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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References

The use of prothrombin complex concentrates (PCCs), a heterogeneous combination of coagulation factors and counterbalancing inhibitor components, has broadened in recent years beyond single-factor replacement in conditions such as hemophilia B, to encompass emergency reversal of anticoagulation secondary to oral vitamin K antagonists, ie, warfarin therapy. PCCs also have been studied in other bleeding disorders, such as surgery-related and trauma-related bleeding. This review provides an updated examination of the differences among PCC formulations, their potential role in the management of bleeding disorders, and the primary safety issues affecting their use. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References

Prothrombin complex concentrates (PCCs) represent a highly purified concentrate of coagulation factors prepared from pooled normal plasma [1]. Initially, PCCs were developed as a source of Factor IX for the management of patients with hemophilia B. In the 1990s, after the introduction of high-purity plasma-derived and recombinant Factor IX, the use of PCCs for hemophilia B declined [2]. Nonetheless, PCCs remained a useful alternative for the management of inherited and acquired coagulation factor deficiencies. In certain circumstances, such as amyloidosis of the spleen with Factor X deficiency due to amyloid fibril binding, PCCs may still play a role in managing bleeding risk [1].

PCCs provide as rapid and complete a reversal of warfarin-related coagulopathy as fresh frozen plasma (FFP); however, the volume of FFP that is needed presents a substantial obstacle to therapy [2, 3]. Additionally, the new (2012) American College of Chest Physicians (ACCP) guidelines recommend that major bleeding associated with the use of vitamin K antagonists (VKAs) be reversed with four-factor PCCs than with plasma. Therefore, PCCs represent an important therapeutic option and, indeed, are now used in most countries primarily for the emergency reversal of bleeding secondary to the use of oral VKAs [4]. PCCs have also been studied experimentally in patients with other bleeding disorders. This review provides an updated examination of the differences among PCC preparations and evaluates the role of PCCs in the management of emergency bleeding disorders and the major safety issues that could influence the use of these agents in the clinical setting.

Prothrombin Complex Concentrates

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References

Composition

PCCs represent a heterogeneous combination of coagulation factors and counterbalancing inhibitor components. Table I [4, 5] displays the composition of currently available PCCs. PCCs typically contain 3 (Factors II, IX, and X) or 4 (Factors II, VII, IX, and X) clotting factors derived from human plasma that has undergone virus reduction [6, 7]. All PCCs include Factors II, IX, and X, with the 4-factor PCCs also containing clinically relevant levels of Factor VII. The overall clotting factor concentrations in PCCs are ∼25 times greater than those in plasma [1]. Activated PCCs were first introduced in the 1970s [2]. Currently, however, most PCCs are inactivated, that is, they contain a small amount of unfractionated heparin (0.5–6 IU heparin/IU Factor IX) and/or antithrombin to prevent clotting factor activation [1, 8]. FEIBA (Baxter Healthcare Corporation, Westlake Village, CA), the only activated factor (Factor VIII) concentrate, is indicated as a “bypass” agent for treatment of bleeding in patients with hemophilia A and hemophilia B with inhibitors [9]. Because of different production processes, some PCCs retain proteins C, S, and Z to attenuate the risk for thrombogenesis, although the clinical benefit of these proteins (C, S, and Z) remains unclear [1, 5].

Table I. Composition of PCCs
PCC (Manufacturer)Factors (IU relative to factor IX) [4]Coagulation proteins (IU/mL) [5]Other antithrombotic additions [4]
Factor IIFactor VIIFactor IXFactor XProtein SProtein CProtein Z
  • IU = international units; NA = not available.

  • a

    Available in the United States.

  • Modified from Sørensen B, et al: Clinical review: Prothrombin complex concentrates –evaluation of safety and thrombogenicity. Critical Care 2011, 15:201. © 2011 BioMed Central Ltd.

Bebulina (Baxter Healthcare Corporation)12013100100NANANAHeparin
Beriplex P/N (CSL Behring)1286810015217.927.351.3Antithrombin
Heparin
Albumin
Cofact (Sanquin)56–14028–8010056–1404.0NA21.0Antithrombin
Feiba NF or VHa (Baxter Healthcare Corporation)NANANANANANANANone
Kaskadil (LFB)1484010016011.815.027.5Heparin
Octaplex (Octapharma)44–15236–961005012.024.016.1Heparin added;
low activated Factor VII
Profilnine SDa (Grifols)1481110064NANANANone
Proplex-T (Baxter)10085100100NANANAAntithrombin
Heparin
Prothrombinex (CSL Limited)100NA100100NANANAAntithrombin
Heparin
Uman (Kedrion)100NA100809.15.02.0Antithrombin
Heparin

Whether 3- or 4-factor PCCs differ in efficacy and safety also remains unclear. It has been postulated that patients with international normalized ratios (INRs) <4.5 may have sufficient Factor VII present to permit efficacy with 3-factor PCCs, whereas patients with INRs >4.5 do not have meaningful Factor VII levels, and thus require 4-factor PCC treatment [10]. This conjecture, however, needs clinical confirmation.

Approved indications

The most common indication overall for PCCs is the treatment of vitamin K–dependent factor deficiency in patients taking VKAs (Table II) [1, 9, 11–19]. However, in the United States, the only PCCs available are Factor IX complexes (Bebulin, Baxter Healthcare Corporation, Westlake Village, CA) and Profilnine (Grifols Biologicals, Inc., Los Angeles, CA), and neither of these 3-factor PCCs has received approval for anticoagulation reversal [20]. In Canada, the 4-factor PCCs, Octaplex® (Octapharma, Vienna, Austria) and Beriplex (CSL Behring, Ottawa, Ontario), have been approved for the reversal of warfarin-related bleeding [21, 22]. As suggested in the 2012 ACCP antithrombotic therapy guidelines for the management of VKA-related bleeding, PCCs should be used in conjunction with a slow intravenous infusion of vitamin K (5–10 mg) [3].

Table II. PCC Indications
PCCManufacturerIndications
Bleeding or factor deficiencies
Hemo A (factor VIII)Hemo B (factor IX)Acquired PCC deficiency (eg, VKA)Congenital PCC deficiency (specific factor not available)Other factor deficiency, such as factor II, VII, X
  • a

    Available in the United States for the prevention and control of hemorrhagic episodes in patients with hemophilia B.

  • b

    Available in the United States for the control of spontaneous bleeding episodes or to cover surgical interventions in patients with hemophilia A and hemophilia B with inhibitors.

  • c

    Available in the United States for the prevention and control of bleeding in patients with factor IX deficiency due to hemophilia B.

Bebulina [11]Baxter Healthcare Corp.    
Beriplex P/N [12]CSL Behring   
Cofact [13]Sanquin   
Feiba NF or VHb [9]Baxter Healthcare Corp.   
Kaskadil [14]LFB    
Octaplex [15]Octapharma   
Profilnine SDc [16]Grifols    
Proplex-T [17]Baxter   
Prothrombinex VF [18]CSL Limited   
Uman [19]Kedrion  

Contraindications

Many PCCs contain small amounts of unfractionated heparin; consequently, they should not be administered to patients with heparin-induced thrombocytopenia [1]. However, there is no clinical evidence to support a connection between the use of a PCC and the development of heparin-induced thrombocytopenia. Because they may increase the risk for thromboembolism, PCCs are not recommended for patients with antithrombin deficiency or disseminated intravascular coagulation, with a possible, rare exception in patients with potentially life-threatening clotting factor deficiency when no other alternative treatment is available [1, 23]. In addition, PCCs should be used withcaution, after a careful benefit-risk analysis, in patients with active thrombosis, including recent myocardial infarction [23]. The efficacy of PCCs has not been established in pregnant or nursing women or in pediatric populations.

Use in Bleeding Disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References

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 [26]. 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 [3].

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 [7]. 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 [31]. These declines were accompanied by a rapid elevation in coagulation factor activity.

Intracerebral hemorrhage represents a serious anticoagulant-related bleeding complication [35]. 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 [36]. 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 [37]. 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 [3]. In asymptomatic patients with elevated INRs, treatment typically consists of withholding VKA treatment and administering vitamin K [6].

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 [38]. 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 [38]. In contrast, PCCs can be administered immediately and at lower volumes [4].

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 [42]. 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 [43]. 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 [43]. 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 [46]. 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 [46], although administration of recombinant Factor VIIa may be an option in some patients [47]. 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 [48]. 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 [48], highlighting the clear need for additional research.

Surgery

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 [4]. 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 [49]. 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) [41]. 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) [41]. 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.

Trauma

Currently, there is little published evidence to support the use of PCCs in the management of trauma-related massive bleeding [50]. 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 [51].

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 [39]. 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 [52]. 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 [53]. 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 [1].

Safety

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References

Adverse events

Potential adverse events that may be encountered with the use of PCCs include hypersensitivity reactions, antibody formation, and other reactions, including chills, pyrexia, urticaria, hypercoagulability, disseminated intravascular coagulation, and hypertension [12, 15, 16]. The emergence of anaphylactic allergic reactions requires the immediate discontinuation of PCC treatment.

Most PCCs contain small amounts of heparin. Consequently, in susceptible hypersensitive patients, a heparin-induced reduction in blood platelet count (heparin-induced thrombocytopenia) may occur 4–14 days after the start of treatment or within hours in patients recently exposed to heparin [12, 15]. Transfusion-related acute lung injury (TRALI), a significant post-transfusion cause of death, has been linked to the use of FFP, which accounts for half of all cases [54]. PCCs are not associated with a risk of TRALI because the manufacturing process eliminates the triggering antibodies [55].

Thrombotic complications

PCC use has been associated with the emergence of serious thrombotic events, especially at high doses and in patients with severe liver disease [2]. Thrombotic complications that have been linked to PCC therapy include venous thromboembolism, disseminated intravascular coagulation, microvascular thrombosis, and myocardial infarction [4]. Results of a recent literature search revealed that the incidence of thromboembolic events with PCC treatment was ∼ 1.8% in patients receiving 4-factor PCCs and 0.7% in patients receiving 3-factor PCCs [56]. These findings suggest that the risk of thromboembolic complications with the use of PCCs is low, but not clinically insignificant. In clinical studies of PCCs, patients manifesting an elevated risk of thrombotic events usually have a relevant medical history or current illness, and these underlying thrombotic risk factors may become clinically salient when VKA-related anticoagulation is reversed [4]. In newer PCCs, the inclusion of proteins C, S, and Z, among other anticoagulation factors depleted by VKAs, may represent a more balanced approach that, in theory, could mitigate thrombotic risks [4].

When treating patients undergoing emergency anticoagulation reversal, the clinical challenge is to identify which patients are at the highest risk for transfusion and thrombotic complications based on their history and to use anticoagulation reversal strategies that provide the most rapid correction with the lowest risk.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References

The use of PCCs has broadened in recent years beyond factor replacement to encompass bleeding disorders secondary to VKA treatment. Moreover, researchers have highlighted a potentially important role for PCCs in bleeding in the surgical and trauma setting. However, the clinical data remain insufficient to provide a sound medical rationale for the use of PCCs beyond their currently approved indications.

PCCs are generally well tolerated when used appropriately. Acute reversal of VKA anticoagulation is associated with a small, but clinically relevant, risk for thrombogenicity. Whether the thrombogenic effects of PCCs are a direct result of treatment or the role of PCCs in unmasking preexisting prothrombotic disease states remains controversial. Nonetheless, PCC use requires careful patient monitoring to identify those individuals at the highest risk for cardiovascular events.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References

Editorial and writing assistance in the development of this manuscript were provided by James M. Kesslick, M.S., of Publication CONNEXION (Newtown, PA) who developed the drafts that were reviewed, edited, and approved by the author, George M. Rodgers. The manuscript was financially supported by CSL Behring (King of Prussia, PA). Dr. Rodgers meets the criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), was fully responsible for all content and editorial decisions, and was involved at all stages of manuscript development. He received no honorarium for his role as author of this manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Prothrombin Complex Concentrates
  5. Use in Bleeding Disorders
  6. Safety
  7. Conclusion
  8. Acknowledgements
  9. References