OAT is an effective, safe and inexpensive method used in the prevention and treatment of thromboembolic complications in patients with cardiovascular diseases5
. Because this therapy prolongs the time for clotting to occur, the risk of haemorrhage and bleeding increases in patients on OAT, especially in the elderly8,9,16,17
. Reduced synthesis of vitamin K-dependent coagulation factors, along with massive bleeding due to the OAT, causes an acquired deficiency of prothrombin complex factors, which prevents normal haemostasis. Although the American College of Chest Physicians guidelines13
recommend the use of rFVIIa and some studies have demonstrated the effectiveness of this drug in the treatment of critical bleeding18,19
, for the management of patients taking vitamin K antagonists with spontaneous or trauma-induced bleeding, other published guidelines do not recommend its routine use due to “insufficient safety data and lack of information on appropriate dose”16
guidelines consider PCC the most appropriate product to reverse the effects of vitamin K antagonists. These concentrates provide prompt restoration of haemostasis and the start of coagulation12,20
. As shown in some studies, both PCC and rFVIIa reverse warfarin anticoagulation, but only PCC restore overall thrombin generation and are more effective than rFVIIa in restoring haemostasis21,22
All PCC contain coagulation factors II, VII, IX and X, but if the amount of FVII is very low, the concentrates are considered as three-factor PCC; conversely if the amount of FVII is normal these products are considered as four-factor PCC. Published studies have been conducted on both these types of concentrates. The efficacy and safety of three-factor PCC shown by Imberti et al.23
was contradicted by the study by Holland et al.24
The major difference between the two studies was the patients’ baseline INR, which was moderately elevated in the Italian study (mean, 3.5), but very high in the Canadian study (mean, 8.6). This might suggest that three-factor PCC are not very effective in the case of high INR, although our study, albeit with some limitations, showed that even in the case of high baseline INR, such as in the group B patients (mean, 6.58), a three-factor PCC was effective in stopping bleeding and restoring haemostasis. Pabinger10
and their colleagues reported the efficacy of four-factor PCC, but also described four cases of venous thromboembolism. Can it be assumed, therefore, that four-factor PCC are less safe than three-factor PCC? The four cases of venous thromboembolism reported in literature occurred in patients at high risk of venous thromboembolism after a high dose of PCC (40–100 IU/Kg). Therefore, as also affirmed by Makris et al.27
, it is impossible to correlate, with absolute certainty, the occurrence of a thrombotic event with the type of PCC infused. Comparative studies between three- and four-factor PCC are needed to determine whether there are differences in efficacy and safety between the tywo types.
In our study, in accordance with guidelines and published studies, physicians who decided to reverse excessive anticoagulation used three-factor PCC. In this study data from 47 consecutive patients were collected over the last 2 years. The baseline characteristics of the patients in this study were similar to those of the studies reported by Imberti et al
and Tran et al
, but the mean age was higher than that of the patients in the studies by Schick et al
and Bruce et al
The number of patients enrolled in our study was comparable to the number in several other studies,23,28
although our cohort was larger than that in the study by Bruce et al
Most of the patients in our study were being treated with OAT for atrial fibrillation; other treatment indications were heart diseases (mechanical valve or ischaemic cardiomyopathy) and previous venous thromboembolism. The INR and vital signs were checked before treatment and were monitored during the post-operative course.
Particular attention was paid to the control of possible adverse reactions caused by the administration of PCC29
. Three cases of thrombosis after the use of PCC were reported by Roddie et al
; Pabinger et al
described only one case of venous thromboembolism, but in these studies a high dose of PCC (40–100 IU/Kg) was administered to patients with multiple risk factors for thrombosis. The dose of PCC in our study, like that of Viguè et al
in which patients were treated at hospitalisation with a bolus of PCC 10 IU/Kg, as in our study, was very low compared to the dose used in the study by Imberti et al
., in which patients received a dose of 35–50 IU/Kg, stratified according to initial INR23
. In our study the risk of venous thromboembolism led physicians to use a low dose of PCC, but we do not think that this was the main cause of the high mortality. Computed tomography scanning performed after treatment showed resolution of cerebral haemorrhages and laboratory tests confirmed, in most patients, a satisfactory recovery of haemostasis. The deaths occurred due to a sudden worsening of the clinical and neurological state in elderly patients in whom treatment had not been prompt. Published guidelines recommend monitoring the INR within 30 minutes after the administration of PCC, but in our study, because the first measurement of INR after treatment was performed at different times for each patient, it was not possible to determine correlations among INR decrease, amount of PCC used and efficacy.
Hanslik et al.31
confirmed the recommendations of international guidelines, establishing that the administration of intravenous vitamin K 10 mg is the first step to take to reverse the effects of oral anticoagulants in patients with massive haemorrhage and a high INR, but in our case, only 25.5% of patients received this therapy, a value that differs substantially from that in other studies10,24,30
, in which vitamin K was infused into 52% to 88% of patients. In the study performed by Imberti et al.23
all patients received vitamin K, but that was a prospective study, unlike our retrospective, observational study.
The present study revealed that, in the absence of a shared protocol, the guidelines are not always applied correctly and consistently, and that variability in treatment often depends on the clinical experience of each physician. If bleeding does not stop and haemostasis is not restored, the guidelines recommend administered FFP or PCC. FFP is often used in such cases, but the ideal dosage to obtain a significant result is unknown32
and the possibility of volume overload, especially in the elderly, must be considered. In our study 34% of the patients received FFP, but all patients receiving FFP also needed PCC to reverse anticoagulation. Only 6.4% of patients required administration of vitamin K, FFP and PCC. In the case of major haemorrhage or when the haemoglobin concentration is below 8.0 g/dL, it is recommended that red blood cells are administered: 25.5% of our patients were give red blood cell transfusions at hospitalization.
In this study no significant differences were found between patients treated with acenocoumarol or warfarin.
The mortality rate in other published studies ranged between 10% and 28%23,28,33
. In our study 46.8% of the patients died, similar to the rate in the study by Bruce et al
In most cases, death was caused by serious head trauma, which produced fatal intracranial bleeding, or by severe spontaneous intracranial haemorrhage, which induced a state of irreversible coma in the anticoagulated elderly patients and subsequent cardiopulmonary arrest. A delay in the administration of therapy, underdosing of PCC and incorrect use of vitamin K may also have been factors contributing to the high number of deaths.
In our retrospective study we observed a discrepancy between the published guidelines on the management of patients on vitamin K antagonists with critical haemorrhage and the actual use of PCC in the different wards of our hospital. The management of these patients was often based only on the experience of the treating physicians rather than on the application of local protocols. In this way, the patients’ management becomes subjective, leading to inappropriate therapeutic variability.