Is there any information on using Kcentra for major bleeding in patients that are not on warfarin?

Comment by InpharmD Researcher

Literature documents use of prothrombin complex concentrate (PCC; Kcentra®) for management of major bleeding under a variety of circumstances not involving the use of warfarin. A retrospective cohort study and meta-analysis described use of PCC for management of major bleeding related to direct factor Xa inhibitors. The results suggested potential efficacy, although these were based on single-arm studies lacking a comparator group. Additionally, PCC has been used successfully in coagulation reversal in patients with liver disease and for mitigation of bleeding, resulting in a subsequent decreased need for allogeneic blood transfusions, associated with various surgeries including cardiac surgery. The majority of data investigating the use of PCC under these circumstances is based on retrospective and observational studies with inherent limitations.

Background

A guidance document from the Anticoagulation Forum suggests treatment with andexanet alfa in patients with rivaroxaban-associated or apixaban-associated major bleeding in whom a reversal agent is warranted. If andexanet alfa (Andexxa) is not available, treatment with 4-factor prothrombin complex concentrate (4F-PCC) 2,000 units is suggested. Similarly, intravenous (IV) idarucizumab (Praxbind) 5 g is recommended for dabigatran-associated major bleeding, and activated PCC (aPCC) 50 units/kg IV is suggested if idarucizumab is unavailable. [1]

In patients with edoxaban-associated or betrixaban-associated major bleeding in whom a versal agent is warranted, off-label treatment with either high dose andexanet alfa (800 mg bolus given at 30 mg/min followed by a continuous infusion of 8 mg/min for up to 120 min) or 4F-PCC 2,000 units is suggested. [1]

These recommendations come from clinical trials involving andexanet alfa and prospective, cohort studies involving 4F-PCC for reversal of factor Xa-associated major bleeding. While some authors recommend weight‐based dosing of 4F-PCC (50 units/kg) for factor Xa inhibitor reversal, the Anticoagulation Forum prefers a fixed dose of 2,000 units because it has been studied in patients with factor Xa inhibitor‐associated bleeding. Additional advantages of fixed dosing include greater simplicity for the ordering provider and pharmacy and reduced cost. [1]

A 2020 expert consensus from the American College of Cardiology provided guidance for management of major bleeding in patients on oral anticoagulants. Based on the quality of data available, the authors recommend andexanet alfa over 4F-prothrombin complex concentrate (4F-PCC) as evidence is mainly derived from small observational studies. [2]

A 2016 guidance statement from the Neurocritical Care Society and the Society of Critical Care Medicine suggests activated charcoal 50 g to intubated intracranial hemorrhage patients presenting within 2 h of ingestion of an oral factor Xa inhibitor. If the intracranial hemorrhage occurred within 3-4 half-lives of ingestion, then 4F-PCC 50 U/kg or aPCC 50 U/kg is recommended. However, since Andexanet was not approved at this time, it was not mentioned in this guideline. [3]

A 2019 systematic review and meta-analysis (N= 340; 10 case series) evaluated the safety and effectiveness of 4F-PCC as an option for managing direct FXa inhibitor-related major bleeding. All patients were receiving rivaroxaban (n= 233) or apixaban (n= 107), with cessation of direct oral FXa inhibitor. No patients received activated prothrombin complex concentrates (PCC). Results revealed that the pooled proportion of patients with effective management of major bleeding was 0.69 (95% confidence interval [CI], 0.61-0.76) in two studies (n= 150 patients) using International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding and 0.77 (95% CI, 0.63-0.92) in eight studies (n= 190 patients) not using ISTH criteria. Pooled data from nine studies (n= 249 patients) indicated that all-cause mortality was 0.16 (95% CI, 0.07-0.26), and pooled data from seven studies (n= 240 patients) indicated that thromboembolism rate was 0.04 (95% CI, 0.01-0.08). Given that the results were based on single-arm case studies without a comparator group, the authors could not reach a definitive conclusion regarding the efficacy of 4F-PCC in addition to the cessation of direct oral FXa inhibitors as opposed to the cessation of direct oral FXa inhibitor alone for the management of major bleeding. [4]

A 2021 article discusses the use of prothrombin complex concentrate (PCC) in the setting of liver failure. Patients with end-stage liver disease (ESLD) are in a fragile state of rebalancing where the reduced procoagulant function is counterbalanced by reducing the anticoagulant activity. This balance can be easily disrupted, leading to bleeding or thromboembolism (TE). Four-factor prothrombin complex concentrate (4F-PCC) has been utilized in scenarios where patients have a high model for end-stage liver disease (MELD) score as an alternative to frozen plasma (FP) for correcting the hypercoagulation state. The primary argument for utilizing 4F-PCC is to reduce the risk of consequences related to FP including FP-associated immunomodulation, transfusion-related acute lung injury, or transfusion-associated circulatory overload (TACO). However, the concern for thromboembolism has prevented the widespread use of 4F-PCC in patients with liver disease. The use of 4F-PCC is mainly observed as prophylaxis prior to surgery or for active bleeding and is typically used in combination with other blood products. 4F-PCC is sometimes used to correct elevated international normalized ratio (INR) with a target INR of <1.5 commonly utilized, but an optimal hemostatic endpoint has not been established in liver failure. The authors conclude that the evidence seems promising but requires further study to determine optimal dosing and thrombotic potential, especially with repeat dosing. [5]

A 2020 abstract poster reported the outcomes of patients with liver disease who received four-factor prothrombin complex concentrate (Kcentra) for management of major/life-threatening hemorrhage or need for emergent surgery that failed to respond to blood products or cannot tolerate fresh frozen plasma (FFP). From a total of 52 patients receiving 72 doses of Kcentra, 67% of patients presented with liver failure secondary to cirrhosis, and 28% had acute liver failure. Kcentra was mostly used for gastrointestinal bleeding followed by use prior to surgery. Hemostasis was achieved in 27.6% of patients. Adverse events within 30 days include venous thromboembolism (7.8%), line-related thrombosis (3.1%), myocardial infarction (1.6%), and other (3.1%). At discharge, 53.1% of patients perished and 4.6% went to hospice while the rest were discharged. The authors noted that the adverse events reported were higher than package insert (7-8%) while only helping a quarter of hepatic impaired patients achieve hemostasis. [6]

A 2015 article provided an overview on the possible use of PCCs in trauma and perioperative bleeding, typically used for rapid replacement of coagulation factors inhibited by vitamin K antagonists, such as warfarin. In trauma and perioperative bleeding, a variety of coagulopathies may be present and based on preclinical evidence, PCCs may be useful in facilitating hemostasis via repletion of key coagulation factors, particularly factor II (prothrombin). However, the evidence also suggests PCCs can cause procoagulant effects such as thromboembolic complications and disseminated intravascular coagulation in animal models. Clinical studies have also reported successful attenuation of bleeding in humans. Three retrospective clinical trials were cited, with one achieving hemostasis with 500-4,000 IU of PCC in 12 of 16 patients undergoing cardiac and other surgeries, as well as reduced transfusion of allogeneic blood products after PCC administration. Another study investigated a 1,500 IU (median) dose of PCC for perioperative coagulopathic bleeding, resulting in bleeding cessation in 4 of 11 patients with surgical bleeding and 26 of 27 patients with diffuse bleeding. The final study investigated the effects of PCC alone (mean 10 IU/kg; n= 24 patients; group 1), fresh frozen plasma (FFP) alone (n= 26 patients; group 2), and a combination of FFP and PCC (mean 14.1 IU/kg; n= 27 patients; group 3) for bleeding associated with cardiac surgery. Mean blood loss during the first hour was 224, 369, and 434 mL in groups 1, 2 and 3, respectively, with a significant difference between groups 1 and 3 (p= 0.02) but not between groups 1 and 2 or 2 and 3. [7]

Another retrospective study (N= 131) investigated the use of PCC (median dose 1,800 IU) in trauma patients who had received coagulation factor concentrate-based therapy (fibrinogen concentrate [median dose 6 g] as first-line therapy. Of this group, patients with prolonged extrinsically activated ROTEM assay clotting time (EXTEM CT; n= 98) were given PCC, with results indicating a mortality rate of 24% (significantly lower than 34% rate predicted by the trauma injury severity score). A similar follow-up study by the same author found concentrate-based treatment reduced exposure to allogeneic blood products compared with FFP-based therapy. Transfusions of erythrocytes were avoided by 29% of patients and platelet concentrate was avoided by 91% of patients receiving concentrate-based treatment compared with 3% and 56% of patients receiving FFP-based therapy. The benefits of PCC must be balanced with potential thromboembolic complications. Although the risk was reported to be low, the majority of this data is reported in the context of vitamin K antagonist reversal. Ultimately, the authors recommended the administration of fibrinogen (fibrinogen concentrate or possibly cryoprecipitate/therapeutic plasma) as first-line hemostatic therapy. If restoration of thrombin generation is indicated by the EXTEM CT diagnostic test, low doses of PCCs should be administered, using a theragnostic approach for dose titration. Patients at risk of thromboembolic complications should be monitored closely. [7]

Literature Review

A search of the published medical literature revealed 9 studies investigating the researchable question:

Is there any information on using KCentra for major bleeding in patients that are NOT on Coumadin? Especially in light of the national critical blood shortage.

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-9 for your response.

Comparison of 4-Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of Hemorrhage During and After Cardiac Surgery: A Randomized Pilot Trial
Design	Parallel-group, randomized pilot study N= 101
Objective	To determine the proportion of patients who received 4-factor prothrombin complex concentrate (PCC) and then required frozen plasma (FP), explore hemostatic effects and safety, and assess the feasibility of study procedures
Study Groups	PCC group (n= 54) FP group (n= 47)
Inclusion Criteria	Adult patients undergoing cardiac surgery for whom coagulation factor replacement with FP or PCC was ordered during surgery for the management of bleeding
Exclusion Criteria	Receipt of FP or PCC within 48 hours before surgery; history of severe allergic reaction to FP or PCC; refusal of blood components; known pregnancy; anticipated high risk of death within 24 hours of surgery; undergoing heart transplantation, ventricular assist device implant or removal, or thoracoabdominal aneurysm repair; history of heparin-induced thrombocytopenia; receipt of warfarin with an international normalized ratio higher than 1.5 at the time of surgery; or receipt of direct oral anticoagulants within 48 hours of surgery
Methods	Eligible patients were randomized (1:1) to receive either PCC (1,500 IU for patients weighing ≤ 60 kg and 2,000 IU for patients weighing > 60 kg) or FP (3 U for patients weighing ≤ 60 kg and 4 U for patients weighing > 60 kg), repeated once as needed within 24 hours. Frozen plasma was used for any subsequent doses in both groups.
Duration	From September 23, 2019, to June 19, 2020
Outcome Measures	Hemostatic effectiveness (whether patients received any hemostatic therapies from 60 minutes to 4 and 24 hours after initiation of the intervention, amount of allogeneic blood components administered within 24 hours after start of surgery, and avoidance of red cell transfusions within 24 hours after start of surgery), protocol adherence, and adverse events
Baseline Characteristics		PCC group (n= 54)	FP group (n= 47)
	Age (interquartile range [IQR]), years	66 (50-73)	67 (55-74)
	Male	40 (74.1%)	33 (70.2%)
	Race/ethnicity White Asian or Pacific Islander Other	31 (57.4%) 12 (22.2%) 10 (18.5%)	26 (55.3%) 10 (21.3%) 10 (21.3%)
	Body mass index, kg/m²	23.6 ± 4.5	23.1 ± 4.7
	New York Heart Association functional class I II III IV	14 (25.9%) 22 (40.7%) 15 (27.8%) 3 (5.6%)	11 (23.4%) 19 (40.4%) 15 (31.9%) 2 (4.3%)
	Comorbidities Hypertension Dyslipidemia Congestive heart failure Atrial fibrillation Diabetes	36 (66.7%) 34 (63%) 12 (22.2%) 8 (14.8%) 11 (20.4%)	31 (66.0%) 28 (59.6%) 13 (27.7%) 7 (14.9%) 10 (21.3%)
	Preoperative laboratory values Creatinine (IQR), mg/dL Hemoglobin, g/dL Platelet count, ×10³/µL International normalized ratio	1.1 (0.8-1.4) 13.2 ± 1.9 205 ± 58 1.2 ± 0.3	1 (0.9-1.2) 12.8 ± 2.1 210 ± 67 1.2 ± 0.3
	Surgical factors Previous cardiac surgery Nonelective surgery Complex surgery Cardiopulmonary bypass duration, min	19 (35.2%) 11 (20.4%) 45 (83.3%) 172 ± 71	11 (23.4%) 15 (31.9%) 37 (78.7%) 166 ± 46
	Tranexamic acid dose, g	4.3 ± 2.3	4.1 ± 1.3
	Heparin dose, IU	53,167 ± 18,107	55,543 ± 20, 996
	Protamine dose, mg	406 ± 98	451 ± 151
	Cell salvage blood, mL	516 ± 660	563 ± 554
Results	Endpoint	PCC group (n= 54)	FP group (n= 47)	p-value
	Median dosage of investigational product (IQR)	24.9 (21.8-27.0) IU/kg	12.5 (10.0-15.0) mL/kg	-
	Doses of investigational product 1 2	49 (90.7%) 5 (9.3%)	38 (80.9%) 9 (19.1%)	0.25
	Postintervention hemostatic therapy from 60 min to 4 h No Yes	43 (79.6%) 11 (20.4%)	32 (68.1%) 15 (31.9%)	0.25
	Postintervention hemostatic therapy from 60 min to 24 h No Yes	41 (75.9%) 13 (24.1%)	31 (66%) 16 (34%)	0.28
	Bleeding categories according to modified UDPB classification Moderate (class 2) Severe or massive (classes 3 and 4)	42 (79.2%) 11 (20.8%)	29 (61.7%) 18 (38.3%)	0.08
	Chest tube drainage (IQR), mL 12 h 24 h	310 (250-455) 450 (370-630)	500 (310-750) 700 (470-950)	< 0.001 < 0.001
	Cumulative allogeneic blood components within 24 h after start of surgery, U RBC + platelet + FP (including IMP) RBC + platelet + FP (excluding IMP)	6 (4-11) 6 (4-11)	14 (8-20) 10 (6-16)	< 0.001 0.15
	Individual allogeneic blood components within 24 h after start of surgery Red blood cell	1.5 (0-4)	3 (1-5)	0.05
	During the first 24 hours after the start of surgery, 15 patients (28%) in the PCC group and 8 patients (17%) in the FP group received no red blood cells (p= 0.24).
	Adverse Events and Other Measured Outcomes at 28-Day Follow-up	PCC group (n = 54)	FP group (n = 47)
	Any adverse event [No. of events]	42 (77.8%) [108]	41 (87.2%) [102]
	Any serious adverse event	19 (35.2%) [29]	14 (28.6%) [22]
	Thromboembolic adverse events	4 (7.4%) [4]	4 (8.2%) [5]
	Acute kidney injury	4 (7.4%)	3 (6.1%)
	Duration of mechanical ventilation (IQR), days	0.5 (0.4-0.9)	0.6 (0.4-0.9)
	Duration of intensive care unit stay (IQR), days	2 (1-4.8)	3 (1.1-4.8)
	Duration of hospitalization (IQR), days	9.3 (8-13.7)	12.3 (9.2-14.5)
	UDPB, universal definition of perioperative bleeding; RBC, red blood cells; IMP, investigational medicinal product;
Adverse Events	See Results
Study Author Conclusions	For patients who require coagulation factor replacement for bleeding during cardiac surgery, this pilot study illustrates that a multicenter randomized trial comparing PCC with FP is feasible. Our results suggest that PCC may be a suitable substitute for FP because it markedly decreases the need for FP and may have hemostatic superiority without increasing the occurrence of adverse events. Adequately powered multicenter randomized clinical trials are warranted to delineate the risk-benefit profile of PCC relative to FP for the management of bleeding during cardiac surgery and other settings.
InpharmD Researcher Critique	The study suggests PCC is a suitable substitute for FP for mitigation of bleeding in cardiac surgery; however, given this is an underpowered hypothesis-generating pilot study, the results are only considered exploratory. The study specifically excluded warfarin recipients with an INR higher than 1.5 at the time of surgery.

References:

Karkouti K, Bartoszko J, Grewal D, et al. Comparison of 4-factor prothrombin complex concentrate with frozen plasma for management of hemorrhage during and after cardiac surgery: a randomized pilot trial. JAMA Netw Open. 2021;4(4):e213936. Published 2021 Apr 1. doi:10.1001/jamanetworkopen.2021.3936

Comparison of blood product use and costs with use of 3-factor versus 4-factor prothrombin complex concentrate for off-label indications
Design	Retrospective cohort study N= 182
Objective	To compare blood product use between patients treated with 3-factor prothrombin complex concentrate (PCC3) and those treated with 4-factor prothrombin complex concentrate (PCC4) for non-warfarin-related indications
Study Groups	PCC3 (n= 118) PCC4 (n= 64)
Inclusion Criteria	Adults, received PCC3 or PCC4
Exclusion Criteria	Received PCC for approved hospital indications
Methods	Data was collected from two affiliated tertiary care institutions in the US. Both initially utilized PCC3 per the formulary, but in early 2015 switched to PCC4 (Kcentra). Blood product use and PCC use were at discretion of the provider, with no standard protocol in place as guidance.
Duration	PCC administration between February 2014 and August 2015
Outcome Measures	Primary: blood product use during hospitalization (particularly plasma) Secondary: drug costs, total hemostasis costs, intensive care unit (ICU) length of stay, hospital length of stay, in-hospital mortality
Baseline Characteristics		PCC3 (n= 118)	PCC4 (n= 64)	p-value
	Age, years	59.1 ± 18	61.2 ± 18.4	0.459
	Male	74 (62.7%)	46 (71.9%)	0.253
	Race White Hispanic Other/unknown	71 (60.2%) 28 (23.7%) 19 (16.1%)	38 (59.4%) 14 (21.9%) 12 (18.8%)	> 0.999 0.855 0.682
	Weight, kg	80.5 ± 20.7	79.4 ± 16.1	0.724
	Charlson Comorbidity Index 0 1 2+	24 (20.3%) 26 (22%) 68 (57.6%)	16 (25%) 11 (17.2%) 37 (57.8%)	0.461 0.563 > 0.999
	Indication Reversal for surgery (drug related) Coagulopathy of liver disease (for surgery) Coagulopathy of liver disease (no surgery) Intraoperative bleeding cessation Nonoperative bleeding cessation Other	4 (3.4%) 6 (5.1%) 3 (2.5%) 74 (62.7%) 26 (22%) 5 (4.2%)	1 (1.6%) 3 (4.7%) 2 (3.1%) 39 (61%) 17 (26.6%) 2 (3.1%)	0.658 > 0.999 > 0.999 0.873 0.584 > 0.999
	Location Emergency department Inpatient unit Operating room Trauma unit	9 (7.6%) 20 (17%) 89 (75.4%) 20 (17%)	9 (14.1%) 4 (6.3%) 51 (79.7%) 21 (32.8%)*	0.196 0.064 0.583 0.017
	Laboratory values Hemoglobin, g/dL Hematocrit, % Platelet count, x10³ cells/mm³	10.3 ± 2.8 31.1 ± 8.9 161 ± 84	10.7 ± 2.7 32.3 ± 7.8 189 ± 103	0.405 0.368 0.064
	*No significant differences between groups except for percentage of patients in trauma unit (p= 0.017)
Results	Endpoint	PCC3 (n= 118)	PCC4 (n= 64)	p-value
	Blood products administered Plasma Volume, mL (IQR) Red blood cells Volume, mL (IQR) Platelets Volume, mL (IQR) Cryoprecipitate Volume, mL (IQR)	67 (56.8%) 638 (550 to 1,355) 73 (61.9%) 1,208 (380 to 3,360) 96 (81.4%) 752 (5,461 to 1,243) 41 (34.8)% 318 (214 to 535)	34 (53.1%) 656 (532 to 1,136) 44 (68.8%) 1,306 (630 to 2,414) 48 (75%) 741 (461 to 1,042) 28 (43.8%) 277 (200 to 438)	0.643 0.946 0.419 0.63 0.343 0.545 0.264 0.409
	Drug costs (IQR), dollars	$3,527 ($2,596 to $4,193)	$5,913 ($4,698 to $6,489)	< 0.001
	Total hemostatsis costs (IQR), dollars	$5,559 ($3,922 to $8,159)	$7,771 ($6,366 to $9,205)	< 0.001
	ICU length of stay (IQR), days	6 (3 to 15)	5 (3 to 11)	0.538
	Hospital length of stay (range), days	12 (7 to 25)	13 (7 to 25)	0.931
	In-hospital mortality	31 (26%)	17 (27%)	1
Adverse Events	Adverse Events: disseminated intravascular coagulation (1.7% PCC3 vs. 1.6% PCC4), venous thromboembolism (2.5% vs. 1.6%), stroke (0 vs. 4.7%)
Adverse Events	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	PCC3 use and PCC4 use were associated with similar blood product use, ICU length of stay, hospital length of stay, and in-hospital mortality when given for non–warfarin-related indications. However, relative to PCC3 use, PCC4 use was associated with an increase in costs that was primarily due to drug costs.
InpharmD Researcher Critique	Despite the increased cost, there was no evidence found in this study suggesting PCC4 is more efficacious for non-warfarin-related indications compared to PCC3, although data does suggest PCC4 is preferred for warfarin reversal. Although not significantly different, the PCC3 group in this study appeared to use more blood products. Additionally, the trauma patients in the PCC3 group had a higher mean injury severity score than those in the PCC4 group; there were also significantly more trauma patients in the PCC4 group. Due to imbalanced number of trauma patients within the two groups and the small sample size, arriving at a definitive conclusion may not be possible for this subset of patients.

References:

DeAngelo J, Jarrell DH, Cosgrove R, Camamo J, Edwards CJ, Patanwala AE. Comparison of blood product use and costs with use of 3-factor versus 4-factor prothrombin complex concentrate for off-label indications. Am J Health Syst Pharm. 2018;75(15):1103-1109. doi:10.2146/ajhp180076

Activated Factor 7 Versus 4-Factor Prothrombin Complex Concentrate for Critical Bleeding Post-Cardiac Surgery
Design	Retrospective chart review N= 129
Objective	To determine whether there is a difference in chest tube output in patients who have received 4-factor prothrombin complex concentrate (PCC) or activated factor seven (rFVIIa) for critical postoperative bleeding associated with cardiovascular surgery
Study Groups	rFVIIa (n= 73) PCC (n= 56)
Inclusion Criteria	Age ≥ 18; had any type of cardiothoracic surgery with bleeding requiring intervention; received rFVIIa or 4-factor PCC
Exclusion Criteria	Pregnant; received 4-factor PCCC or rFVIIa for indications other than bleeding associated with cardiac surgery; received both 4-factor PCC and rFVIIa
Methods	Patients either received a rFVIIa 45 mcg/kg bolus administered over 2 to 5 minutes or 4-factor PCC 25 units/kg (maximum dose of 2,500 units) infused at a rate no greater than 8.4 mL/min (maximum infusion time of 12 minutes). Patients who received rFVIIa were considered the control group, and patients who received 4-factor PCC were considered the intervention group. Surgeons were allowed to use their clinical judgment for the administration of blood products, including fresh frozen plasma (FFP), or additional doses of the recommended factor products.
Duration	Surgery with bleeding requiring intervention: April 2015 to December 2016
Outcome Measures	Coprimary outcomes: average total chest tube output in the first 24 hours postoperatively and average total chest tube output postoperatively Secondary outcomes: average number of postoperative units of FFP; average total hospital length of stay; incidence of re-exploration for bleeding; incidence of thromboembolic events
Baseline Characteristics		rFVIIa (n= 73)	PCC (n= 56)	p-value
	Age, years	64	68	0.833
	Male	60%	68%	0.452
	Weight, kg	83.9	86.5	0.588
	Past medical history Ischemic stroke Venous thromboembolism	10 (14%) 5 (7%)	11 (20%) 7 (13%)	0.62 0.884
	Laboratory values Hemoglobin, g/dL Hematocrit, g/dL	10.6 31.8	8.7 25	< 0.0001 < 0.0001
	Average cumulative dose	5.55 mg	2,199 units	-
	Type of surgery Coronary artery bypass graft Valve repair Aortic dissection	47 (64%) 19 (26%) 7 (10%)	29 (52%) 19 (34%) 8 (14%)	0.207 0.663 0.035
Results	Endpoint	rFVIIa (n= 73)	PCC (n= 56)	p-value
	Average chest tube output postoperatively, mL 24 hours Total	1,239 3,156.5	1,218.9 2,669.6	0.937 0.937
	Units of FFP	4.2	2.4	0.016
	Hospital length of stay, days	15.9	11.7	0.048
	Incidence of re-exploration	5 (7%)	3 (5.4%)	0.999
	Incidence of thromboembolic events	4 (5.5%)	2 (3.6%)	0.159
Adverse Events	Common Adverse Events: Not disclosed
	Serious Adverse Events: See results section for incidence of thromboembolic events.
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	4-Factor PCC may be an equally efficacious alternative to rFVIIa for patients experiencing significant bleeding during cardiac surgery. There is no difference in chest tube output; therefore, there is no difference in bleeding—either at 24 hours postoperatively or total.
InpharmD Researcher Critique	This study shows that 4-factor PCC may be an appropriate option to reduce significant bleeding during cardiac surgery and may also help reduce the units of FFP needed during a time of shortage. According to baseline laboratory parameters, patients in the PCC group may have been more severe in regards to bleeding risk, which may have led to better outcomes for rFVIIa, but length of hospital stay and units of FFP needed were still significantly lower in the PCC group.

References:

Mehringer SL, Klick Z, Bain J, et al. Activated Factor 7 Versus 4-Factor Prothrombin Complex Concentrate for Critical Bleeding Post-Cardiac Surgery. Ann Pharmacother. 2018;52(6):533-537. doi:10.1177/1060028017752365

The Use of 3- and 4-Factor Prothrombin Complex Concentrate in Patients With Elevated INR
Design	Retrospective analysis N= 189
Objective	To characterize the use of 3- and 4- factor prothrombin complex concentrates (PCCs) for patients identified with a non-warfarin-related coagulopathy (WRC)
Study Groups	WRC (n= 128) Non-WRC (n= 61)
Inclusion Criteria	Age ≥ 18 years; received PCCs for elevated international normalized ratio (INR); had pre- and post-PCC administration coagulation panels, dosing of PCC, and clear documentation of when PCCs were administered
Exclusion Criteria	Patients not meeting inclusion criteria
Methods	Patients were divided into 2 groups: those with WRC and those with non-WRC; patients in the non-WRC group were subdivided according to presumed cause of coagulopathy—liver disease, novel oral anticoagulant use, sepsis, or trauma. Patients received either 3- or 4-factor PCC.
Duration	January 1, 2012 to July 1, 2015
Outcome Measures	Primary outcome: change in INR before and after PCC administration Secondary outcome: patient outcomes (e.g., survival to discharge, transferred to hospice, death)
Baseline Characteristics		Warfarin-related (n= 128)		Non-warfarin-related (n= 61)
	Age, years	73.54		59.75
	Male	83 (65%)		33 (54%)
	Weight, kg	77.98		78.16
	Admitting diagnosis Intracranial hemorrhage Gastrointestinal bleed Lone bone fractures	42 (33%) 25 (20%) 5 (4%)		15 (25%) 11 (18%) 2 (3%)
	Medications Low-molecular-weight heparin IIa or Xa inhibitors Antiplatelets Aspirin Clopidogrel	6 (5%) 0 - 52 (41%) 14 (11%)		5 (8%) 10 (16%) - 12 (20%) 0
	Laboratory values Platelets, x10⁹/L Hemoglobin, g/dL Hematocrit, %	223 ± 136 10.6 ± 2.95 32.2 ± 9		148 ± 118 9 ± 2.4 27.3 ± 7.5
	PCC indication Intracranial hemorrhage Gastrointestinal bleed Periprocedural	45 (35%) 33 (26%) 21 (16%)		16 (26%) 17 (28%) 13 (21%)
	Other blood products Vitamin K, mg Fresh frozen plasma, units Packed red blood cells, units Platelets, units	128 28 30 19		24 23 18 26
Results	Endpoint	Warfarin-related (n= 128)		Non-warfarin-related (n= 61)
		3 Factor (n= 32)	4 Factor (n= 96)	3 Factor (n= 13)	4 Factor (n= 48)
	Total PCC dose, units	3,073 ± 1,654	2,472 ± 930	2,253 ± 1,261	2,413 ± 1,030
	INR decrease	2.8 ± 2.33	3.23 ± 3.48	1.13 ± 2.02	1.15 ± 1.57
	INR decrease in non-warfarin related coagulopathy secondary to liver disease	-	-	0.98 ± 0.77	1.43 ± 1.81
	While the majority of patients in both groups survived to discharge (84% in the WRC group and 59% in the non-WRC group), there was a greater proportion of patients in the non-WRC group who were either transferred to hospice (13% vs 7%) or died (28% vs 9%) as compared to the WRC group.
Adverse Events	Common Adverse Events: Not disclosed
	Serious Adverse Events: Not disclosed
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Three and 4-factor PCCs can reduce INR in patients with WRC and in those with non-WRC secondary to liver disease.
InpharmD Researcher Critique	This study was designed to characterize the use of PCCs for non-WRC, and no detailed analysis was performed beyond descriptive statistics. Overall, this study shows PCC may be useful in reducing the INR, which can decrease bleeding, in patients with non-WRC.

References:

Mohan S, Howland MA, Lugassy D, Jacobson J, Su MK. The Use of 3- and 4-Factor Prothrombin Complex Concentrate in Patients With Elevated INR. J Pharm Pract. 2018;31(3):262-267. doi:10.1177/0897190017707119

Prothrombin Complex Concentrates for Coagulopathy in Liver Disease: Single-Center, Clinical Experience in 105 Patients
Design	Retrospective, single‐center audit/service evaluation N= 105 (194 episodes of Prothrombin complex concentrates [PCC] administration)
Objective	To evaluate the indications for PCC use and the correction of PT/INR at each administration
Study Groups	All (n= 105)
Inclusion Criteria	Patients with acute or chronic liver disease who received PCC
Exclusion Criteria	Hepatectomy, episodes that required coadministration of rFVIIa
Methods	The effect of PCC on coagulation was analyzed in patients for whom coagulation results were available 7 hours before and after PCC. Data on thromboembolic events and mortality within 4 weeks of PCC administration were captured.
Duration	Between January 2008 and June 2012
Outcome Measures	Primary: categorization of indications for PCC administration, the ability of PCC to correct PT/INR at each administration, potential relation to the dose administered Secondary: assessment of coadministration of other hemostatic products
Baseline Characteristics		All (N= 105)
	Age, years ≤ 40 41‐50 51‐60 61‐70 > 70	25 (24%) 27 (26%) 32 (30%) 14 (13%) 7 (7%)
	Female	69 (66%)
	Type of liver failure Chronic liver disease Acute liver failure	81 (77%) 24 (23%)
	Chronic liver disease etiology* ALD PBC/PSC/AI Viral NASH CCF HCC Other	44 (42%) 10 (10%) 25 (24%) 5 (5%) 4 (4%) 11 (10%) 15 (14%)
	Severity of liver disease at admission (Child‐Pugh grade)† < 7 = A 7-9 = B > 9 = C	4 (6%) 27 (38%) 40 (56%)
	Severity of liver disease at admission (MELD)† ≤ 9 10-19 20-29 30-39 ≥ 40	4 (5%) 42 (53%) 22 (28%) 10 (13%) 2 (3%)
	Acute liver failure etiology Acetaminophen overdose Viral/HBV Other	11 (46%) 4 (17%) 9 (38%)
	Patients undergoing OLT Chronic liver disease Acute liver failure	18 (17%) 6 (6%)
	^*Patients may have more than one etiology. Percentage values will add up to more than 100%. ^†Figures based on patients with chronic liver disease only. Percentages are of those patients with available data. Abbreviations: AI, adrenal insufficiency; ALD, acute liver disease; CCF, congestive cardiac failure; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MELD, Model for End‐Stage Liver Disease; NASH, nonalcoholic steatohepatitis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.
Results	Variable	No Fibronogen or Cryoprecipitate				Concurrent Administration of Fibrinogen or Cryoprecipitate
	Variable	N	Pre-PCC Median (interquartile range [IQR])	Post-PCC Median (IQR)	p-value	N	Pre-PCC Median (IQR)	Post-PCC Median (IQR)	p-value
	PT	46	27 (23, 34)	23 (20, 26)	< 0.001	43	30 (23, 54)	21 (18, 28)	< 0.001
	INR	49	2.3 (1.9, 2.9)	1.8 (1.6, 2.1)	< 0.001	52	3.1 (2.0, 7.0)	1.9 (1.5, 2.8)	< 0.001
	INR ≤ 1.5	49	6%	22%	0.005	52	4%	25%	< 0.001
	aPTT	46	46 (38, 63)	45 (39, 56)	0.06	28	56 (45, 67)	46 (40, 66)	0.09
	Fibrinogen	28	1.6 (1.2, 2.3)	1.7 (1.2, 2.3)	0.37	22	1.0 (0.6, 1.4)	1.6 (1.1, 2.1)	< 0.001
	Hemoglobin	39	8.4 (7.8, 8.8)	8.3 (7.9, 8.8)	0.75	31	8.1 (7.3, 9.3)	8.3 (7.2, 9.5)	0.36
	Indications for PCC were pre-procedure prophylaxis and treatment for active/recent bleeding in 48% and 52% of 194 treatment episodes, respectively. The median dose of PCC administered was 22 IU/kg (IQR, 16‐29 IU/kg).
Adverse Events	No cardiovascular or cerebrovascular adverse events. Forty-six patients died of causes unrelated to PCC treatment.
Study Author Conclusions	In patients with liver disease, PCC therapy was effective in improving coagulation test results without an excess of thrombotic events. Further assessment of PCC as hemostatic therapy in this setting is required.
InpharmD Researcher Critique	Most patients (77%) had chronic liver disease. The study lacks a comparator (patient who did not receive PCC) and is subject to the limitations inherent to a retrospective analysis. Other hemostatic agents were used in addition to PCC which limits the interpretation of the results in terms of PCC use. The authors noted substantial heterogeneity across included patients.

References:

Drebes A, de Vos M, Gill S, et al. Prothrombin complex concentrates for coagulopathy in liver disease: single-center, clinical experience in 105 patients. Hepatol Commun. 2019;3(4):513-524. doi:10.1002/hep4.1293

Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study
Design	Retrospective, cohort study N= 31
Objective	To assess the safety and efficacy of 4F-PCC for the management of major bleeding related to oral factor Xa (fXa) inhibitors
Study Groups	4F-PCC (n= 31)
Methods	Inclusion criteria: >18 years, received 4F-PCC (Kcentra) for fXa inhibitor-related major bleeding Exclusion criteria: pregnancy, incarceration, perioperative reversal unrelated to bleeding Patients received 4F-PCC (Kcentra) 25-50 units/kg of actual body weight (max dose 5,000 units) per an institutional protocol from a hospital in South Carolina. Additional doses to achieve hemostasis were given at the provider's discretion.
Duration	July 2014 to May 2018
Outcome Measures	Effectiveness of 4F-PCC for the management of fXa inhibitor-related major bleeding, incidence of thromboembolism, length of stay, mortality, cost analysis comparing 4F-PCC to andexanet alfa for reversal of oral fXa inhibitors
Baseline Characteristics		4F-PCC (n= 31)
	Age, years	74
	Men	23 (74.2%)
	Race White African American	28 (90.3%) 3 (9.7%)
	Leading indication for reversal Intracranial hemorrhage Pericardial	18 (58%) 5 (16.1%)
	Factor Xa inhibitors involved Apixaban Rivaroxaban	17 (54.8%) 14 (45.2%)
Results		4F-PCC (n= 31)
	Dose of 4F-PCC, units Needed repeat doses	3,070 ± 1,225 2 (6.5%)
	Hemostatic effectiveness	25 (80.6%)
	Thrombotic events	0
	Length of ICU stay, days	2.6
	In-hospital mortality	5 (16.1%)
	Based on this population and the average wholesale price (AWP) of Kcentra being $1.62 per unit, the mean cost for reversal would be $4,973. If an additional 500 units were required for hemostasis, leading to an additional cost of $810, this would result in a total cost of $5,783. Based on the current AWP of $3,300 per 100 mg, andexanet alfa costs $29,040 for the low dose regimen and $58,080 for the high dose regimen. This presents a cost difference of about $53,107 between the therapies.
Adverse Events	Serious adverse events: pericardial tamponade (9.7%), intracranial bleeding (6.5%), intrathoracic bleeding (3.2%)
Study Author Conclusions	Administration of 4F-PCC was effective for most patients requiring emergent reversal of anticoagulation with apixaban or rivaroxaban and was associated with a low risk of thromboembolic events. Considerable cost differences limit the use of andexanet alfa and may warrant further study of 4F-PCC for fXa inhibitor reversal.
InpharmD Researcher Critique	Some of the limitations are based on Caucasian and African American patients, small sample size, and lack of comparator arms of a retrospective study. Only half of the patients received the recommended 50 units/kg dose of 4F-PCC. Lastly, the definition of major bleeding was derived from an institutional protocol for anticoagulation reversal and used any blood product administration. Additionally, there was no phytonadione use in these patients.

References:

Smith MN, Deloney L, Carter C, Weant KA, Eriksson EA. Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study. J Thromb Thrombolysis. 2019;48(2):250-255.

Four-Factor Prothrombin Complex Concentrate for Coagulopathy Reversal in Patients With Liver Disease
Design	Single-center, retrospective, observational study N= 85
Objective	To analyze the efficacy and safety of 4-factor prothrombin complex concentrate (4F-PCC) in patients with and without liver disease (LD) when used for the treatment or prophylaxis of significant bleeding.
Study Groups	Liver disease (LD group; n= 31) Without liver disease (non-LD group; n= 54)
Inclusion Criteria	Received at least 1 dose of 4F-PCC, had at least 1 international normalized ratio (INR) prior to 4F-PCC administration (pre-INR) and at least 1 INR after 4F-PCC administration (post-INR) both obtained within 48 hours of 4F-PCC administration.
Exclusion Criteria	Age < 18 years, documented congenital factor deficiency, pregnancy
Methods	Patient data with documented LD based on the international classification of disease (ICD-9) codes, type of bleeding, and indication for 4F-PCC administration were collected for analysis. For warfarin reversal, patients received 4F-PCC 25 to 50 units/kg based on patient INR and body weight. For use prior to surgery, fixed low-dose 4F-PCC (approximately 500 units) was administered for INR reversal in nonbleeding coagulopathic patients. Concurrent use of blood products including fresh frozen plasma (FFP), packed red blood cells, platelets, and cryoprecipitate were allowed.
Duration	Data collection period: July 1, 2013 to April 20, 2014
Outcome Measures	Primary: coagulopathy reversal defined as post-INR < 1.5 collected at least 30 minutes after 4F-PCC Secondary: Hemostasis at 48 hours defined as the composite endpoint of all three of the following: achieved and maintained hemoglobin ≥ 7 g/dL for 48 hours after 4F-PCC administration, discontinuation of all blood products, and physician documented assessment of hemostasis in the electronic medical record within 48 hours of 4F-PCC administration.
Baseline Characteristics		LD group (n= 31)	Non-LD group (n= 54)	p-value
	Age, years (interquartile range [IQR])	58 (50 to 62)	70 (60 to 82)	<0.01
	Male	17 (54.8%)	36 (66.7%)	0.35
	Body mass index, kg/m² (IQR)	23 (22 to 24)	23 (21 to 27)
	Type of bleeding Procedural associated Intracranial hemorrhage Gastrointestinal bleed Other trauma bleeds Other bleeds No bleed	5 (16.1%) 5 (16.1%) 10 (32.3%) 0 3 (9.7%) 8 (25.8%)	3 (5.6%) 23 (42.6%) 8 (14.8%) 4 (7.4%) 5 (9.3%) 11 (20.4%)	0.73
	Etiology of liver disease Hepatitis C cirrhosis Alcoholic cirrhosis Acute hepatitis, liver injury, liver failure Nonalcoholic steatohepatitis Isoniazid-induced hepatitis Crypotgenic cirrhosis Cardiac cirrhosis Sarcoidosis Unknown	10 (32.3%) 8 (25.8%) 4 (12.9%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 3 (9.7%)	-	-
	Severity of liver disease Child-Pugh A Child-Pugh B Child-Pugh C Model for End-Stage Liver Disease (MELD) score (IQR)	1 (3.2%) 6 (19.4%) 24 (77.4%) 29 (21 to 40)	-	-
	Antiplatelet use prior to 4F-PCC None Aspirin Clopidogrel Other	27 (87.1%) 3 (9.7%) 0 1 (3.2%)	33 (61.1%) 18 (33.3%) 1 (1.9%) 2 (3.7%)	-
	Anticoagulant use None Warfarin Dabigatran Rivaroxaban Edoxaban	25 (80.7%) 4 (12.9%) 0 1 (3.2%) 1 (3.2%)	10 (18.5%) 40 (74%) 1 (1.9%) 2 (3.7%) 1 (1.9%)	-
	Concurrent use of packed red blood cells Concurrent use of fresh frozen plasma	22 (70.1%) 26 (83.9%)	20 (37.0%) 23 (42.6%)	<0.01 <0.01
	Median dose of 4F-PCC, units	1638 (537 to 2220)	2146 (1608 to 2785)
Results	Endpoint	LD group (n= 31)	Non-LD group (n= 54)	p-value
	Coagulopathy reversal	6 (19.4%)	44 (81.5%)	< 0.01
	Hemostasis at 48 hours	6 (19.4%)	23 (42.6%)	0.03
	Thrombotic events	1 (3.2%)	8 (14.8%)	0.15
	Mortality	51.6%	18.5%	< 0.01
Study Author Conclusions	In conclusion, 4F-PCC appears to be safe in patients with liver disease when administered judiciously; however, further studies are necessary to optimize its use and elucidate its hemostatic potential in this patient population.
InpharmD Researcher Critique	The majority of patients also received additional blood products along with the 4F-PCC, making it difficult to assess the pro-coagulation effects of 4F-PCC.

References:

Huang WT, Cang WC, Derry KL, Lane JR, von Drygalski A. Four-Factor Prothrombin Complex Concentrate for Coagulopathy Reversal in Patients With Liver Disease. Clin Appl Thromb Hemost. 2017;23(8):1028-1035. doi:10.1177/1076029616668406

Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital
Design	Retrospective study N= 24
Objective	To investigate the use of a prothrombin complex concentrate (PCC) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy, and other surgery
Study Groups	Study participants (N= 24)
Inclusion Criteria	Received PCC for treatment of severe bleeding during cardiac surgery
Exclusion Criteria	Inadequate documentation regarding the timing or administration of PCC, hemophilia
Methods	Patients admitted received blood perfusion in accordance with their hospital guidelines. PCC was given when the response to blood products was poor (fresh frozen plasma, platelets, or cryoprecipitate). Poor response is defined as continued bleeding despite correction of clotting parameters. Each vial of PCC contains factor II (400 to 960 IU), factor VII (200 to 500 IU), factor IX (400 to 620 IU) and factor X (440 to 1,200 IU), as well as the coagulation inhibitors protein C (300 to 900 IU), protein S (260 to 520 IU), antithrombin (4 to 30 IU) and heparin (8 to 40 IU).
Duration	Enrollment period: April 2002 to July 2004
Outcome Measures	Achieve partial or complete hemostasis, mortality
Baseline Characteristics		Study participants (N= 24)
	Age, years	68.5
	Primary indication Coronary artery bypass graft Mitral/aortic valve replacement Other surgery Warfarin reversal	5 2 9 8
	Mean dose of PCC given per patient, IU (range) Coronary artery bypass graft Mitral/aortic valve replacement Other surgery Warfarin reversal	1,250 (500 to 4,000) 1,500 (500 to 4,000) 500 (500 to 500) 850 (500 to 2,000) 1,800 (1,000 to 4,000)
Results	Endpoint	Study participants (N= 24)
	Partial or complete hemostasis	14/18 (77.8%)
	Death Unrelated to bleeding Related to bleeding	12 (50%) 8 (33%) 4 (16.6%)
	Three of four patients who did not achieve hemostasis were given PCC for warfarin reversal.
Adverse Events	Thrombotic complications or adverse events were not observed
Study Author Conclusions	This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.
InpharmD Researcher Critique	The PCC observed in this study is an international drug product (Beriplex). There may be some differences in the formulation compared to the U.S. counterpart (for example, not all PCC products contain heparin). Due to the small patient population and retrospective design, the results remain speculatory at best.

References:

Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care. 2008;12(4):R105. doi:10.1186/cc6987

The Use of Kcentra® in the Reversal of Coagulopathy of Chronic Liver Disease
Design	Case reports
Case presentation 1	A 55-year-old male presented with a history of nonalcoholic steatohepatitis cirrhosis, coronary artery disease, and end-stage renal disease on dialysis to be treated for non-healing heel ulcer with osteomyelitis, requiring below-the-knee amputation. On day 57 of hospitalization, the patient had hypoxemia with INR of 2.0 and on day 60, the patient developed shock and lactic acidosis. The patient's INR increased to 7.3, and he was given 1 unit of fresh frozen plasma (FFP) along with Kcentra 50 units/kg and 10 mg of intravenous (IV) phytonadione, leading to INR reduction to 1.7 in < 80 minutes. After the shock management, the patient was eventually transferred out of the ICU and discharged into a long-term care facility.
Case presentation 2	A 53-year-old male with a history of alcoholic cirrhosis, hypertension, and type II diabetes mellitus presented with worsening renal function, leading to dialysis on hospital day 6. On the day of anticipated discharge (day 15), the patient developed an intracerebral hemorrhage with INR at 2.2 and platelet at 23. The patient received IV phytonadione 10 mg, 2 units of FFP, and 2 units of platelets. After repeat testing showed INR at 2.0, 25 units/kg of Kcentra was administered with repeat INR of 1.5 reported 60 minutes after the infusion. While the hematoma did not progress, the patient developed acute respiratory distress syndrome due to repeated blood pack transfusion and perished 5 days later from septic shock and organ failure.
Case presentation 3	A 66-year-old male with a history of alcoholic liver cirrhosis, esophageal varices treated with a shunt, and gastrointestinal bleeding presented with symptomatic subdural hematoma. He had previously been admitted 3 weeks prior for an acute subdural hematoma. After the procedure, the patient's mental status returned to baseline, and the patient received 2 platelet transfusions for a platelet count of 67 (1000/mL), 5 mg IV phytonadione, and 12.5 units/kg Kcentra for INR 1.6. The INR lowered to 1.4 ten minutes after starting Kcentra and was successfully discharged on day 12 of hospitalization.
Case presentation 4	A 46-year-old male with a history of alcoholic liver cirrhosis and end-stage renal disease presented with bleeding from his dialysis catheter. On day 1 of hospitalization, the patient developed hypotension and encephalopathy which improved with broad-spectrum antibiotics and fluid resuscitation, leading to transfer to the medical floor on hospital day 3. However, he returned to the ICU 4 days later with intracranial hemorrhage, altered mental status, and an INR of 5.9. The patient was treated with 2 units of FFP and 10 mg of IV phytonadione which reduced INR to 3.6 along with improvement to platelets; however, intracranial hemorrhage worsened and the patient received 30 units/kg of Kcentra the next day which lowered INR to 1.8 two hours after infusion. The patient relatively improved until three days later when he developed brain herniation and cardiac death on day 14.
Study Author Conclusions	Kcentra may be a safe, effective, and rapid treatment option to be considered for hemorrhagic emergencies associated with CCLD, particularly when there are concerns for cardiopulmonary complications related to FFP dosing. Further research is needed to determine the ideal monitoring and dosing regimen for use in coagulopathy of chronic liver disease.

References:

Pereira D, Liotta E, Mahmoud AA. The use of Kcentra® in the reversal of coagulopathy of chronic liver disease. J Pharm Pract. 2018;31(1):120-125. doi:10.1177/0897190017696952