Case Vignette
LF is a 45-year-old male with past medical history significant for advanced cirrhosis secondary to alcohol use who presents to the emergency department with variceal bleeding. The team managing this patient is discussing administering 4-Factor Prothrombin Complex Concentrate (4F-PCC) to combat this patient’s coagulopathy associated with his advanced liver disease.
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ACEP Now: August 2026 (Digital)When?
Use of Prothrombin Complex Concentrates (PCCs) in patients with liver failure and subsequent coagulopathies remains controversial and is not recommended as part of standard care at this time. There may be a role for PCCs in patients experiencing life-threatening bleeding in the setting of liver disease; however, data are lacking to support this practice at this time.2,3
Why?
PCCs are products that contain either three (II, IX, and X) or four (II, VII, IX, and X) vitamin K-dependent procoagulant proteins, as well as proteins C and S, all of which are deficient in patients with cirrhosis.2 This deficiency makes PCCs an attractive treatment option to help restore the altered hemostatic system in patients with advanced liver disease.3 Based on the literature, however, PCCs appear to actually do little to reduce the International Normalized Ratio (INR) value, lead to little or no clinical improvement, and not come without risk, potential harm, or cost to the patient.4-9
How?
No standard dose for coagulopathy associated with liver disease has been established, and doses used in the literature vary based on INR value and patient weight. If opting to use PCCs for coagulopathies associated with liver disease, always refer to your institution’s dosing practices to help guide dosing.
Overview of Evidence
| Author | Design/ sample size | Intervention & Comparison | Outcome |
|---|---|---|---|
| Dodhiawala P, et al., 2023.4 | Single-center retrospective study
N = 159 |
4F-PCC for vitamin K antagonist (VKA) coagulopathy (N = 121)
versus 4F-PCC for non-VKA coagulopathy (N = 38) 4F-PCC dosing: |
-Post-administration INR values were significantly higher in the non-VKA group (2.1 versus 1.39; P=0.001)
-Significantly fewer patients in the non-VKA group achieved INR of <1.5 (11% versus 79%; P=0.001) -Incidence of thrombotic events was similar between groups (5% versus 11%; P=0.490) -30-day mortality rate was significantly higher in the non-VKA group (42% versus 20%; P=0.040) -In a subgroup analysis: 30-day mortality rate for patients with advanced liver disease was not significantly different between groups(60% versus 38%; P=0.301) |
| Small C, et al., 2022.5 | Single-center, retrospective study of patients with cirrhosis who received 4F-PCC versus standard of care
N = 58 |
4F-PCC (N = 21)
versus Standard of care (N = 37) |
-Stable intracranial hemorrhage (ICH) within 24 hours was not different between groups (68.4% versus 72.7%; P=0.11)
-4F-PCC associated with a greater change in INR within 24 hours (-0.2 versus 0; P=0.02) -4F-PCC associated with significantly higher rates of mortality (61.9% versus 18.9%; P=0.001) -Length of intensive care unit (ICU) and hospital stay were no different between groups |
| Drebes A, et al., 2019.6 | Retrospective, single-center review of adult patients with acute or chronic liver disease who were administered PCCs
N = 105 |
No comparator | -Mean dose of PCC administered was 22 units/kg
-PCC significantly reduced prothrombin time (PT) and INR (in the setting of coadministration with fibrinogen or cryoprecipitate – 3.1 > 1.9; P<0.001, no coadministration - 2.3 > 1.8; P<0.001) -2.9% developed thrombotic events |
| Larson J, et al., 2018.7 | Retrospective study of patients with liver disease who received 4F-PCC for coagulopathy reversal
N = 30 |
No comparator | -INR correction to <1.5 was achieved in 20% of patients (50% on VKA versus 9.1% not) -INR reduction was greater in patients also on VKA compared to those not (2.4 on VKA versus 0.9 not) -Resolution of bleeding was achieved in 50% of patents with documented hemorrhage (57.1% on VKA versus 47.1% not) -Overall 30-day mortality was 50% (37.5% on VKA versus 54.5% not) -Authors concluded that response to 4F-PCC is deemed suboptimal in patients with liver disease |
| Kim K, et al., 2018.8 | Retrospective, single-center study of patients with liver disease who received PCC for urgent reversal of coagulopathy (INR >1.5)
N = 13 |
No comparator | -Median PCC dose was 2000 units (~28 units/kg)
-INR of <1.5 was achieved in 46% of patients -Thromboembolic events occurred in 30% of patients -Authors concluded that PCC use in liver disease results in suboptimal correction of INR |
| Huang W, et al., 2017.9 | Retrospective, single-center study in patients with and without liver disease who were given 4F-PCC for INR reversal
N = 85 |
4F-PCC administration in patients with liver disease (N = 31)
versus 4F-PCC administration in patients without liver disease (N = 54) |
-Post-administration INR was significantly higher in the liver disease group (2 versus 1.3; P<0.05) -Significantly fewer patients achieved INR <1.5 at 24 hours in the liver disease group (22.6% versus 87%; P<0.01), and at 48 hours (19.4% versus 87%; P<0.01) -Hemostasis at 48 hours was achieved in fewer patients with liver disease (19.4% versus 42.6%; P=0.03) -ICU stay was significantly longer in patients with liver disease (11 versus 3 days; P<0.01) -All-cause in-hospital mortality was significantly higher in patients with liver disease (51.6% versus 18.5%; P<0.01) -No significant difference in thromboembolic events at 30 days |
Dr. May is an emergency medicine pharmacy specialist at Carolinas Medical Center in Charlotte, NC.
Dr. Gibbs is the chair of the department of emergency medicine at Carolinas Medical Center in Charlotte, NC.
References
- Micromedex® 2.0 (Healthcare Series), (electronic version). Truven Health Analytics, Greenwood Village, CO. Available at: http://www.micromedexsolutions.com/.
- “EASL Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis.” J Hepatol. 2022; 76: 1151-1184.
- Lisman T, et al., “The concept of rebalanced hemostasis in patients with liver disease: Communication from the ISTH SSC working group on hemostatic management of patients with liver disease” J of Thromb and Haemos. 2021; 19(4): 1116-1122.
- Dodhiawala P, et al., “Outcomes of 4-factor Prothrombin Complex Concentrate in Patients with Liver Disease and Nonvitamin K Antagonist-Related Coagulopathy: A Retrospective Study.” Clin Appl Thromb Hemost. 2023; 29.
- Small C, et al., “Prothrombin Complex Concentrate Use in Intracranial Hemorrhage Patients with Cirrhosis Not on Prior Anticoagulation.” J Intensive Care Med. 2022; 37(5): 633-640.
- Drebes A, et al., “Prothrombin Complex Concentrates for Coagulopathy in Liver Disease Single-Center, Clinical Experience in 105 Patients.” Hepatol Commun. 2019; 3(4): 513-524.
- Larson J, et al., “Use of Four-factor prothrombin complex concentrate in patients with liver disease.” Crit Care Med. 2018; 46(1): 243.
- Kim K, et al., “Evaluation of Prothrombin Complex Concentrates for the Reversal of Liver Coagulopathy.” Crit Care Med. 2018; 46(1): 263.
- Huang W, et al., “Four-Factor Prothrombin Complex Concentrate for Coagulopathy Reversal in Patients with Liver Disease.” Clin Appl Thromb Hemost. 2017; 23(8):1028-103.
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