Oral or intravenous vitamin K and fresh frozen plasma were the two available agents for the reversal of vitamin K antagonist, until evidence from randomized clinical trials supported the use of prothrombin complex concentrate (PCC).
There are significant limitations for vitamin K and fresh frozen plasma. First of all, the reversal of vitamin K antagonist with vitamin K is a time dependent process because it relies on the vitamin K dependent synthesis of the coagulation factors 2, 7, 9 and 10. As for the treatment with fresh frozen plasma, it is also time dependent due to the need of cross matching before administration in addition to being associated with a risk of fluid overload particularly among patients with heart or kidney diseases.[1]
The need for a rapid reversal for vitamin K antagonist has fueled interest in prothrombin complex concentrate (PCC), which can be classified into two types:
"1. For intra- or postoperative bleeding clearly related to aspirin, we suggest that platelettransfusion be considered (dose: 0.7 × 1011 [i.e. two standard concentrates] per 7 kg body weight in adults). (Level of Evidence: C)"
"5. According to pharmacological characteristics, we suggest that the management of ticagrelor may be comparable to clopidogrel (i.e. withdrawal interval of 5 days). (Level of Evidence: C)"
"3. We suggest that severe bleeding associated with subcutaneous LMWH and unresponsive to initial administration of protamine could be treated with a second dose of protamine (0.5 mg per 100 anti-FXa units of LMWH administered). (Level of Evidence: C)"
"1. We suggest that the administration of rFVIIa could be considered to treat severe bleeding associated with subcutaneous administration of fondaparinux (off-label treatment). (Level of Evidence: C)"
"2. We recommend that for low-risk patients (e.g. atrial fibrillation patients with CHADS2 score ≤2, patients treated for > 3 months for a non-recurrent VTE) undergoing procedures requiring INR <1.5, VKA should be stopped 5 days before surgery. No bridging therapy is needed. Measure INR on the day before surgery and give 5 mg oral vitamin K if INR exceeds 1.5. (Level of Evidence: C)"
"3. We recommend bridging therapy for high-risk patients (e.g. atrial fibrillation patients with a CHADS2 score > 2, patients with recurrent VTE treated for <3 months, patients with a mechanical valve). Day 5: last VKA dose; Day 4: no heparin; Days 3 and 2: therapeutic subcutaneous LMWH twice daily or subcutaneous UFH twice or thrice daily; Day 1: hospitalisation and INR measurement; Day 0: surgery. (Level of Evidence: C)"
"4. We recommend that for groups 1 and 2 above, VKAs should be restarted during the evening after the procedure. Subcutaneous LMWH should be given postoperatively until the target INR is observed in two measurements. (Level of Evidence: C)"
"6. We recommend that, in VKA treated patients undergoing an emergency procedure or developing a bleeding complication, PCC (25 IU FIX/kg) should be given. (Level of Evidence: B)"
"1. We recommend that for low-risk patients (e.g. atrial fibrillation patients with CHADS2 score 2, patients treated for >3 months for a non-recurrent VTE) undergoing procedures requiring normal coagulation (normal diluted thrombin time or normal specific anti-FXa level), NOAs can be stopped 5 days before surgery. No bridging is needed. (Level of Evidence: C)"
"1. We suggest that new oral anticoagulant agents (NOAs) should not be interrupted for skin surgery, dental and other oral procedures, gastric and colonic endoscopies (even if biopsy is scheduled, but not polypectomy), nor for most ophthalmic surgery, (mainly anterior chamber, e.g. cataract), although vitreoretinal surgery is sometimes performed in NOA treated patients. (Level of Evidence: C)"
"2. In patients treated with rivaroxaban, apixaban, edoxaban and in patients treated with dabigatran in which creatinine clearance is higher than 50 ml/min, we suggest bridging therapy for high-risk patients (e.g. atrial fibrillation patients with a CHADS2 score >2, patients with recurrent VTE treated for <3 months). Day 5: last NOA dose; Day 4: no heparin; Day 3: therapeutic dose of LMWH or UFH; Day 2: subcutaneous LMWH or UFH; Day 1: last injection of subcutaneous LMWH (in the morning, i.e. 24 h before the procedure) or subcutaneous UFH twice daily (i.e. last dose 12 h before the procedure), hospitalisation and measurement of diluted thrombin time or specific anti-FXa; Day 0: surgery. (Level of Evidence: C)"
"4. We suggest that for groups 2 and 3, heparin (UFH or LMWH) should be restarted 6–72 h after the procedure, taking the bleeding risk into account. NOAs may be resumed when surgical bleeding risk is under control. (Level of Evidence: C)"
"1. We suggest that patients with hemostatic derangements associated with systemic, metabolic and endocrine diseases should be managed perioperatively in collaboration with a hematologist. (Level of Evidence: C)"