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Clinical Applications of 4-Factor Prothrombin Complex Concentrate: A Practical Pathologist's Perspective.

Anonactivated, 4-factor prothrombin complex concentrate (4F-PCC) known as Kcentra (CSL Behring, Kankakee, Illinois) has been approved in the United States for the reversal of vitamin K antagonist (VKA) anticoagulation in patients with major acute hemorrhage, or in patients who require urgent surgical intervention. (1) Given the fact that a pure 4F-PCC has not been available in the United States for several decades, expertise with such factor concentrates is limited. Nonetheless, clinical pathologists and blood bankers may be consulted for advice on indications, dosage, and side effects of these products and therefore should be prepared to counsel clinicians on the appropriate use of 4F-PCCs.

Because of the lack of expertise with 4F-PCCs among US providers, and the increasing demand for laboratory-based physicians to play consultative roles in managing factor concentrate dosing/administration for a variety of bleeding disorders, the overall goal of this review is to explore practical issues related to 4F-PCCs that are relevant to the clinical pathologist who provides blood bank coverage. To this end, we will (1) examine the primary label indication of 4F-PCCs (ie, VKA reversal), (2) review off-label applicability of 4F-PCCs in the treatment of hemorrhage due to novel oral anticoagulants, and (3) explore its other potential off-label uses in complex bleeding disorders due to liver disease, trauma, and rare coagulopathies. In addition, safety and practical issues of 4F-PCCs will also be discussed.

VITAMIN K ANTAGONISTS: BACKGROUND AND HISTORICAL APPROACHES TO REVERSAL

Vitamin K antagonists are anticoagulants that function by inhibiting the enzyme vitamin K epoxide reductase. In the liver, vitamin K epoxide reductase converts reduced vitamin K to the oxidized form used in the y-carboxylation of the "vitamin K-dependent" coagulation factors II, VII, IX, and X (as well as the natural anticoagulants protein C and protein S). Patients treated with VKAs are at increased risk for bleeding, including an increased risk for intracranial bleeds. (2) Thus, VKA reversal may be necessary for the acutely bleeding patient, or in the prophylactic setting for an individual about to undergo an invasive procedure.

When considering a reversal strategy for a VKA, there are currently several options. One standard approach is simply holding future doses of the VKA with administration of vitamin K. However, this approach is of limited value when rapid correction of abnormal coagulation values is desired. Therefore, in the setting of more severe bleeds, or where a more timely reversal of VKA anticoagulation is desired, the administration of blood products and components must be considered. As summarized in Table 1, there are several options available for VKA reversal, including fresh frozen plasma (FFP), 3F- and 4F-PCCs, and recombinant activated factor VIIa. Fresh frozen plasma, the oldest and most widely available of these agents, is a potentially useful therapy. However, reversal of a VKA by FFP can be slow in part because of the time it takes to transfuse multiple units of this product (typically, 4 to 5 U are required for adults when dosed at 10-15 mL/kg). Moreover, transfusion of FFP carries the added risk of adverse events such as allergic reactions, transfusion-associated circulatory overload, transfusion-related acute lung injury, and transfusion-transmitted diseases. (3)

In addition to the above "tried and true" methods for VKA reversal, and without 4F-PCCs, rapid correction of VKAs can involve creative off-label uses of the products outlined in Table 1. For instance, some clinicians have administered 3F-PCC containing factors II, IX, and X either alone or in combination with either FFP or activated recombinant activated factor VII. This latter option--the factor "cocktail"--has been shown to be effective in reducing the international normalized ratio (INR), but puts a patient at an increased risk for thrombosis. (4) It has been shown that the activated 4F-PCC known as factor eight inhibitor bypassing activity (FEIBA, containing factors II, activated VII, IX, and X; Baxter Healthcare Corporation, Westlake Village, California) is useful for reversing the effects of VKA therapy, (5) but this product is approved only for treating hemophiliac patients with factor VIII or factor IX inhibitors who are bleeding or require surgical intervention. (6) Products with an activated factor VII component, such as recombinant fVIIa and FEIBA, also carry an increased risk for thrombosis. Thus, counseling on the use of these products for VKA reversal can be challenging because neither appropriate dosing nor expected efficacy is established for such off-label use. Additionally, thrombosis incurred as a result of such administration may be difficult to justify.

Because of the limitations associated with other forms of VKA reversal, 4F-PCCs have gained favor (and US Food and Drug Administration approval) for this indication. In fact, in other parts of the world, 4F-PCC products have been available for some time under a variety of commercial names. For instance, the analogue to Kcentra is Beriplex (CSL Behring, Marburg, Germany), a product widely used in Europe. Because of the international availability of these drugs, the medical literature is composed of many articles examining different 4F-PCCs. As such, while Kcentra is the only currently available US 4F-PCC, we will be extrapolating data from international studies (as well as our personal experiences) for some aspects of pharmacokinetics as well as off-label indications.

CHARACTERISTICS OF 4F-PCC

Kcentra contains factors II, VII, IX, and X in addition to the natural anticoagulants protein C and protein S (1) (see Table 2 for additional details on the contents of 4F-PCCs and FFP). None of the factors are activated, as opposed to FEIBA. (1,5,6) It is notable that Kcentra has a higher reported range of concentration of protein C than other 4F-PCCs, which suggests a theoretical "balanced" safety profile compared to other concentrates, but this has not been proven in any study known to these authors. (7) Also present in Kcentra is heparin, antithrombin, human albumin, sodium chloride, sodium citrate, hydrochloric acid, and sodium hydroxide. (1,7) The amount of heparin present ranges from 8 to 40 U per 500-U vial. (1) The presence of heparin makes Kcentra contraindicated for patients with known heparin-induced thrombocytopenia. (1) Of 7 commercially available 4F-PCCs studied in a 2008 article, (7) Beriplex was found to be the "purest" on the basis of gel protein studies evaluating for "therapeutically relevant" proteins, but the true clinical significance or impact on efficacy of such purity is unknown.

In a study of healthy human volunteers receiving 50 IU of factor IX per kilogram of Beriplex, a higher than expected median terminal half-life for in vivo levels of protein C was observed (47.2 hours); factor X, protein C, and factor II had the highest median percentage increase in levels at 5 minutes. (8) Factor VII had the shortest median terminal half-life as well as the lowest percentage increase in levels at 5 minutes. (8)

APPROVED AND POTENTIAL OFF-LABEL INDICATIONS FOR 4F-PCC

Reversal of VKAs

Kcentra has been approved in the United States for the reversal of VKA anticoagulation in patients with major acute hemorrhage, or in patients who require urgent surgical intervention. (1) In a randomized phase IIIb study involving bleeding patients receiving VKAs and with international normalized ratio (INR) of 2.0 or greater, Kcentra corrected the INR to a value of less than 1.3 at 30 minutes after completion of infusion and at 1 hour after the start of infusion; these results were achieved for significantly more patients than with FFP. (9) With continued evaluation after the start of infusion, this shortened INR finding was still evident even 24 hours later. (9) Additionally, the median INR in the 4F-PCC group was significantly lower up to 12 hours after the start of infusion. (9)

In that same study, there was no overall difference between the 4F-PCC group and the FFP group in the number of patients who achieved significant hemostatic efficacy at 24 hours. Hemostatic efficacy at an earlier time point (4 hours) was studied only in patients with visible and/ or musculoskeletal bleeds; Kcentra was determined in those cases (and at that time point) to be superior to FFP. (9) Given the superior changes in INR observed, it might be conjectured that the hemostatic efficacy difference observed at the earlier time point for visible and musculoskeletal bleeds might carry over to other types of bleeds, but this was not definitively demonstrated in the phase IIIb study of Kcentra. (9)

It is notable that in this same phase IIIb study examining Kcentra, a number of exclusion criteria may be clinically relevant when considering 4F-PCC use. (9) Trauma patients with uncontrollable bleeds, patients with large blood vessel rupture, and patients with severe intracranial hemorrhage were all excluded. (9) In our experience, there are some patients who may meet one of these exclusion criteria and for whom Kcentra is requested. In the absence of additional evidence, the potential benefits of the 4F-PCC for these patients can only be hypothesized and weighed against inherent risks of factor concentrate therapy.

For VKA reversal, Kcentra is dosed to correct INRs of 2.0 or greater per the package insert. (1) Dosing varies by the patient's weight and underlying INR. Patients with an INR ranging from 2 to less than 4 receive 25 U/kg, while those with an INR between 4 and 6 receive 35 U/kg. (1) Individuals with an INR greater than 6 receive 50 U/kg. (1) There is no guidance regarding the use of ideal body weight versus actual body weight, but for each INR category, there is a maximal dosage that should not be exceeded (2500 U at 25 U/kg, 3500 U at 35 U/kg, and 5000 U at 50 U/kg). (1) More details regarding the practical nuances of Kcentra dosing are discussed later in this article.

It is strongly recommended that 4F-PCC be administered with Vitamin K (phytonadione) (1); this capitalizes upon the differing mechanisms of action of the 2 therapies (factor replacement affords rapid correction by supplementation of absent coagulation factors, while phytonadione replaces vitamin K, allowing for ongoing factor synthesis). (10)

One potential off-label use of 4F-PCC may be the reversal of a severely elevated INR for a patient receiving a VKA who has a nonemergent bleed, but who may be sensitive to the large volume associated with FFP infusion. Such patients include those with congestive heart failure, renal failure, and underlying pulmonary disease. Notably, the phase IIIb study examining Kcentra found 0% fluid overload or cardiac event-related adverse events in the 4F-PCC group versus 6.4% of such events in the plasma group. (9) Nevertheless, other options for fluid-sensitive patients include simply withholding additional doses of VKA and/or administration of vitamin K. One might argue that if a patient does not require acute reversal of VKA, then perhaps intervention with a 4F-PCC is unnecessary; however, clinicians may feel compelled to treat intermediate-type bleeds in order to prevent hemorrhage progression or continued blood loss.

Reversal of Novel Anticoagulants

Novel anticoagulants, in intravenous and oral formulations, include direct thrombin inhibitors and factor Xa inhibitors. (11) These novel anticoagulants have variable but relatively short half-lives, and, as opposed to INR assays for patients receiving warfarin therapy, there is no universally accepted way to monitor or measure these drugs. Moreover, there are currently no commercially available antidotes for these anticoagulants (although work is being done to develop directed reversal agents). (12-14) Additionally, certain direct thrombin inhibitors can be efficiently removed by using hemodialysis. (15) Given the limited options for urgent reversal of these agents, mitigating their anticoagulant effects can be attempted using, among other therapies, 4F-PCC in an off-label fashion. (11)

The reversal of the oral anticoagulants dabigatran etexilate (Pradaxa, Boehringer Ingelheim Inc, Ridgefield, Connecticut) and rivaroxaban (Xarelto, Bayer Healthcare Corporation, Westlake Village, California) using 4F-PCC has been studied primarily in animal models. In rabbits receiving dabigatran, increasing doses of 4F-PCC were shown to decrease kidney-incision bleeding time and blood loss. (16) In mice receiving dabigatran, 4F-PCC was shown to be most effective (versus FFP and activated factor VII) in reducing the size of induced intracranial hematoma. (17) In rats receiving dabigatran, 2 different formulations of 4F-PCC were effective in reducing induced tail bleeding. (18) On the other hand, another study (19) found that 4F-PCC (Octaplex, Octapharma AG, Lachen, Switzerland) did not decrease blood loss due to tail transection in rats receiving dabigatran.

In rats receiving rivaroxaban, high-dose 4F-PCC was shown to produce the most profound decrease in mesenteric bleeding time (versus FEIBA and activated factor VII). (20) Another study (21) found partial correction of prothrombin time (PT) and normalization of the partial thromboplastin time (PTT) with administration of 4F-PCC (Kaskadil, LFB, Courtaboeuf, France) in rabbits that received rivaroxaban; however, there was no effect on blood loss.

Human subject studies have essentially involved healthy volunteers who undergo dosage with rivaroxaban or dabigatran and treatment with a 4F-PCC, rather than acutely bleeding patients. The endpoint in such studies is generally a correction of laboratory test values. In one study, (22) 4F-PCC reversed prolongation of the PT and restored endogenous thrombin potential in subjects receiving rivaroxaban. In the same study, 4F-PCC did not reverse elevated PTT, ecarin clotting time, and thrombin time in subjects receiving dabigatran, and it had no effect on endogenous thrombin potential. (22) Another study (23) demonstrated significant reduction of PT values in healthy subjects when rivaroxaban was administered followed by 4F-PCC; 3F-PCC also reduced PT values but to a lesser extent. Additionally, endogenous thrombin potential was corrected by the administration of 4F-PCC; however, faster reversal was observed with administration of a 3F-PCC. (23)

The clinical relevance of these studies is difficult to assess since none examined the use of 4F-PCC in treating clinically relevant bleeding events. Thus, it is difficult to declare that 4F-PCCs have a definitive role in the reversal of novel anticoagulants. On the other hand, 4F-PCCs offer an option when virtually no other therapies exist. From the limited experimental and case report literature available, the corresponding author's institution approves administration of a minimal off-label dose (25 U/kg not to exceed 2500 U) of Kcentra to those patients who have recently received an oral direct thrombin or factor Xa inhibitor, who are experiencing massive hemorrhage (ie, World Health Organization grade III or higher), and for whom treatment with dialysis or active drug removal is not an option.

Liver Disease

Patients with advanced liver disease may have deficiencies in clotting factors because of poor liver function and resultant decreased protein synthesis. This coagulopathy, combined with the clinical manifestation of gastrointestinal varices, not uncommonly results in clinically significant bleeding. Patients with liver disease may be treated with FFP and cryoprecipitate to supplement the deficiency of coagulation factors and fibrinogen. Given their composition, 4F-PCCs (at least theoretically) may be an off-label alternative for treatment of patients with liver disease who present with acute or emergent bleed. (24)

An open, non-controlled, prospective multi-center study (24) examined patients with severe liver disease and related coagulopathy who were bleeding (eg, stomach ulcer or gastrointestinal hemangiomas), needed a diagnostic procedure (eg, biopsy), or needed a therapeutic procedure (eg, femur fracture repair or endoscopic retrograde cholangiopancreatography). Patients who received 4F-PCC (Beriplex) either had their bleeding controlled or were able to undergo a procedure without bleeding complication. (24) For 5 of these patients, 4F-PCC was re-dosed during the intervention. (24)

A retrospective, nonrandomized, noncontrolled, observational, open-label, and multicenter study from 2010 looking at the utility of Octaplex for the correction of INR in a variety of patients included individuals with liver disease. (25) Significant decreases in INR were observed in the setting of liver disease and (1) accompanying surgery or an invasive procedure; (2) ongoing general, nontraumatic bleeding; and (3) trauma. (25) It is important to note that while this study demonstrated significant changes in INR, clinical endpoints (such as bleeding reduction or improved survival) were not evaluated.

More investigations are necessary to establish a role for 4F-PCC in patients with liver disease. A multi-center, double blind, randomized placebo-controlled study known as the PROTON-trial (26) is currently underway to assess the possible efficacy of a 4F-PCC (Cofact, Sanquin, Amsterdam, the Netherlands) for patients with cirrhosis who are undergoing liver transplant. In this study, (26) the need for RBC transfusion will be the primary endpoint, with decreased need reflecting improved hemostasis.

At the corresponding author's institution, all requests for 4F-PCC are screened by a covering blood bank physician. While no formal guidelines for use of 4F-PCC in the setting of liver disease have been established, we generally discourage its use as a solo hemostatic therapy or a first-line agent owing to the complexity of liver disease-associated coagulopathy. Despite this generally restricted use, some clinical circumstances for which 4F-PCC may be appropriate would be for patients with liver disease to whom plasma cannot be given (eg, volume overload) or for an individual with laboratory evidence of acquired factor deficiency affecting primarily vitamin K-dependent factors. As with all other off-label uses, caution must be used when dosing in this situation and we recommend administration of a minimal dose (25 U/kg not to exceed 2500 U). Of course, it should be noted that bleeding in liver disease often involves deficiencies in multiple coagulation factors, some of which (eg, fibrinogen, factor V) are not present in 4F-PCC. As such, other blood components may still be needed even after 4F-PCC administration.

Trauma and Severe Bleeding

In the 2010 study referenced above, significant decreases in INR were seen in all trauma patients except those treated with oral anticoagulants (explained by the study authors (25) as being due to variability in pretreatment INR values in these patients). Given that clinically based endpoints were not studied, potential clinical benefits can only be conjectured from the favorable changes in INR.

Porcine animal studies have also examined the utility of 4F-PCC in simulated trauma situations. A study examining standardized blunt abdominal trauma with induction of hypothermia and hemodilution with subsequent administration of 4F-PCC (Cofact) at 35 U/kg demonstrated higher fibrinogen levels, higher hemoglobin concentration, higher platelet counts, and decreased PT values compared to a control group. (27) Additionally, higher mean arterial pressure, decreased blood loss, and improved survival were observed in those animals receiving 4F-PCC. (27) Another porcine model, using infliction of splenic laceration or femoral trauma with hemodilution and resultant hypothermia, demonstrated superior efficacy (versus FFP) of 4F-PCC (Beriplex) at 25 U/kg to achieve hemostasis, decreased blood loss, and normalized PT. (28) Yet another porcine trauma model study (29) demonstrated that 4F-PCC (Beriplex at 35 U/ kg) was superior to recombinant FVIIa in the time to achieve hemostasis (but they were equivalent in correction of the PT).

In comparison to the above studies, a similar animal study examining the effect of administration of 4F-PCC (Cofact) in the porcine trauma model (also simulating blunt liver injury and hemodilution) reported not only decreases in PT, clotting time, and blood loss with administration of both 35 U/kg and 50 U/kg of 4F-PCC, but also an increase in thrombosis (interpreted as disseminated intravascular coagulation [DIC]) in animal subjects that had received 50 U/ kg of 4F-PCC. (30) It is well known that trauma patients are at risk for coagulopathy and DIC. Although there was no significant difference in survival between those animals that developed DIC and those that did not, this finding is worrisome because it accentuates the (at the least) theoretical risk of thrombosis of a 4F-PCC (see below for discussion of product safety). It is notable that DIC is a general contraindication to the administration of Kcentra because of the prothrombotic effects of the drug. (1)

One other area that presents challenges in transfusion management is major obstetric hemorrhage. To date, there are few clinical or animal model data examining the safety and efficacy of 4F-PCC in this setting (one case report is discussed in the next section, but 4F-PCC use in that case was associated with pregnancy in a patient with a rare congenital factor deficiency). (31) A potentially confounding variable is the general hypercoagulability seen in the setting of pregnancy: 4F-PCC could theoretically increase the risk for pathologic thrombosis. As such, and in the absence of rigorous clinical trials or even case series, we cannot recommend 4F-PCC as a first-line therapy for most forms of obstetric bleeding; adherence to institutional massive transfusion protocols is likely the best approach for such patients.

Congenital Factor Deficiencies

With the advent of specific factor concentrates (including recombinant products), most patients with inherited coagulopathies or factor deficiencies may be supported without the aid of 4F-PCC. There are, however, reports of rare factor deficiencies in which 4F-PCC has been used (note that 3FPCC may also be used, depending on the factor profile). For instance, 3F- and 4F-PCC have been reported for use as bleeding prophylaxis in patients with factor X deficiency. (31-36) Factor X is a critical coagulation factor in the common pathway, which serves to activate prothrombin to thrombin. Deficiency of factor X confers an increased risk for bleeding to the patient. There is no package insert guidance regarding dosing of 4F-PCC to treat the bleeding patient with factor X deficiency. (1) However, when looking at published reports, there is some reasonable guidance available. For instance, a pregnant patient with congenital factor X deficiency (unknown weight) received 500 U of Beriplex on the day leading up to delivery and epidural, 1500 U on the day of delivery and epidural, and 2 additional 500-U dosages during and after delivery (for 2 days). (31) In addition, a report on the use of Beriplex as bleeding prophylaxis for neonates with factor X deficiency indicated that patients were successfully treated with doses between 15 U/kg and 30 U/kg. (32) Finally, another factor X-deficient neonate with a history of recurrent intracranial bleeds was treated prophylactically with 40 U/kg of a 3F-PCC, Konyne-HT (Cutter Laboratories, Berkeley, California), twice per week. (33)

There is also a report in the literature of the use of 4F-PCC to treat factor Z deficiency (article in German and only the abstract was assessed by these authors). (37) Factor Z is a vitamin K-dependent coagulation factor that acts in both a procoagulant and anticoagulant fashion in that it facilitates thrombin-phospholipid interactions, and it also indirectly inhibits factor Xa by interacting with plasma protein Z-dependent protease inhibitor (an inhibitor of factor Xa). (37,38) Affected patients have primarily abnormal bleeding. (38) The factor Z composition of 4F-PCC is not officially reported, but it is possible that treatment with 4F-PCC may supplement this factor or promote coagulation via activation of an alternative part of the coagulation cascade.

SAFETY

The package insert for Kcentra accentuates the risk for thrombosis with administration of the product. (1) Patients who receive anticoagulation therapy with VKAs, and who subsequently present with bleeding related to or exacerbated by VKA, have a history of thrombosis or hypercoagulability and are (at least theoretically) at increased risk of provoking thromboembolism with the administration of a procoagulant drug such as 4F-PCC. A black box warning is present for Kcentra, targeted at patients who have had thromboembolic disease in the 3 months preceding product administration; the warning is present to remind clinicians that such patients were not included in the initial evaluation of the product and their thrombotic risk is unknown. (1) Stated contraindications to administration of the Kcentra include "known anaphylactic or severe systemic reaction to" the product or its components, DIC, and heparin-induced thrombocytopenia. (1)

In the original phase IIIb study of Kcentra, 1 patient died possibly because of administration of the drug (although this was not proven). (9) According to the authors, (9) the study was not powered to assess safety, but it is notable that 3.9% of patients receiving 4F-PCC had a thromboembolic adverse event deemed to be related to administration of the product (versus 2.8% of patients receiving FFP). Study of the safety of Beriplex (via pharmacovigilance data) revealed a total of 21 thromboembolic events out of 647 250 "standard applications" of the drug, but this study suffers from possible underreporting. (39) Analysis of a review (40) published in 2010 shows that 2% of 383 patients receiving Beriplex throughout 13 studies developed some form of thrombosis. These cumulative data are difficult to evaluate because of the variability of the reports. Therefore, it is most prudent to mind the product warning and consider 4F-PCC administration to be associated with a potential risk for thrombosis.

A practical question may arise from clinicians with regard to the safety of administration of a 4F-PCC following treatment with FFP or an antifibrinolytic agent (eg, tranexamic acid or aminocaproic acid). The decision to switch to a 4F-PCC from FFP requires clinical judgment, bearing in mind the degree to which the INR was elevated, the severity of bleeding, and the amount of FFP already administered. Repeated testing of the INR may be useful to aid in decision making. Administration of 4F-PCC with an antifibrinolytic agent increases the patient's risk of thrombosis, at least theoretically, although there are no formal studies available to quantify this risk.

Other possible adverse reactions to Kcentra include headache, nausea/vomiting, hypotension, and anemia, and there is a theoretical risk of transmission of infectious diseases given that the 4F-PCCs are a product of human blood donation. (1) It is important to note that transmission of infectious disease is very unlikely given that manufacture of the product involves "two dedicated virus reduction steps" to prevent viral transmission. (1) Importantly, pharmaco-vigilance data for Beriplex failed to reveal any instances of virus transmission. (39)

OTHER PRACTICAL CONSIDERATIONS Preparation and Administration

Kcentra is generally available in 500-U or 1000-U vials and requires reconstitution of the lyophilized drug with 20 mL or 40 mL of sterile water, respectively (this is supplied with each vial). (1) Once reconstituted, it must be used within 4 hours or discarded. (1) It is useful for a blood bank or pharmacy to decide what system will be enforced with regard to the time of reconstitution in relation to ordering, given the potential for wastage and the high cost of the product (approximately $1-$2 per unit at the corresponding author's institution). It is the experience of these authors that product wastage is most common because of a change in level of patient care (most often, a poor prognosis whereby ongoing treatment is halted). Therefore, clinicians should be counseled to order the drug only at the point at which they are definitively going to administer it. Additionally, we recommend that the product be hand delivered with avoidance of delivery through the pneumatic tube system to avoid breakage or loss.

Administration is via a slow intravenous push, with the product insert specifying that the rate is not to exceed 8.4 mL/min (approximately 210 U/min). (1) An inherent problem arises in the practicality of staff physically administering this drug over an extended period of time (given the doses that may need to be given, this can be around 30 minutes). One option is the use of a syringe pump appropriately programmed to infuse the drug at the specified rate. Some clinical teams may desire to "push" the drug in at a much quicker rate. A study of Octaplex revealed no decrease in drug effectiveness when the 4F-PCC was infused at a higher rate than instructed (as high as 40 mL/min); however, 1 patient did develop pulmonary embolus after a second dose was administered 4 days after the first, although it was thought that this was not related to the rate of infusion. (41)

General Dosing-Related Questions

Pathologists may be faced with some practical questions related to 4F-PCC dosing. In our experience, one frequent question is whether it is safe to administer multiple doses of 4F-PCC within a 24-hour window of time. This question is difficult to address as there are no clear-cut studies that have explored it. We generally discourage provision of more than 1 dose of 4F-PCC per day owing to potential prothrombotic complications (notably, repeated dosing is discouraged by the package insert). (1) The corresponding author's institution allows for 1 exception regarding repeated dosing: a second dose of Kcentra can be given to supplement an earlier, lower dose administered before an INR could be obtained (when INR data are unavailable at the time of a request, we typically initiate a standard 25 U/kg dose). If pathologists are faced with requests for multiple doses in a 24-hour period, we would advise consulting with the clinical team to assess coagulation studies (PT, PTT, INR, platelet count) and clinical status to determine if some other form of coagulopathy has developed that could be addressed by an alternative transfusion or pharmacologic product.

It is important to briefly mention some nuances of actual 4F-PCC dose calculation. The package insert for Kcentra dictates that a specific volume-based dose should be calculated and titrated for each patient (specific to the actual factor IX potency of each vial--this information provided with each package of the product). (1) However, practical considerations seem to preclude such specific calculations in daily practice. For example, even if the added complication of using a per-package factor IX concentration was avoided (ie, by assuming approximately 500 U of factor IX per 500-U vial or 25 U/mL after reconstitution), a blood bank technician or the ordering clinician would still need to calculate a volume-based dose. Alternatively, if receiving reconstituted vials in their entirety, the administering clinician would need to limit infusion to the appropriate volume of product (and discard the remainder). Given the potential complexities of appropriate dosage and administration of this product, the corresponding author's institution uses a simpler off-label strategy for most patients: a 500-U-per-vial concentration of factor IX is assumed for every 500-U vial, and calculated doses are rounded up or down to allow for a vial-by-vial administration.

If the above strategy is used, then occasionally the question of whether to round up or down may be raised. One simple off-label approach in such settings is to round up to the closest available dose--in the example above, provision of three 1000-U vials would likely be safe and efficacious. However, for those patients with a concern for thrombosis, or for whom an exact dose is specifically required, another approach would be to follow the package insert and titrate the dose according to the factor IX activity per milliliter of reconstituted solution. (1) The Kcentra package insert notes approximately 20 to 31 U of factor IX activity per milliliter of reconstituted 4F-PCC, and the actual factor IX concentration is included with each package. (1) Administering clinicians/providers can use this number to guide how much of the reconstituted solution they should provide to achieve the exact dose requested.

Introduction of a 4F-PCC at a Hospital Transfusion Service or Blood Bank

Rollout of a new 4F-PCC should be preceded by education of clinicians who will most likely prescribe or administer the drug. Education early in the process ensures that an institution is "on the same page" with regard to the indications for a drug as well as expected system processes. Specialties involved include, but may not be limited to, emergency medicine, internal medicine-hematology, surgery, neurosurgery, neurology, and critical care. Special attention should be paid to the education of house staff, who are likely to be unfamiliar with the product and its indicated uses, and nursing staff who will need education regarding handling and administration of the product. Alerts or communique's placed in physician newsletters, electronic medical record "splash screens," or hospital computer screensaver alerts can help to make known important information about a 4F-PCC. Important phone numbers (blood bank, pharmacy, on-call staff responsible for approval of the product) should be made known to clinical services.
Patient evaluated:

Patient receiving VKA, INR > 2 and

* Acute, life-threatening bleed and/or
* Need for urgent surgery

[down arrow]

Dose of Kcentra calculated:

* INR 2-4: 25 U/kg (up to 2500 U)
* INR 4-6: 35 U/kg (up to 3500 U)
* INR > 6: 50 U/kg (up to 5000 U)

[down arrow]

Order placed and blood bank notified:

* Pager No. for blood bank physician
visible on order screen

[down arrow]

Indication and dose reviewed:

* If appropriate, order approved
* If inappropriate, additional
recommendations given
* Blood bank staff notified of final
decision

Sample stepwise algorithm for Kcentra (CSL Behring, Kankakee,
Illinois) ordering. Each step of the process should be reviewed
with the parties to be involved. Abbreviations: INR,
international normalized ratio; VKA, vitamin K antagonist.


The entire process of 4F-PCC ordering should be outlined and reviewed with all potential parties (and at least representatives) involved. An example of the steps that may be involved is demonstrated in the Figure. Official institutional polices should be documented in standard operating procedures addressing the new product, and these can be made available to clinical staff. Clinicians' input early in the process can help address issues that would otherwise arise during the treatment of a bleeding patient.

CONCLUSION

The 4F-PCC Kcentra, now available in the United States, is a potentially useful tool for the treatment of VKA-associated coagulopathy in patients presenting with acute life-threatening bleed or who necessitate urgent lifesaving surgical intervention. It is also possible that 4F-PCC could be effectively used in other clinical settings as reviewed in the above article. Ultimately, further clinical studies are needed to determine the safety and efficacy of 4F-PCCs for off-label indications. Until such studies are performed, we believe that the collective evidence and experience shared in this review make for an excellent starting point for blood bankers and pathologists who are consulted for 4F-PCC dosing and administration.

References

(1.) CSL Behring full prescribing Information: Kcentra prothrombin complex concentrate (human) [electronic prescribing information]. CSL Behring. http:// labeling.cslbehring.com/PI/US/Kcentra/EN/Kcentra-Prescribing-Information.pdf. Accessed June 14, 2014.

(2.) Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e44S-e88S.

(3.) Torres R, Kenney B, Tormey CA. Diagnosis, treatment, and reporting of adverse effects of transfusion. Lab Medicine. 2012; 43(5):217-231.

(4.) Sarode R, Matevosyan K, Bhagat R, et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor Vila cocktail for intracerebral hemorrhage. J Neurosurg. 2012; 116(3):491-497.

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David Unold, MD; Christopher A. Tormey, MD

Accepted for publication October 6, 2014.

From the Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut (Drs Unold and Tormey); BloodSource, Inc, Mather, California (Dr Unold); and Pathology & Laboratory Medicine Service, VA Connecticut Healthcare System, West Haven, Connecticut (Dr Tormey).

The authors report no relevant conflicts of interest; however, Dr Unold discloses receiving pre-employment compensation from BloodSource, Inc. before initial submission of the manuscript.

Corresponding author: Christopher Tormey, Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar St, PO Box 208035, New Haven, CT 06520 (e-mail: christopher. tormey@yale.edu).
Table 1. Transfusion Options for Vitamin K
Antagonist (VKA) Reversal

Transfusion    Content           Advantages          Disadvantages
Product

Fresh frozen   All elements of   * Can replace       * Large volumes
plasma         the coagulation   all coagulation     needed to
               cascade,          factors that        achieve
               including         are deficient       significant
               procoagulants                         increases in
               and                                   coagulation
               anticoagulants                        factor activity

                                 * Anticoagulants    * Carries risks
                                 may reduce          for infectious
                                 thrombotic          and
                                 risks               noninfectious
                                                     diseases

                                 * Inexpensive       * Must be ABO
                                 (relative to        compatible
                                 factor
                                 concentrates)

                                 * Widely
                                 available
                                 available

Recombinant    Factor VIIa       * Fast-acting       * Lacks all
activated                        reversal of INR     other elements
factor VII                       with a small        of the
concentrate                      volume product      coagulation
                                                     cascade

                                 * Virtually no      * VKA reversal
                                 risk for            is "off label"
                                 transfusion-
                                 transmitted         * Thrombotic
                                 diseases            risk

                                 * No concerns       * Cost
                                 for ABO
                                 incompatibility

Three-factor                     * Very low risk     * Lacks
prothrombin                      for                 therapeutic
complex                          transfusion-        levels of
concentrate                      transmitted         factor VII and
                                 diseases            has been shown
                                 Factors II, IX, X   to be
                                                     suboptimal for
                                 * Small volume      VKA reversal (42)
                                 product

                                 * No concerns       * Cost
                                 for ABO
                                 incompatibility

Four-factor    Factors II,       * Fast-acting       * Thrombotic
prothrombin    VII, IX, X        reversal of INR     risk
complex                          with a small
concentrate                      volume product      * Availability
                                                     (ie, may not be
                                                     stocked at all
                                                     hospitals)

                                 * FDA approved      * Cost
                                 for VKA
                                 reversal

                                 * Very low risk
                                 for
                                 transfusion-
                                 transmitted
                                 diseases

                                 * No concerns
                                 for ABO
                                 incompatibility

Activated 4-   Factors II,       * Fast-acting       * Thrombotic
factor         VII, IX, X        reversal of INR     risk
prothrombin                      with a small
                                 volume product      * VKA reversal
                                                     is off label

                                 * Very low risk     * Availability
                                 for                 (ie, may not be
                                 transfusion-        stocked at all
                                 transmitted         hospitals)
                                 diseases

                                 * No concerns       * Cost
                                 for ABO
                                 incompatibility

Abbreviations: FDA, US Food and Drug
Administration;INR, international normalized
ratio.

Table 2. Concentration (lU/mL) of Individual
Factors in Products Used for Vitamin K Antagonist
Reversal (a)

Product            II          VII         IX

Kcentra           19-40       10-25       20-31
Octaplex          14-38       9-24         25
FFP (at thaw)   0.83-1.25   0.5-1.63    0.62-1.08

Product             X           C           S

Kcentra           25-51       21-41       12-34
Octaplex          18-30       13-31       12-32
FFP (at thaw)   0.71-1.12   0.74-1.48   0.61-1.23

(a) Factor quantity is given in international
units per milliliter of respective reconstituted
4-factor prothrombin complex concentrate (4F-PCC)
or per mL of fresh frozen plasma (FFP). The
4F-PCC data are recalculated from Table 7 in the
Kcentra (CSL Behring, Kankakee, Illinois)
prescribing information package insert (1) and
from an unlabeled table in the Octaplex
(Octapharma AG, Lachen, Switzerland) prescribing
information package insert. (43) The FFP quantities
are recalculated from data in Table 1 of Scott et
al. (44)
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Author:Unold, David; Tormey, Christopher A.
Publication:Archives of Pathology & Laboratory Medicine
Date:Dec 1, 2015
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