To the Editor: Current Australian guidelines for urgent warfarin reversal recommend withholding warfarin, and giving vitamin K as well as factor replacement (Prothrombinex HT; PTX) with or without fresh frozen plasma (FFP).1 PTX administration without FFP is recommended only when FFP is unavailable, as PTX factor VII levels are low and unquantified.2 Transfusion of 25–50 IU/kg PTX and 150–300 mL of FFP is advised. We examined the effectiveness of warfarin reversal using PTX alone or combined with FFP.

One hundred and fifty-five patients given PTX were identified from the transfusion medicine unit’s computer records. Fifty patients were excluded — no warfarin (19), non-hospital patients (11), no record of PTX administration (14), no monitoring (5), normal international normalised ratio (INR) (1).

One hundred and five patients who had received warfarin were reviewed. The reasons for anticoagulation were atrial fibrillation (45 patients), venous thromboembolism (22 patients), cardiac valve replacement (21 patients), myocardial infarction (9 patients), and other (8 patients). PTX was administered for bleeding in 51 patients (32 had major bleeds), suspected bleeding in eight patients, high INR in 11 patients, and before a procedure in 35 patients. Bleeding severity was graded using published criteria.3 Post-treatment INR and patient details were used to determine clinically significant INR lowering and haemostasis.

The patients were divided into two groups — patients administered PTX without FFP (n = 74) and patients administered PTX and FFP (n = 31) (Box 1). Seventy-four patients (71% receiving PTX; 67.7% PTX + FFP) were given vitamin K (71 intravenously) to ensure ongoing correction of coagulopathy. This was administered within 2 hours of PTX (77%), with doses 1–2.5 mg (44 patients), 3–6 mg (13 patients), and 10 mg (17 patients).

The mean PTX dose used was 862 IU or 12.9 IU/kg. Slightly higher PTX doses were administered to patients in the PTX group (913 IU or 13.1 IU/kg) than to patients receiving PTX and FFP (742 IU or 12.3 IU/kg) (Box 1). Seven of 89 patients (7.9%) received the published recommended PTX dose.1 The remaining patients received < 25 IU/kg. Neither the degree of warfarin coagulopathy nor FFP transfusion appeared to influence PTX doses administered. One patient in the PTX group with end-stage renal impairment failed to show any reduction in INR, but did achieve haemostasis. All patients with bleeding achieved haemostasis after PTX.

The degree of INR correction after PTX varied considerably, with the percentage reduction in INR after PTX ranging from 0 to > 90% per vial of PTX transfused (Box 2). Achievement of haemostasis did not require normalisation of INR (Box 2). The INR is designed for monitoring therapeutic warfarin levels and its accuracy declines with excessively prolonged clotting times. As PTX is more likely to produce correction of coagulopathy through increased thrombin rather than through factor VII replacement, INR may not be the best test for monitoring haemostatic changes after PTX.

Our data suggest that FFP may be unnecessary when PTX is used to reverse warfarin coagulopathy. We have also shown that doses of PTX under 25 IU/kg are effective. Administration of low-dose PTX will produce cost savings and may reduce PTX-associated adverse events (including infusional reactions, thrombocytopenia [secondary to heparin], and thrombosis). The risks associated with FFP transfusion (including allergic reaction, transfusion-related acute lung injury, fluid overload, and infection transmission) would be eliminated. A prospective study is necessary to confirm our findings and assess the efficacy of lower PTX doses, so that, if our results are confirmed, warfarin reversal guidelines can be reviewed.