Activated FVII has recently been used to correct bleeding diatheses in several scenarios, including warfarin-associated intracranial and intraspinal hematomas (11
). It acts by directly binding to tissue factor to activate thrombin generation, bypassing much of the cascade of coagulation factors (14
). There may also be an independent effect on activated platelet function (15
). FVIIa can be administered without typing or crossmatching, in minimal volumes of fluid, and with few reported immune-mediated reactions to date (16
). It also appears to have a low incidence of major prothrombotic complications, with only 17 thrombotic events reported for more than 480,000 standard doses administered between 1996 and October 2001(17
In this study, the use of FVIIa in conjunction with FFP was associated with shortened times to correction of INR and reduced the total dose of FFP required for correction of coagulopathy. However, the mortality rate was higher and discharge GCS scores were lower in patients treated with FVIIa. There are several possible explanations for this. There was bias in selecting patients to be treated with FVIIa: they tended to be in worse clinical condition on admission, with a lower GCS and higher APACHE II score. Half of the patients given FVIIa, but only 1 of 15 patients given FFP, had an admission GCS of 8 or less. Additionally, patients who were neurologically stable were generally not administered FVIIa, whereas patients given FVIIa often experienced progressing neurological deficits required urgent surgery, or heart failure.
Although there was a fourfold shorter time to correction with FVIIa, the median time from presentation was still 8.8 hours. This was largely because the decision to administer FVIIa was often not made at presentation. It is likely that with an established protocol, this time can be shortened significantly, to the order of minutes. On the other hand, the median time to correction with FFP alone was 32.2 hours from the time of admission. The long time resulted from numerous factors, including delays in getting FFP from the blood bank, time taken to administer the prescribed dose, and the almost invariable underestimation of the dose of FFP required. Even in a prospective trial where FFP was administered at the maximal tolerated rate according to a protocol, the mean time to correction was 9 hours. Additionally, in that trial, rapid infusion of FFP led to a significant complication rate (five of eight patients) (7
Despite the high incidence of coronary artery and cerebrovascular disease in the FVIIa group, there was only one thrombotic complication. A patient with severe peripheral vascular disease and end-stage renal disease who received multiple doses of FVIIa developed DIC and peripheral thrombotic complications. Both peripheral vascular disease and renal failure might have contributed to this complication. Pickard et al. (18
) reported a case of middle cerebral artery stroke after administration of FVIIa in a patient with subarachnoid hemorrhage and polycystic kidney disease with renal failure.
Our study had several drawbacks. It was retrospective in nature. There were no predetermined criteria for the administration of FVIIa, and the timing of administration of FVIIa and FFP and the timing of determination of the INR were not standardized. The patient population is heterogeneous regarding the location of the bleed, presentation, degree of anticoagulation, and comorbidities. Radiological data, such as serial CT scans to determine the degree of hemorrhage growth, would have been helpful but were not systematically available because of the retrospective nature of this report. Finally, because most of the patients who received FVIIa received it after a certain amount of FFP had already been infused, it is also possible that corrected INR reflects, to a certain extent, the FFP already infused.
It can also be argued that using the INR to define correction of coagulopathy is an unreliable indicator of the risk of ongoing bleeding. In fact, the INR is extremely sensitive to FVII levels and does not accurately reflect the prothrombin level (19
). Therefore, faster correction of INR may not necessarily translate to faster correction of coagulopathy. However, FVIIa also increases the plasma activities of factors IX and X in a dose-dependent manner (20
). Observations of our patients and several previously published case series have demonstrated the efficacy of FVIIa in normalizing the INR as well as in stopping bleeding in a variety of clinical situations, including bleeding associated with excessive anticoagulation (9
). Therefore, we believe that correction of the abnormal INR is likely to be associated with a correction of the in vivo coagulopathy as well.