BJA Advance Access originally published online on August 16, 2006
British Journal of Anaesthesia 2006 97(4):476-481; doi:10.1093/bja/ael205
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Predicting response to recombinant factor VIIa in non-haemophiliac patients with severe haemorrhage
1 Department of Haematology, Addenbrooke's Hospital Cambridge CB2 2QQ, UK
2 Department of Surgery, Addenbrooke's Hospital Cambridge CB2 2QQ, UK
3 John Farman Intensive Care Unit, Addenbrooke's Hospital Cambridge CB2 2QQ, UK
*Corresponding author: John Farman Intensive Care Unit, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: gilbertpark{at}doctors.org.uk
Accepted for publication June 14, 2006.
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Abstract |
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Background. Despite increasing use of recombinant factor VIIa (rFVIIa) in non-haemophiliac patients, it is unclear when rFVIIa might be effective.
Methods. A single centre review of consecutive non-haemophiliac patients receiving rFVIIa for the management of severe haemorrhage. Treatments with rFVIIa were at a dose of 90 µg kg–1 repeated at three hourly intervals at the clinicians' discretion.
Results. Eighteen patients received rFVIIa. Six patients survived to discharge and 12 patients died in hospital. The median (range) Sequential Organ Failure Assessment (SOFA) score at the time of administration of rFVIIa for the group that survived was 8.0 (5–12) compared with the group that died 12.0 (7.0–14.0) (P=0.03). One of the patients who survived (17%) had organ failure at the time of rFVIIa administration compared with 11 of those who died (92%) (P=0.004). Fifteen patients survived long enough to consider a second dose of rFVIIa, one patient who survived to discharge needed more than one dose (1/6, 17%), compared with seven of those who later died in hospital (7/9, 78%) (P=0.04). The survivors had a significant reduction in blood product requirements after rFVIIa, while patients who died did not. Neither the prothrombin time nor the activated partial thromboplastin time before or after rFVIIa predicted survival.
Conclusions. High SOFA score and failure to respond to one adequate dose of rFVIIa appear to identify patients with poor prognosis. These observations may help in determining when rFVIIa treatment is likely to be futile.
Keywords: blood, coagulation; blood, loss; blood, transfusion; intensive care
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Introduction |
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Recombinant factor VIIa (rFVIIa, Novoseven®, Novo Nordisk A/S) activates haemostasis by binding to tissue factor and platelets, resulting in thrombin generation at sites of haemorrhage.1 It is licensed in the UK for the treatment of bleeding in haemophiliacs who have factor VIII inhibitors2–4 although it is increasingly being used in the treatment of a broad spectrum of acquired bleeding disorders5 (discussed further by Mittal and Watson6). rFVIIa is expensive at approximately £3500 per dose for a 70 kg patient (90 µ kg–1). Randomized placebo-controlled trials of rFVIIa in non-haemophiliacs have shown it to be beneficial in some specific disease states7 8 but not in others.9 10 Case reports have shown its effectiveness in those with massive or life-threatening haemorrhage who fail to respond to surgery, blood product replacement therapy or both,11–14 but others have shown that ‘last ditch’ use is ineffective.15 As the mechanism of action of rFVIIa may differ between haemophiliac patients with localized bleeding and non-haemophilic patients with widespread haemorrhage and complex multi-organ damage similar efficacy cannot be assumed. To determine the factors that indicate whether treatment with rFVIIa is likely to be futile, we reviewed our use of rFVIIa in non-haemophiliac patients and compared patient characteristics and laboratory indices of those who survived to discharge with those who died in hospital.
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Methods |
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Haematology laboratory records were used to identify all non-haemophiliac patients treated with rFVIIa at Addenbrooke's Hospital between January 2003 and January 2005. Recombinant FVIIa was given as per our hospital protocol (Appendix 1; local protocol used during the time studied) and its use was always recorded on the haematology database. All treatments with rFVIIa were given at an initial dose of 90 µg kg–1, which was repeated at 3-h intervals16 at the discretion of the treating clinicians.
Notes from these patients were reviewed and data were collected on: patient characteristics, co-existing medical problems, prothrombin time (PT), activated partial thromboplastin time (APTT), and blood product requirement before and after treatment with rFVIIa, number of doses given, survival, and thrombotic complications after the use of rFVIIa. Sequential Organ Failure Assessment (SOFA) scores17 18 were calculated on day of administration of rFVIIa. The SOFA score is composed of scores from six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological) graded from 0 to 4 according to the degree of failure (Table 1) and is a reliable and accurate assessment of the severity of a patient's illness.18 Survival was defined as discharge from hospital. When the presence or absence of individual major organ failure was assessed separately, and not in the context of the SOFA score, definitions were as follows: renal failure—the need for haemofiltration, liver failure—any combination of jaundice, ascites, prolonged PT/APTT and (if unsedated) encephalopathy in patients with known liver disease, cardiovascular failure—the need for inotropic drug support or pre-morbid New York Heart Association (NYHA) grade III or IV cardiac failure, chronic reticulo-endothelial failure as patients who had chronic bone marrow failure with a combined need for regular supportive blood transfusion and a co-existing pre-morbid thrombocytopenia (platelet count <30x109 litre–1). Patients who developed thrombocytopenia as part of the acute illness were not considered to have chronic reticulo-endothelial failure. Respiratory failure was defined by clinical and laboratory assessment as the need for mechanical ventilatory support because of failure of the pulmonary system to meet the metabolic demands of the body. Patients who were ventilated as part of an airway protective strategy, but who did not have pulmonary failure, were not considered to have respiratory failure. Blood products were defined as packed red cells, fresh frozen plasma, cryoprecipitate and platelets.
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, partial pressure of O2 in arterial blood; 
, inspiratory O2 fraction; MAP, mean arterial pressure (mmHg); NOR, norepinephrine; Db, dobutamine; Dp, dopamine; EPI, epinephrine [Db, Dp, EPI and NOR given for at least 1 h (µg kg–1 min–1)]; GCS, Glasgow Coma ScaleContinuous variables are summarized as median with range. Categorical variables are expressed as a number with percentage. Groups were compared using the Mann–Whitney test for independent continuous variables, the Wilcoxon signed rank test for paired continuous variables and Fisher's exact test for categorical variables. Significance was defined as P<0.05.
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Results |
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Eighteen patients (17 surgical, 1 medical) received rFVIIa (Table 2) during the period studied. There were 12 males, and the median (range) age was 52 (17–82) yr. Twelve patients died in hospital. Of those, eight patients had clinically active bleeding at the time of death.
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Table 3 shows a comparison between those who died in hospital and those who survived to discharge. There were no statistically significant differences observed between the two groups in terms of median age, platelet count, PT pre- and post-rFVIIa, APTT pre- and post-rFVIIa, and blood product units transfused pre- and post-rFVIIa treatment.
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The SOFA score at the time of administration of rFVIIa was significantly lower in the group of patients that survived when compared with the group of patients who subsequently died. The median (range) SOFA score for the group that survived was 8.0 (5–12) compared with the group that died 12.0 (7–14) (P=0.03) (Table 3). The failure of an individual organ system at the time of rFVIIa administration was also associated with death in hospital. Eleven of the twelve patients who died (92%) had organ failure at the time of rFVIIa administration compared with one of the six patients who survived (17%) (P=0.004). The one patient who died but did not have organ failure at the time of dosing had uncontrolled thrombotic thrombocytopenia purpura refractory to plasma exchange and with platelets persistently <10x109 litre–1.
For all 18 patients, the median (range) PT was 23.4 (13.9–29.3) s pre- and 12.1 (9.7–16.3) s post-rFVIIa (P<0.01), while the median (range) APTT was 86 (30–240) s pre- and 50 (27–74) s post-rFVIIa (P<0.01). All patients with prolonged PT, APTT or both showed improvement in these blood clotting parameters after rFVIIa.
In our series two-thirds of the patients died despite rFVIIa treatment, nine of organ failure and three from uncontrolled haemorrhage. None of the patients treated with rFVIIa were bleeding exclusively into surgical drains with many bleeding from multiple sites and the majority bleeding internally making assessment of haemorrhagic response to rFVIIa difficult. We compared the blood product requirement before and after rFVIIa as a surrogate marker of haemorrhagic response to rFVIIa, because blood loss was occult in the majority of patients. The median number of blood product units transfused was significantly lower after rFVIIa administration in the group that survived (45 units pre, 19 units post; P=0.03), but there was no reduction in blood product requirements after the administration of rFVIIa in the group that died (28 units pre, 33 units post; P=0.94) (Table 3).
A second dose of rFVIIa was recommended if patients had significant bleeding 3 h after the first dose. Of the 12 patients who died, three did so within 3 h of rFVIIa treatment (Patients 8, 14 and 15). From the 15 patients who survived long enough to consider a second dose of rFVIIa, one patient who survived to discharge needed more than one dose (1/6, 17%), compared with seven of those who later died in hospital (7/9, 78%) (P=0.04).
Four patients (22%) developed arterial or venous thrombosis. Patient 1 suffered a crush injury and required military anti-shock trousers at the scene; 4 days post-rFVIIa he developed an ischaemic leg as a result of femoral artery thrombosis and had an above knee amputation. Patient 2 suffered a pulmonary embolus 2 weeks after rFVIIa treatment. Patient 11 had a massive gastrointestinal haemorrhage with coexisting, severe aortic valve stenosis, and known left anterior descending coronary artery stenosis. Considered unfit for surgery he continued to bleed despite rFVIIa, dying of a myocardial infarction 2 days later. Patient 17 had a bleeding duodenal ulcer complicating end stage liver disease. After rFVIIa and surgery the patient developed pneumonia, respiratory failure and renal failure. Four days after receiving rFVIIa the patient suffered a myocardial infarction and died.
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Discussion |
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Recombinant FVIIa is being increasingly used in the management of non-haemophiliac patients with life-threatening bleeding.5 Numerous case reports have described successful outcomes in a variety of patients, although data from randomized placebo-controlled trials have not found a universally beneficial effect. We and other groups15 19 20 have found that the majority of non-haemophiliac patients treated with rFVIIa are bleeding after operation or from trauma. Previous studies have highlighted a large proportion of patients who die despite rFVIIa treatment. However, information to guide clinicians as to which patients are likely to benefit, and when and how many times they should be treated is limited.20
Blood product transfusion before and after rFVIIa treatment was used as a surrogate marker for blood loss as haemorrhage was occult in the majority of patients. After rFVIIa, we only observed a reduction in blood product requirement in the group of patients that survived. There was no reduction in blood product requirements after rFVIIa treatment in the group of patients that died. This suggests a physiological difference in terms of capacity to respond to rFVIIa existed at the time of administration of the drug between the two groups of patients and that this difference may have prognostic value. This observation was supported by a difference in the SOFA scores between the two groups.
The SOFA score, a well-established assessment of the severity of illness, at the time of starting rFVIIa was significantly lower in survivors compared with patients who died in hospital. However, the number of patients in this series is too small to accurately quantify the predictive value of such a scoring system. In keeping with this finding we observed that patients with organ failure at the time of administration of rFVIIa treatment had a high mortality, whereas those patients without organ failure had a good prognosis. The one survivor with organ failure had acute alveolar haemorrhage suggesting that the use of rFVIIa may be of lesser value in patients with insidious development of organ failure or organ failure not directly attributable to bleeding, such as pulmonary haemorrhage. Frequently excessive blood loss (especially when it is becoming life threatening) and organ failure will occur simultaneously, our data raises the hypothesis that rFVIIa treatment should be considered early and before the onset of organ failure. This hypothesis needs to be tested prospectively for feasibility and efficacy, but the potential utility of the SOFA score is supported by recent work on risk assessment in this clinical setting.20
Importantly, patients in our series with a pre-morbid uncorrected haemorrhagic illness, such as leukaemia (n=1), thrombotic thrombocytopenia purpura (n=1) and end-stage liver failure (n=5) all died. The short half-life of rFVIIa on the background of a chronic irreversible coagulopathy may in part account for this. The powerful, but transient, procoagulant effect of rFVIIa may also in part explain our finding that all patients, irrespective of whether they subsequently lived or died, had an in vitro response to rFVIIa as defined by improvements in the PT and APTT. In addition, the PT is a test driven in vitro by the mixing of tissue thromboplastin (tissue factor) to plasma, as a result the presence of even traces of rFVIIa in the test plasma is likely to shorten the PT, this being an in vitro effect rather than an in vivo effect. This may explain our observation that in vitro blood test results (PT and APTT) either before or after rFVIIa were not associated with survival to discharge.
Thrombocytopenia has been shown to reduce efficacy of rFVIIa in treating bleeding after bone marrow transplantation21 although in vitro rFVIIa enhances platelet adhesion and activation at normal and reduced platelet count.22 In our patients platelet count at the time of administration of rFVIIa did not differ between the group that survived and the group that died. This in part may reflect the different aetiologies of the causes of thrombocytopenia and bleeding in our study patients, which were mainly trauma and surgical with consumptive thrombocytopenia compared with the bone marrow transplant population where bone marrow failure is likely to be the primary cause for a low platelet count. Larger prospective randomized trials in the context of trauma and surgical bleeding will be able to evaluate further the effect of thrombocytopenia in this group of patients receiving rFVIIa.
The half-life of rFVIIa is approximately 3 h in haemophiliac patients, which is shortened in bleeding episodes.16 Although the half-life in non-haemophiliac recipients of rFVIIa is unknown, these data suggest that repeated doses would need to be given at approximately 3-h intervals to maintain a sustained haemostatic benefit. However, given the high cost of the drug, futile treatment should be avoided. Once treatment has been started with rFVIIa it is presently unclear how many doses patients should receive. The above data suggest that patients who fail to substantially respond to a single 90 µg kg–1 dose of rFVIIa have a poorer outcome than patients that do respond, despite further dosing.
Thrombosis occurred in 4 of 18 patients. Given the medical complexity of the patients in this series and the presence of several other risk factors it is impossible to estimate the contribution (if any) the use of rFVIIa had in the development of the thromboses. The incidence of thrombosis complicating rFVIIa treatment is reported as approximately 1%.23 The safety of rFVIIa is probably because of its localization to injured areas of the vascular tree by binding to tissue factor and activated platelets at the bleeding site, thus, avoiding systemic activation of coagulation.23 However, much of the clinical experience is in haemophiliacs whose bleeding is more commonly from relatively minor and, therefore, localized trauma. In non-haemophiliacs suffering from multi-organ trauma or sepsis endothelial damage/activation and coagulation activation is more widespread and thrombotic complications may theoretically be more common. One phase II randomized controlled trial of the use of rFVIIa/placebo in 277 patients with haemorrhage after blunt and penetrating trauma found no difference in thromboembolic events between treatment and control group.24 However, further prospective studies are required to fully assess the safety of rFVIIa in non-haemophiliac patients.25
The findings reported here lead us to hypothesize that high SOFA score and failure to respond to one adequate dose of rFVIIa identify patients with poor prognosis. Presently many physicians use rFVIIa when conventional surgical, interventional and blood product support measures have failed26 and after correction of acidosis5 (Appendix 2; our current protocol for the use of rFVIIa). The observations described here highlight a potential role for the SOFA score and other clinically based assessments at the time of considering rFVIIa use in determining when rFVIIa treatment is likely to be futile.
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Appendices |
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These can be viewed as supplementary data at BJA online.
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References |
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