Bleeding secondary to VKA anticoagulation
VKAs block the γ-carboxylation of the procoagulant factors, II, VII, IX, and X, and the anticoagulant factor proteins, C and S [24, 25]. All of these factors remain inactive in the absence of carboxylation. PCCs replenish the coagulation factors suppressed by VKAs. The concurrent inhibition of the regulatory anticoagulant proteins, such as proteins C and S, by VKAs may elevate the risk for thrombogenicity, because anticoagulant proteins are reduced more rapidly than procoagulant factors by warfarin . With the use of “balanced” PCCs, this thrombogenicity potential is theoretically addressed by the addition of coumarin-inhibited coagulation factors such as proteins C, S, and Z .
PCCs have emerged as an important therapeutic option for the rapid reversal of VKA-related bleeding, in conjunction with withholding VKA therapy, and the administration of oral or intravenous vitamin K [3, 24]. Numerous, mostly small, clinical studies have shown that in the VKA-reversal setting, PCCs can be effective in rapidly reversing elevated INR values, improving hemostasis, and in elevating coagulation factors in patients who require emergency hemostasis [7, 27–34]. In a prospective, cohort study that included 43 subjects requiring emergency VKA reversal—26 pending an interventional procedure and 17 experiencing acute bleeding—PCC treatment (Beriplex P/N) resulted in a decrease in INR to ≤1.3 for the majority (93%) of patients . In this study, baseline INRs were ≥4 in 39% of patients. In addition, hemostatic efficacy was considered very good or satisfactory in virtually all (98%) PCC-treated patients, and both procoagulant and anticoagulant proteins increased rapidly after treatment. Other investigators have also demonstrated the rapid effect of PCCs in lowering INR values in patients requiring rapid VKA reversal. In a prospective, open-label study in 56 patients who required VKA reversal to control bleeding during surgical procedures, PCC treatment (Octaplex) reduced INR to <1.4 within 1 hr after dosing in 93% of patients, with a median decline of INR values from 2.8 to 1.1 within 10 min after dosing . These declines were accompanied by a rapid elevation in coagulation factor activity.
Intracerebral hemorrhage represents a serious anticoagulant-related bleeding complication . In a study that included 46 patients receiving VKA treatment and experiencing an acute intracranial hemorrhage, PCC treatment (Uman Complex DI, Kedrion S.p.A., Castelvecchio Pascoli, Italy) rapidly reversed INR elevations for up to 96 hr after single administration . INR values declined from 3.5 (median) to 1.3 at 30 min after PCC administration. Neurologic outcomes, however, were not assessed in this study. Other investigators have shown that PCC treatment (PPSB-HT: a 4-factor PCC available in Japan) not only blunts hematoma enlargement in patients with an intracerebral hemorrhage who are receiving long-term warfarin therapy but also significantly improves clinical outcomes and reduces in-hospital mortality when admission INR values exceed 2 when compared with no PCC treatment . In the VKA-reversal setting, however, PCCs are indicated only for the treatment or prevention of bleeding. In cases of life-threatening bleeding, PCCs are the preferred option for achieving rapid INR correction, because the volume of FFP required can be substantial and can take hours to infuse . In asymptomatic patients with elevated INRs, treatment typically consists of withholding VKA treatment and administering vitamin K .
PCCs versus FFP in VKA reversal.
In the United States, FFP, in conjunction with vitamin K, is currently considered a standard of care for VKA reversal because it is widely available . However, because the concentration of coagulation factors in plasma is so low, FFP administration requires large volumes (typically 10–20 mL/kg), which increases the risk for intravascular volume overload and edema, a special concern for populations such as the elderly, those with preexisting cardiac conditions, and those receiving dialysis [3, 4, 39]. In addition, the FFP product often must be thawed, prolonging administration time . In contrast, PCCs can be administered immediately and at lower volumes .
Few studies have compared PCCs directly with FFP in the setting of urgent VKA anticoagulation reversal. Typically, PCCs reverse anticoagulation faster and with less bleeding when compared with FFP [40, 41]. In a retrospective study that compared strategies for the management of VKA-related intracerebral hemorrhage, PCC-based treatment was associated with less hematoma growth than was FFP-based treatment, an effect apparently related to the more rapid INR reversal achieved with PCC treatment . However, there was no difference between treatments in terms of clinical outcomes. A study conducted in the United Kingdom estimated the cost effectiveness of PCC versus FFP treatment in the context of emergency VKA reversal . Based on estimates of healthcare resource utilization associated with managing VKA-related intracranial, gastrointestinal, or retroperitoneal hemorrhage, the cost per life-year gained with the use of PCCs was £1,000 to £2,000 versus FFP depending on the hemorrhage type . These findings show that in the UK national health system, the use of PCCs was more cost effective than FFP for emergency warfarin reversal. However, whether these cost-effectiveness findings can be generalized to other nations with radically different healthcare delivery systems, particularly the United States, will remain the subject of further study.
Reversal of newer anticoagulant agents
Three novel, oral anticoagulant agents—dabigatran (Pradaxa, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT), rivaroxaban (Xarelto, Janssen Pharmaceuticals, Inc., Titusville, NJ), and apixaban (Eliquis, Bristol-Myers Squibb Company, New York, NY/Pfizer, Inc., New York, NY)—have been introduced to provide alternatives to traditional VKAs. Dabigatran and rivaroxaban have received FDA approval to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and the latter has also been approved to reduce the risk for deep vein thrombosis and subsequent pulmonary embolism in patients undergoing knee or hip replacement surgery [44, 45]. Apixaban remains in late-stage clinical development and is approved in certain jurisdictions.
Unlike VKAs, which inhibit the synthesis of multiple vitamin K–dependent proteins, these new agents target single clotting factors: Factor IIa (thrombin) in the case of dabigatran, and Factor Xa in the cases of rivaroxaban and apixaban . There is currently no clinical evidence to support an anticoagulation reversal strategy or antidote for these three novel agents in the case of severe bleeding , although administration of recombinant Factor VIIa may be an option in some patients . A recent clinical study in 12 healthy male volunteers using an ex vivo model suggests that a 4-factor PCC, Cofact (Sanquin, Amsterdam, The Netherlands), can rapidly and completely reverse the changes seen in coagulation test results after administration of rivaroxaban 20 mg twice daily, but not after administration of dabigatran 150 mg twice daily . However, the generalizability of these findings to the clinical setting is limited because only surrogate markers of bleeding were used, by the small sample size, and the fact that the study did not include patients experiencing major bleeding or requiring invasive procedures while treated with these new anticoagulants , highlighting the clear need for additional research.
The use of PCCs for perioperative-related bleeding is intended to correct attenuated thrombin generation in patients receiving oral VKAs. Although few studies have supported a role for PCCs in surgery, their use in this setting appears to be gaining acceptance in European countries . In a retrospective German study of 38 hospital surgical cases not requiring oral anticoagulant reversal, the use of a PCC (Beriplex P/N) to treat severe bleeding in patients undergoing surgery resulted in a statistically significant reduction in INR, from 1.7 at baseline to 1.4 after treatment, a decrease apparently unrelated to concurrent FFP or vitamin K administration . Furthermore, PCC treatment yielded satisfactory hemostasis in 36% of the surgical bleeding patients and 96% of the patients with diffuse bleeding (no evidence of damaged blood vessels). In a randomized study that used rapid point of care monitoring of thrombin generation to evaluate the need for factor replacement, significantly more patients achieved target INR (≤1.5) with PCC (Cofact) versus FFP therapy within 15 min after the procedure (7/16 vs. 0/15; P = 0.007) . However, the percentage of patients achieving the target at 15 min was considered low in both groups, and there was no statistical difference between groups 1 hr after the procedure (PCC = 6/15, FFP = 4/15) . In this study, postsurgery blood loss through chest tube drainage was less with PCC than with FFP therapy at 1, 4, and 24 hr after surgery.
Currently, there is little published evidence to support the use of PCCs in the management of trauma-related massive bleeding . The results of one retrospective analysis demonstrated that in trauma patients receiving warfarin, the addition of PCC treatment to FFP and vitamin K treatment yielded a more rapid INR reversal; however, no clear improvement in clinical outcomes was noted .
Coagulopathy of liver disease
The use of PCC therapy in the treatment of coagulopathy secondary to hepatic failure has been examined in small case studies; however, no controlled trials have been performed . In 22 patients with coagulopathy resulting from severe liver disease who required rapid hemostasis because of bleeding or pending surgery, PCC therapy (Beriplex P/N) rapidly restored coagulation factors and yielded “very good” clinical efficacy (avoidance or cessation of bleeding) in 76% of patients after a single dose . In addition, the results of a recent case report found that 4-factor PCC treatment (Octaplex), in conjunction with vitamin K, yielded well-tolerated, immediate hemostasis in an infant with liver failure and severe bleeding secondary to dilutional coagulopathy after multiple transfusions . The clinical evidence, however, remains insufficient to justify the routine use of PCCs for correction of coagulopathy secondary to liver failure. PCC treatment may be considered as an option in certain limited circumstances as 4-factor PCCs contain only Factors II, VII, IX, and X, whereas the coagulopathy of liver disease is polyfactorial. In cases in which there is a risk for volume overload with the use of FFP or in which massive bleeding is present, the use of PCCs may be considered .