombosis, clotted intravascular catheters,

cerebrovascular thrombosis, cardiac ischemic events, and anaphylactoid reactions

have been reported in patients who have received rFVIIa, but trials to date have

been too small to determine if these complications are occurring at an increased

frequency compared with a comparable population that has not been treated with

rFVIIa. Many of these adverse events have occurred in patients with other risk

factors for thrombosis. It is clear that for off-label indications, larger, controlled

trials are needed to establish the safety profile.

Efficacy

As of yet, precious little data support drug efficacy for off-label indications,

except as noted in a few RCTs above. Many of the randomized trials published so

far have been phase II trials that primarily address safety. University Health

Consortium recently presented its survey data from 315 patients who received

rFVIIa in 21 participating institutions between January 2002 and May 2004 for

off-label indications. For preventative indications (n = 119), efficacy was found

to be very high (86.6%), while it was lower (52.8%) for treatment indications

(n = 195), with the end point being no bleeding at 6 hours. Efficacy varied with

treatment indication; while it was 65% for intracranial or surgical site bleeding, it

was only 40% to 46% for gastrointestinal and other bleeding sites. These data

were not corrected for severity [72]. Of particular interest in this material was the

fact that 33% of the treated patients were either acidotic (pHb7.20) or hypo-

thermic or both, conditions known to be associated with alterations in effec-

tiveness of rFVIIa [73]. Acidosis decreases the activity of the prothrombinase

complex in particular. TF-dependent rFVIIa activity decreases with decreasing

temperature, but equal and opposite increases in TF-independent rFVIIa activity

results in consistent rFVIIa activity over a wide temperature range. In addition,

for rFVIIa to be work, the thrombin burst we hope to see requires platelets, fi-

brinogen, and an active FXa/FVa complex, so it is therefore reasonable to keep

platelets above 50 � 109/L, fibrinogen above 80 mg/100 mL, and give FFP

should the aPTT be more than 45 seconds. As an observation, some of the treat-

ment failures at our institution have been associated with low platelets, low fi-

brinogen, or severe acidosis and hypothermia.

Summary

Recombinant factor VIIa holds a great deal of promise as a hemostatic agent

in many clinical settings; however, more large, randomized, controlled trials are


needed to evaluate both the safety and efficacy of this apparently effective he-

mostatic agent, particularly in view of its cost. Cost-effectiveness studies are

only in the planning stage for rFVIIa as of yet. To become cost-effective, dosing

of rFVIIa should avoid costly returns in the operating room, shorten stays in the

ICU, and prevent the need to give an additional 10 units of blood.

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Emerging Off-Label Uses for Recombinant Activated Factor VII: Grading the Evidence