1. Safety and efficacy of off-label use of recombinant factor VIIa in the treatment of life threatening haemorrhage during and after surgery.
Qureshi H1, Hofer D1, Aneva P1, Esmail F2, Crucean A2, Masala N2, Rai V2, Archdeacon C3, Ahmed A2, Peek G2
Department of Transfusion Medicine1 Cardiac Surgery2, and Clinical Audit, Standard & Effectiveness3
University Hospitals of Leicester NHS Trust, Leicester, LE1 5WW, U.K.
INTRODUCTION
RESULTS Figure 3
Surgical re-exploration to determine cause of bleeding (n=26)
Efficacy of rVIIa (n=90)
Recombinant factor VIIa (rVIIa) plays a central role in initiating coagulation and is often used as a ‘universal haemostatic agent’ to control life threatening haemorrhage resulting from acquired coagulopathy associated with trauma or complex major surgery. Published literature and anecdotal experience suggests variable success rates for its use in these settings. However, there are concerns about the safety of this drug, especially its potential for serious thromboembolic complications, as reported in various publications1,2,3,4 and a prospective randomized study in patients with intracranial haemorrhage5. Factor VIIa is not licensed for use in acquired coagulopathy, and given its high cost, and concerns about safety, there is a need to limit its use to those situations where it is likely to be most effective.
MODE OF ACTION OF F VIIa
Figure 1 – Institution’s guideline
Factor VIIa initiates thrombin generation primarily through two pathways.
The first pathway occurs at the site of tissue injury, where FVIIa is complexed with Tissue Factor (TF).
The second pathway occurs on the surface of activated platelets, independent of tissue factor.
1: Following injury, TF, present in the vascular subendothelium, is exposed to circulating FVIIa, and forms an active VIIa-TF complex. This complex, in turn, activates FIX and X. FXa then forms a complex with FVa. FXa-FVa complex, known as Prothrombinase, converts Prothrombin to Thrombin. Thrombin then converts Fibrinogen to Fibrin.
2: At pharmacological concentrations FVIIa directly activates FX on the surface of locally activated platelets. This activation then initiates the ‘thrombin burst’, independently of FVIII and FIX. This pathway is independent of TF.
The ‘thrombin burst’ leads to the formation of a stable clot.
Table 1: Blood loss and coagulation parameters before administration of rVIIa
Treatment Success Group
Median (Interquartile Range)
Treatment Failure Group
P Value
Volume of Blood Loss (mls)
1125 (IQR 815 – 1423)
1000 (IQR 643 – 1322)
0.348
Platelet count (x 109/L)
129 (IQR 102 – 180)
143 (IQR )
0.818
Activated Partial Thrombin Time (APTT, seconds)
38.7 (IQR )
40.6 (IQR 37 – 49)
0.243
Prothrombin Time (INR)
1.2 (IQR 1.1 – 1.3)
1.3 (IQR 1.1 – 1.4)
0.155
Table 2: Blood components use before and after administration of rVIIa
Before rVIIa
After rVIIa
P Value
Total
Median
IQR
Packed Red Cells (Units)
300 4
2-6
200 3
0.0061
Platelets (Units)
100 1
1-2 43
0-1
0.0072
Fresh Frozen Plasma (Units)
194 2
2-4 49
0-2
0.0001
Cryoprecipitate (5 units Pool)
123
2-2 26
0.5
METHODS
We carried out a retrospective cohort study of 68 adults and 22 children or neonates, consecutively treated with rVIIa to control major or life threatening haemorrhage in the setting of major surgery or Extra Corporeal Membrane Oxygenation (ECMO) therapy, in a single large institution. A standard dataset was designed to collect data on patient demography, indications and dose of rVIIa, volume of post-operative blood loss, laboratory coagulation parameters before and after the administration of rVIIa, and clinical outcomes in terms of its efficacy in arresting or significantly reducing bleeding, and the incidence of major thromboembolic complications. Data was collected by one of four physicians trained in the use of pre-defined dataset, and the accuracy of data collection was validated by another physician who recollected data, using the same dataset, in 11 randomly selected case records from this cohort. Statistical analyses were performed using Microsoft excel® v 2007.
DISCUSSION
RESULTS
This study was carried out in a single large institution where local guidelines (Figure 1) have been implemented for the use of rVIIa to control major bleeding resulting from acquired coagulopathy following trauma or surgery. Our guideline states that a surgical cause of bleeding is excluded and attempts are made to identify and reverse any residual heparin (cardiac bypass surgery), to correct coagulation abnormalities by appropriate blood component therapy and antifibrinolytics, and to correct hypothermia and acidosis before considering the use of rVIIa. In this cohort, successful outcome was demonstrated in just under half the patients treated with rVIIa. Due to the limitations of a retrospective cohort study, and variable quality of documentation in clinical case records, it was not possible to determine whether the above pre-requisites, stated in our guideline, had been met in all cases. There was no consistent documentation of arterial blood pH to determine if significant acidosis or residual heparin might have contributed to treatment failure. Point of care monitoring of whole blood coagulation, using thromboelastography, has been implemented in our institution in order to identify and correct underlying cause of coagulopathy at an early stage. However, data included this study precedes the implementation of thromboelastography in our institution.
The incidence of major thrombotic complications in our series appears to be similar to that quoted in the manufacturer’s product datasheet. However, it is not clear from this study whether rVIIa caused, or contributed to the development of acute renal failure or Multi-Organ Dysfunction observed in a small number of patients in this cohort.
The majority (83%, n=75) of patients in this series received rVIIa following cardiac surgery (n=54 adults and n=21 children or neonates). Figure 2 shows patients demography and various clinical settings in which rVIIa was used. Median dose of rVIIa was 85 ug/Kg (range ). Second dose of rVIIa was administered to 17 patients, and of these, three patients were given a 3rd dose.
Following administration of rVIIa, treatment was considered successful if there was either complete cessation or greater than 50% reduction in bleeding, and or greater than 50% reduction in the volume of packed red blood cells (RBC) transfused. This successful outcome was observed in 42 (47%) patients (Figure 3). Of the 17 patients who received a second dose of rVIIa, only 3 responded ather the second dose, and of the 3 patients receiving the third dose, successful outcome was observed in only one patient.
There was no significant difference in laboratory coagulation parameters or the volume of blood loss recorded prior to the administration of rVIIa between responders and non-responders (Table 1). No data was available to determine whether patients who failed to respond to rVIIa had significant acidosis.
Overall, a significant reduction was observed in the volume of RBC, Fresh Frozen Plasma (FFP), Platelets or Cryoprecipitate transfused after the administration of rVIIa (Table 2).
Major thrombotic complications were observed in 4 patients (4.5%). One patient developed a fatal thrombus in left ventricle and arch of aorta immediately after receiving rVIIa. The second patient suffered a thrombotic stroke, the third, a thrombotic stroke and MI, and the fourth patient developed extensive deep vein thrombosis. All four patients received a single dose of rVIIa and the thrombotic episodes were considered to be related to this treatment.
Acute renal failure, requiring haemodialysis, was observed in 7 patients (8%), and two other patients developed multi-organ dysfunction. However, due to other variables, it was not possible to attribute these complications to the administration of rVIIa.
CONCLUSION
Our study demonstrates that treatment with rVIIa was effective in controlling bleeding in 47% of patients who received this drug. Moreover, a significant reduction in the requirement for blood component therapy was demonstrated after the administration of rVIIa. However, major thrombotic complications were observed in 4.5% of patients treated. Although this treatment is often used as a desperate measure in situations of life threatening, and otherwise uncontrollable haemorrhage, the associated risks require careful consideration. There is a need for a large, appropriately designed, prospective, comparative study to provide definitive evidence of efficacy and safety of rVIIa in acquired coagulopathy.
REFERENCES
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M.C.Reade, Y.N. Toyoda and H.N. Murray, Failure of an Abiomed ventricular assist device in association with factor VIIa administration, Minerva Anestesiol 74(2008),pp
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Results - Figure 2
Clinical categories of patients – n90