Recombinant Activated Factor VII: Current Perspectives and Epworth Experience

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Original Article

Recombinant Activated Factor VII: Current Perspectives and Epworth Experience Matthew P. Labattaglia, MBBS, GradCertPubHlth and Benno Ihle, MD, FJFICM ∗ Intensive Care Unit, Epworth Hospital, 89 Bridge Road, Richmond, Melbourne, Victoria 3121, Australia

Recombinant factor VII was first developed for control and prevention of bleeding in haemophilia with antibodies to factor VIII and IX. Its efficacy in these situations is well established. Over recent years, the ‘off-label’ use of this substance has become more widespread in trauma, surgery and obstetric bleeding. Here we describe the mechanism of action of recombinant factor VII, review current literature of ‘off-label’ usage and our initial experience in surgical related cases of bleeding at Epworth Hospital. (Heart, Lung and Circulation 2007;16:S96–S101) © 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Bleeding; Factor VII; Haemostasis

Introduction

F

actor VII was first isolated, purified and activated from human plasma for clinical applications in 1983.1 However, its short half-life and low plasma concentrations limited its usefulness. Around this time, Davie and coworkers from the University of Washington, Seattle, USA were able to clone the gene for human FVII2 . A master cell bank of this transgene cell line is now the basis for industrial production of recombinant activated coagulation factor VII (rFVIIa) known as NovoSeven. In Australia eptacog alfa (NovoSeven) is approved for treatment of spontaneous and surgical bleeding for patients with Haemophilia A or B and with antibodies to factor VIII or factor IX. Indeed, there is a reported efficacy of 85–92% in these patients.3–5 Recently rFVIIa has been increasingly used for indications outside the approved areas, particularly in cardiac surgery, trauma and other critical bleeding episodes. Use in these areas remains controversial.

tiates the coagulation cascade by activating factor X and factor IX. Factor Xa catalyses the conversion of prothrombin to thrombin which then converts fibrinogen to fibrin. This process can occur independently from factors VIII or IX (bypass effect),7 which explains the potential utility of rFVIIa in patients with coagulation defects. Another interesting feature of rFVIIa is that its therapeutic effect occurs at concentrations 10 times normal physiological concentrations of endogenous factor VII. This is in contrast to most other factor preparations such as fresh frozen plasma or factor VIII. These supraphysiological concentrations allow rFVIIa to bind to the phospholipid membranes of activated platelets8 (Fig. 4). On this surface, rFVIIa is able to activate factor X independently of TF. This results in a massive rise in thrombin generation, known as a ‘thrombin burst,’ and the formation of a thrombin clot. Factor XIII and thrombin activatable fibrinolysis inhibitor (TAFI) are also activated by the ‘thrombin burst’ resulting in increased fibrin cross linking (factor XIII) and suppression of fibrinolysis (TAFI).9

Mode of Action of rFVIIa

Current Literature

It is the recently described cell based model of coagulation6 that may explain the efficacy of rFVIIa (Figs. 1–3). Based on this model, rFVIIa enhances haemostasis at the site of injury without a systemic, hypercoagulable state. Naturally occurring FVII circulates in small quantities and has very weak enzymatic activity until it binds to tissue factor (TF) that normally is not exposed to the circulating blood. When TF is exposed at the site of endothelial damage the complex TF–VIIa ini-

The literature on rVIIa can be divided into articles describing its use in haemophiliacs with inhibitors and ‘off-label’ uses:

Available online 12 July 2007 ∗

Corresponding author. Tel.: +61 3 9426666; fax: +61 3 94268571. E-mail address: [email protected] (B. Ihle).

Haemophiliacs with Inhibitors Recombinant factor VIIa was first used in 1988 in haemophiliacs with inhibitors. Since this time, many prospective randomised trials have shown the efficacy and safety of rFVIIa in the treatment and prevention of bleeding diatheses.10 Shapiro et al. published a double-blind study which showed that the perioperative administration of 90 ␮g/kg rFVIIa in haemophilia patients with inhibitors leads to sufficient haemostasis in 97% of cases.3 Another

© 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.

1443-9506/04/$30.00 doi:10.1016/j.hlc.2007.05.011

Labattaglia and Ihle Recombinant Activated Factor VII: Current Perspectives and Epworth Experience

Figure 1. Initiation of coagulation, new model. From: Rott H, Trobisch H, Kretzxchmar E. Use of recombinant factor VIIa, Novo Seven, in the management of acute haemorrhage. Rott: Curr Opin Anaesthesiol, Volume 17(2). April 2004. 159–163. Permission granted to reproduce by Lippincott Williams & Wilkins.

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multicentre, randomised trial came to the conclusion that boluses at 35 ␮g/kg or 70 ␮g/kg are effective and well tolerated in the treatment of joint bleeding in haemophiliacs with inhibitors.11 Indeed, an investigation by Hay et al. showed that first-line treatment with rVIIa in patients with acquired haemophilia is effective in 100% of cases, whereas conventional therapy is effective in only 75% and partly effective in another 16%.12 However, rFVIIa’s short half-life requires that it should be administered every 2–4 h. Thus, the possibility of infusion was investigated by Schulman et al. He found that the overall consumption of rFVIIa can be reduced by 50% compared with bolus application.13 Nevertheless, to treat ongoing bleeding, bolus application is preferred to achieve a fast thrombin burst. Therefore, rFVIIa is a safe and effective option in the treatment and prophylaxis of bleeding complications in patients with allo- or auto-antibodies against factor VIII or IX. In acquired haemophilia, rFVIIa has become established as the gold standard.14,15

‘Off-label’ Uses of rFVIIa Many ‘off-label’ uses have been proposed for rFVIIa. These include: • • • • • • • Figure 2. Amplification of coagulation, new model. From: Rott H, Trobisch H, Kretzxchmar E. Use of recombinant factor VIIa, Novo Seven, in the management of acute haemorrhage. Rott: Curr Opin Anaesthesiol, Volume 17(2). April 2004. 159–163. Permission granted to reproduce by Lippincott Williams & Wilkins.

Figure 3. Propagation of coagulation, new model. From: Rott H, Trobisch H, Kretzxchmar E. Use of recombinant factor VIIa, Novo Seven, in the management of acute haemorrhage. Rott: Curr Opin Anaesthesiol, Volume 17(2). April 2004. 159–163. Permission granted to reproduce by Lippincott Williams & Wilkins.

Reversal of oral anticoagulation. Reversal of heparin, lepirudin and fondaprinux. Thrombocytopaenia and thrombocytopathy. Bleeding with impaired liver function. Gastrointestinal bleeding. Trauma. Scheduled surgery.

The use of rFVIIa in trauma patients with intractable bleeding is particularly interesting. However currently there are no evidence-based guidelines for this indication. The only randomised, placebo-controlled, double-blind clinical trial to date has been carried out by Boffard et al. in a 2005 international multicentre trial. Boffard et al. looked at 143 blunt trauma patients and 134 penetrating trauma patients who were randomised to receive 200 mcg/kg of rFVIIa after the 8th unit of red blood cells (RBC) followed by 100 mcg/kg at 1 and 3 h, or placebo. Their end point was the number of units of RBC’s transfused within 48 h of the first dose of rFVIIa. They found that in blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (2.6 RBC units, p = 0.02) and the need for massive transfusion (>20 units RBC’s) was reduced (14% versus 33% of patients; p = 0.03). In penetrating trauma there were similar trends, however, statistical significance was not reached. Additionally, there were trends towards a reduction in mortality and critical complications. Importantly, adverse events, including thromboembolic events, were evenly distributed between treatment groups.16 Whilst awaiting more definitive trials, Martinowitz and Michaelson, on behalf of the Israeli Multidisciplinary rFVIIa Task force, published some guidelines for the use of rFVIIa in uncontrolled bleeding.17 They set out to develop expert recommendations for the use of rFVIIa

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Labattaglia and Ihle Recombinant Activated Factor VII: Current Perspectives and Epworth Experience

Heart, Lung and Circulation 2007;16:S96–S101

Figure 4. Proposed haemostatic mechanism of recombinant activated factor VII (rFVIIa). AT, antithrombin; Ca++ , calcium; PL, phospholipid; PAR, platelet thrombin receptor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand factor; II, V, VII, IX, X, and XI, coagulation factors (Va, activated factor V, etc.). From: Eikelboom J, Bird R, Blythe D, Coyle L, Gan E. Recombinant activated factor VII for the treatment of life-threatening haemorrhage. Blood Coagul Fibrinolysis, Volume 14(8). December 2003. 713–717. Permission granted to reproduce by Lippincott Williams & Wilkins.

in patients suffering from uncontrolled bleeding (with a special emphasis on trauma) until randomised controlled trials allow the introduction of more evidence-based guidelines. To do this, they used expert opinion based on the first 36 multi-trauma patients accumulated in the prospective national registry of the use of rFVIIa in trauma and an extensive literature search. Accordingly, they found that cessation of bleeding was achieved in 26 of 36 (72%) patients and that acidosis diminished haemostatic effect of the drug, while hypothermia did not affect it. A survival rate of 61% seemed better than published survival of similar, or less severe trauma patients (30–57%). Their guidelines specify indications, contraindications, administration and preconditions for the use of rFVIIa in these patients. (See Appendix A). At the Epworth, rFVIIa is most commonly used in the setting of cardiac surgery. Indeed, the major haemostatic alterations associated with cardiopulmonary bypass can result in excessive intra- and post-operative bleeding. Many factors are implicated, including: hypothermia, haemodilution and activation of the clotting, fibrinolytic and inflammatory pathways. Other factors include technical aspects of the procedure such as repetitive or combined operations, prolonged duration of cardiopulmonary bypass time and pre-operative use of antiplatelet and anticoagulant agents. Increasingly, cardiac centres are starting to use rFVII off-label in the management of uncontrolled bleeding in cardiopulmonary bypass patients. Small case series

have demonstrated consistent shortening of INR, reduced bleeding and a low rate of adverse events attributable to rFVIIa. This seems to apply when rFVIIa is given intraop/or post-op for intractable bleeding.18 Nevertheless, the possibility of publication bias exists in that therapeutic failures or increases in adverse events may be underreported. Randomised, double-blinded, placebo-controlled trials are yet to be performed using rFVIIa in cardiopulmonary bypass population. Although used safely in the treatment of haemophiliac patients with inhibitors, various authors19 have raised concerns about an agent, which enhances thrombin generation and may trigger more generalised coagulation. This may be especially problematic if monocytes in general circulation express TF after cardiopulmonary bypass. Thus, the concern is both around disseminated intravascular coagulation and thrombotic complications. Nevertheless, current reports of its use for refractory bleeding are indicating few adverse events. At this point in time there is no published study that establishes a risk profile for the use of rFVIIa in uncontrolled cardiopulmonary bypass bleeding.

The Epworth Experience The Epworth Hospital currently performs in excess of 12,000 surgical cases per year of which 400 are cardiac operations. Operating theatre, pharmacy and intensive care records were searched to find any patients who were admin-

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Table 1. Recombinant factor VIIa use in Epworth Hospital (1/05 to 10/06) Gender

Age

Weight

Context

Temp.

pH

Dose (mg)

␮g/kg

Effect

Outcome

M M F M F F M M M M M

73 32 82 66 79 82 72 77 75 53 81

74 110 67 88 49 70.5 78 98 63 85 62

Cardiac Cardiac Cardiac Cardiac Cardiac Cardiac Cardiac Vascular Vascular Other surgeries Cardiac

35.8 ? 36.4 35.9 36.5 35.6 ? 35.3 ? 35 35.4

7.36 7.444 7.48 7.45 7.38 7.45 7.482 7.11 7.325 7.172 7.41

3.6 9.6 6 8.4 4.8 7.2 8.4 2.4 6 7.2 4.8

49 87 90 95 98 102 108 24 95 85 77

2 1 1 1 0 1 1 2 then 3 3 3 3

Living Living Living Living Living Living Living Deceased Deceased Deceased Deceased

Gender: M male, F female. Weight: kg. Context: Type of surgery preceding recombinant factor VIIa (rFVIIa). Temp.: ◦ C around time of rFVIIa administration. Dose: 1st dose of rFVIIa. Effect: 0 unknown, 1 bleeding stopped, 2 bleeding decreased, 3 bleeding unchanged. Outcome: Living to discharge from hospital.

istered rFVIIa over the preceding 21 months (1/05 to 10/06) at the Epworth’s Richmond campus. A chart review was performed to determine demographics and clinical parameters around the time of rFVIIa administration. Eleven patients were identified. They were aged between 32 and 82 with a median age of 75. There were eight males and three females. The surgery performed was eight cardiac, two vascular and one general surgical procedures. Four of the patients had their rFVIIa administered in the intensive care unit, and seven in theatre. An average of 10 units of RBC’s was administered prior to the rFVIIa with a range of 2–25 units prior. The average pH at the time of administration was 7.36 (Table 1). Six patients had a reduction or cessation in their bleeding after rFVIIa. One patient’s records were incomplete but survived to discharge. Four patients died soon after the administration of rFVIIa with intractable bleeding. Of those that died, two had a pH < 7.2 at the time of administration. The average first dose of rFVIIa was 83 mcg/kg, with a dose range from 24 to 108 mcg/kg. Two of the patients who subsequently died had received a second dose.

Haemostasis Registry The Haemostasis Registry was established in February 2005 at the Monash University Department of Epidemiology and Preventive Medicine. The purpose of this registry is to gain information on safety, efficacy and appropriateness of use and dosages of rFVIIa where it is used for nonhaemophiliac patients. To date, more than 650 patients around Australasia have been enrolled (Appendix A).

Summary Activated recombinant factor VII is firmly established as a treatment for haemophiliacs with inhibitors and it seems promising as a novel treatment for bleeding in many other scenarios. However, it is unlikely that randomised trials will be performed to guide our further usage. In order to provide appropriate and cost-effective prescription of this therapy, large scale registry data will be required. The Epworth has begun to use rFVIIa in cases of uncontrolled haemorrhage with some encouraging results.

Appendix A. Recommendations for the Use of rFVIIa in Uncontrolled Haemorrhage Indication Any salvageable patient suffering from massive, uncontrolled haemorrhage that fails to respond to appropriate surgical measures and blood component therapy.

Definitions Massive bleeding is defined as one of the following:20,21 (1) Loss of entire blood volume within 24 h (10 U of packed RBC in a patient weighing 70 kg). (2) Loss of 50% of blood volume within 3 h. (3) Blood loss at a rate of 150 mL min−1 . (4) Blood loss at a rate of 1.5 mL kg−1 min−1 for ≥20 min. Failure to arrest the haemorrhage despite: (1) Application of all accepted and available surgical measures (e.g. ligation of damaged vessels, tamponade, or packing of the bleeding site, and induction of localised thrombosis). Appropriate replacement therapy:21–23 (1) FFP: 10–15 mL kg−1 (4–6 U for a patient weighing 70 kg). (2) Cryoprecipitate: 1–2 U 10 kg−1 (10–15 U for a patient weighing 70 kg). (3) Platelets: 1–2 U 10 kg−1 (10–15 U for a patient weighing 70 kg). (4) Correction of acidosis (defined as pH ≥ 7.2). (5) Warming of hypothermic patients (recommended, but not mandatory for administration of rFVIIa).

Contraindications Absolute unsalvageable patients, as identified according to the clinical evaluation of the treating medical team. Relative history of thromboembolic events (e.g. pulmonary emboli, myocardial infarction, cerebrovascular accident, deep vein thrombosis) within the previous six months.

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Labattaglia and Ihle Recombinant Activated Factor VII: Current Perspectives and Epworth Experience

Administration Guidelines for rFVIIa (1) The blood bank should be immediately alerted to incidents of massive bleeding to facilitate timely preparation of the various blood components required.21 (2) rFVIIa should be administered as early as possible (after conventional treatments have failed to arrest bleeding), and should be given in conjunction with transfusion of 8–10 U of packed RBC in order to avoid further loss of clotting factors, exacerbation of acidosis, and further lowering of body temperature (all of which adversely affect the prognosis).

Preconditions for rFVIIa Administration Haematological parameters As rFVIIa acts on the patient’s own clotting mechanism, its administration should be considered after blood component therapy has achieved the following: (1) Fibrinogen levels of ≥50 mg dL−1 100 mg dL−1 ). (2) Platelet levels of ≥50 000 × 109 L−1 100 000 × 109 L−1 ).

(preferably (preferably

If these parameters cannot be monitored on an immediate basis (i.e., in ‘real time’ by point of care testing), as is usually the case, the patient should receive appropriate empirical replacement therapy (as previously defined). pH: Clinical and laboratory evidence suggests that the efficacy of rFVIIa decreases at a pH of ≤7.124 Hence, correction of the pH to ≥7.2 is recommended prior to its administration. Body temperature: rFVIIa retains its activity in the presence of hypothermia, hence the latter does not limit its use. Nonetheless, body temperature should be restored to physiological values as much as possible. Note: As laboratory tests are conducted at 37 ◦ C, they may not demonstrate the true measure of coagulopathy in a hypothermic patient.

Dosage The recommended initial dose of rFVIIa for treatment of massive bleeding is ∼ =20 (100–140) ␮g kg−1 administered intravenously over 2–5 min. This is based on the experience in haemophilia patients and analysis of data of our trauma patients.

Repeat Dosage If haemorrhage persists beyond 15–20 min, following the first administration of rFVIIa, an additional dose of ∼ =100 ␮g kg−1 should be considered. If the response remains inadequate following a total dose of >200 ␮g kg−1 , the preconditions for rFVIIa administration should be re-checked, if possible, and corrected as necessary before a third dose is considered. If this is not feasible, the empirical administration of FFP (10–15 mL kg−1 or 4–6 U for 70 kg), cryoprecipitate (1–2 U 10 kg−1 or 10–15 U for 70 kg), and platelets (1–2 U 10 kg−1 or 10–15 U for 70 kg) should be considered,

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and the pH and calcium should be checked and corrected. Only after these measures have been applied should a third dose of rFVIIa ∼ =100 ␮g kg−1 be administered.

Monitoring Currently, there is no laboratory method for monitoring the effect of rFVIIa. The best available indicator of rFVIIa efficacy is the arrest of haemorrhage judged by visual evidence, haemodynamic stabilisation and a reduced demand for blood components. The PT is expected to shorten, frequently below the normal expected range (as there is TF in the test tube), but this does not reflect efficacy. Rotation thromboelastography and thrombin generation are future candidate tests for evaluation of efficacy of rFVIIa. pH and platelet levels were identified as independent predictors of both patient response and mortality (p < 0.001 and p = 0.003, respectively). Only pH was found to be a significant independent predictor of patient response (p < 0.001) Patients with pH less than 7.2 were significantly more likely to die [OR = 7.760 (95% CI = 4.372–13.773)] and were less likely to respond to rFVIIa than those with normal pH [OR = 0.240 (95% CI = 0.129–0.447)]

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Labattaglia and Ihle Recombinant Activated Factor VII: Current Perspectives and Epworth Experience

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