Abstract
Purpose: Patients presenting with life-threatening bleeding associated with oral anticoagulants (OACs) are challenging with few available treatments. Prothrombin complex concentrate (PCC) is an option for OAC reversal in the setting of life-threatening bleeding with a relatively benign safety profile. Little is known about the risk of developing thromboembolic complications (TEC) in patients receiving PCC who were previously anticoagulated. The aim of this study is to characterize the rate of TEC after receipt of PCC. Methods: All adult patients who received 4-Factor PCC for life-threatening bleeding were retrospectively evaluated over a 2-year time period. Data collected included anticoagulant and indication, bleeding source, PCC dose, INR, and TEC within 14 days of PCC dose, including venous thromboembolism (VTE), acute myocardial infarction, and ischemic stroke. Results: Three hundred thirty-three patients received 383 PCC doses. Of these, 55 (16.5%) patients developed TEC, including VTE, ischemic stroke, and acute myocardial infarction. There was increased rivaroxaban use in patients who developed TEC (25.4% vs 12.2%; P = .011). Additionally, there were more patients who had anticoagulation for a previous TEC in those who developed a new TEC (38.2% vs 23.4%; P = .022). Lastly, there was a higher rate of TEC in those who received >1 dose of PCC (21.8% vs 7.9%; P = .002). Conclusion: PCC administration in the setting of life-threatening bleeding is not benign. Risk of TEC increases in patients who have rivaroxaban reversal, receive a repeat dose of PCC, and have a TEC indication for their anticoagulation and these factors should be further investigated.
Keywords: anticoagulation reversal, thrombosis, oral anticoagulation, warfarin, rivaroxaban, apixaban
Introduction
Use of oral anticoagulation (OAC) is common in patients with atrial fibrillation, venous thromboembolism, and a variety of other indications. 1 Because of their mechanism of action and indications for use, patients receiving an OAC are inherently at a higher risk of bleeding. Life-threatening bleeding in the presence of OAC use is complicated, with few definitive treatments. Multiple guidelines recommend patients who are therapeutically anticoagulated with OACs who develop life-threatening bleeding be reversed of the anticoagulant effect.1,2
Prothrombin complex concentrate (PCC) is one option for oral anticoagulation reversal that has historically been used.3,4 Four factor PCC or Kcentra® is the most common PCC used for the reversal of OACs. It contains factors 2, 7, 9, and 10, along with proteins C and S, to replace the factors that are inhibited by warfarin; thus, Kcentra® is FDA-approved for the reversal of life-threatening bleeding in patients who are receiving OAC with warfarin. In addition to being used for warfarin reversal, Kcentra® has been used to reverse bleeding in patients receiving other OACs, including the factor Xa inhibitors, such as apixaban and rivaroxaban. Use for OAC reversal for agents other than warfarin is not FDA approved and limited clinical data exists. Additionally, patients who are not on OACs, but coagulopathic, have received PCC in the setting of life-threatening bleeding or need for emergent reversal of coagulopathy.5,6
Regardless of the agent used for anticoagulation, patients on OACs are at a baseline higher risk for developing thromboembolic complications (TEC) as evidenced by their need for therapeutic anticoagulation. Reports of TEC in the literature in patients receiving warfarin reversal range from around 6% to 28% after receiving PCC compared with 7% to 12% with FFP comparator groups; this is a much higher rate than is generally seen in the general population of non-anticoagulated patients (0.1%).7-15 While current studies evaluating TEC in patients receiving PCC have only looked at the reversal of warfarin, they have not well characterized TEC in patients receiving direct oral anticoagulants (DOACs) or coagulopathic patients on no anticoagulant who receive PCC to mitigate life-threatening bleeding. Additionally, most evaluations have commented on venous thromboembolism, but little data exists on arterial thromboembolism post-PCC.
Because of this gap in the literature, the aim of this study is to describe the rate of TEC after receipt of PCC and identify factors that were more common in patients who developed TEC compared with those who did not.
Methods
This study is a retrospective observational study conducted at Barnes-Jewish Hospital, an academic medical center in St. Louis, Missouri. The electronic health record was queried for all adult patients who received at least 1 dose of PCC (Kcentra®) between January 2014 and December 2015 in the emergency department or inpatient setting. Patients received Kcentra® at the discretion of the primary provider. Data was manually collected from the electronic health record via chart review. This study was approved by the Washington University Institutional Review Board.
The institution maintains guidelines for anticoagulation reversal among patients with life threatening bleeding to help guide clinicians in clinical decisions related to anticoagulation reversal. In addition to providing dosing recommendations consistent with the package insert dosing of Kcentra® for warfarin reversal, the institutional guidelines also recommend Kcentra 50 units/kg for factor Xa inhibitor reversal. Due to internal data and published literature, the guidelines evolved throughout the study period. Re-dosing guidance was incorporated about a year into the study period, recommending a fixed dose of 500 units be used if an additional dose is clinically indicated. Use of PCC outside of the institutional guideline is recognized.
Charts were evaluated for the presence or absence of TEC within 14 days of receipt of PCC via review of existing data and testing. If patients received more than 1 dose of PCC, they were evaluated for 14 days from the last dose. This time period was chosen to allow for approximately 5 half-lives to pass from PCC dose. TEC was defined as presence of at least one of the following: lower extremity VTE (deep and superficial), upper extremity VTE (deep and superficial), acute myocardial infarction, ischemic stroke, pulmonary embolism, or other sign of thrombosis on imaging. Patients with TEC and without TEC were compared to determine rate of TEC and factors that were more common in those with TEC compared to those without. Factors evaluated include dose, number of doses, type of anticoagulant reversed, indication for anticoagulation, and trauma status.
Statistical analysis was conducted using IBM SPSS Version 25. Nominal variables were compared using chi squared test and continuous variables were compared using the Mann–Whitney U test. A P value of .05 was considered statistically significant.
Results
Three hundred thirty-three patients received PCC during the 2-year study period and received a total of 383 doses. Fifty-five patients developed thromboembolic complications and 278 patients did not develop thromboembolic complications resulting in an overall thromboembolic rate of 16.5%. Table 1 describes baseline characteristics between the 2 groups. There were no significant differences in gender (55.3% vs 60% male; P = .529) and weight (80.8 kg vs 81.6 kg; P = .818), but patients who developed TEC were statistically younger than those who did not (69 years vs 67 years; P = .049). There was no difference in trauma patients seen between those who did not develop TEC and those that did (34.5% vs 27.2%; P = .297). Patients who developed TEC had lower admission Glasgow Coma Scale (GCS) scores than those who did not (14 vs 9; P = .008). There were no differences seen in initial anti-factor Xa level (1.81 vs 1.55; P = 1.000), PT (22.3 vs 18.6; P = .393), and INR (2.08 vs 1.72; P = .288). Although initial aPTT was statistically higher, the difference is unlikely to be clinically significant (36.2 vs 32.2; P = .008). Indication for anticoagulation was more likely to be for a thrombotic indication (eg, DVT/PE) in patients who developed TEC (23.4% vs 38.2%; P = .022).
Table 1.
Baseline Characteristics.
| Characteristic | No TEC (N = 278) | TEC (N = 55) | P value |
|---|---|---|---|
| Male, n (%) | 154 (55.3) | 33 (60) | .529 |
| Age, years, median (IQR) | 69 (60-85) | 67 (48-75) | .049 |
| Weight, kg, median (IQR) | 80.8 (68.0-99.2) | 81.6 (68.6-99.8) | .818 |
| Trauma, n (%) | 96 (34.5) | 15 (27.2) | .297 |
| GCS, median (IQR) | 14 (9-15) | 9 (6-15) | .008 |
| Pre-AntiFXa, median (IQR) | 1.81 (0.43-3.36) | 1.55 (0.83-3.23) | 1.000 |
| Pre-aPTT, median (IQR) | 36.2 (31.7-44.5) | 32.2 (28.9-36.5) | .008 |
| Pre-PT, median (IQR) | 22.3 (16.5-34.2) | 18.6 (16.3-40.6) | .393 |
| Pre-INR, median (IQR) | 2.08 (1.52-3.2) | 1.72 (1.52-2.48) | .382 |
| Pre-INR < 2, n (%) | 148/306 (48.4) | 44/70 (62.9) | .288 |
| Thrombotic indication of anticoagulation, n (%) | 65 (23.4) | 21 (38.2) | .022 |
Warfarin and rivaroxaban were the most common anticoagulants reversed, with the third largest group being those with no OAC (Table 2). Rivaroxaban use was higher in those that developed TEC (12.2% vs 25.4%; P = .011). A trend toward a lower percentage of patients on warfarin was seen in the TEC group (57.6% vs 43.6%; P = .058). No patients with apixaban reversal developed TEC (P = .040). Atrial fibrillation and DVT/PE were the top indications for anticoagulation (Table 3). The most common bleeding source in both groups was non-traumatic intracerebral hemorrhage (Table 4).
Table 2.
Cause of Coagulopathy.
| Characteristic, n (%) | No TEC (N = 278) | TEC (N = 55) | P value |
|---|---|---|---|
| Warfarin | 160 (57.6) | 24 (43.6) | .058 |
| Rivaroxaban | 34 (12.2) | 14 (25.4) | .011 |
| No OAC | 21 (11.1) | 10 (18.1) | .147 |
| Hepatic failure | 19 (6.8) | 4 (7.2) | .907 |
| Apixaban | 20 (7.2) | 0 (0) | .040 |
| Dabigatran | 6 (2.1) | 1 (1.8) | .872 |
| DIC | 5 (1.8) | 0 (0) | .316 |
| Other | 3 (1.2) | 2 (3.6) | .154 |
Table 3.
Indication for Anticoagulation.
| Characteristic, n (%) | No TEC (N = 278) | TEC (N = 55) |
|---|---|---|
| AFib/Aflutter | 131 (47.1) | 17 (30.9) |
| No anticoagulation prior to PCC | 56 (20.1) | 16 (29.1) |
| DVT/PE | 41 (14.7) | 16 (29) |
| CVA | 11 (4.0) | 2 (3.6) |
| Peripheral vascular disease | 9 (3.2) | 1 (1.8) |
| LVAD | 7 (2.5) | 1 (1.8) |
| Mechanical heart valve | 17 (6.1) | 2 (3.6) |
| Other | 11 (4.0) | 2 (3.6) |
Table 4.
Bleeding Source.
| Characteristic, n (%) | No TEC (N = 278) | TEC (N = 55) |
|---|---|---|
| Non-traumatic intracranial bleed | 167 (60.1) | 41 (74.5) |
| Traumatic intracranial bleed | 26 (9.4) | 5 (9.1) |
| GIB/rectal bleeding | 33 (11.9) | 4 (7.2) |
| No source identified | 13 (4.7) | 8 (14.5) |
| Reversal for surgery | 27 (9.7) | 11 (20) |
| Major trauma | 5 (1.8) | 2 (3.6) |
| Hematoma | 10 (3.6) | 2 (3.6) |
| Other | 28 (10.1) | 1 (1.8) |
Patients received a range of 1 to 7 doses (Table 5). A higher percentage of patients who developed TEC received more than 1 dose (7.9% vs 21.8%; P = .002). There was no significant difference between median first dose (2288 units vs 2248 units; P = .966), cumulative dose (2500 units vs 2625 units; P = .144), weight-based dose (28.1 units/kg vs 32.3 units/kg; P = .123), or FFP use (10% vs 16.4%; P = .447).
Table 5.
Dosing Information.
| Characteristic | No TEC (N = 278) | TEC (N = 55) | P value |
|---|---|---|---|
| Number of doses received, n (%) | |||
| 1 dose | 256 (92.1) | 43 (78.2) | |
| 2 doses | 17 (6.1) | 7 (12.7) | |
| 3 doses | 4 (1.4) | 3 (5.5) | |
| 4 doses | 0 (0) | 2 (3.6) | |
| 7 doses | 1 (0.4) | 0 (0) | |
| >1 dose | 22 (7.9) | 12 (21.8) | .002 |
| First dose, units | 2288 (1695-3325) | 2248 (1722-2775) | .966 |
| Cumulative dose, units | 2500 (1750-3500) | 2625 (2122-4416) | .144 |
| Weight based dose, units/kg cumulative dose | 28.1 (25.0-28.2) | 32.3 (22.9-50.6) | .123 |
| FFP | 58 (10.0) | 9 (16.4) | .447 |
There was no difference in mortality (26.3% vs 23.6%; P = .685) (Table 6). However, patients who developed TEC had longer hospital lengths of stay (5.6 days vs 10.8 days; P < .001). There were no differences seen in the post dose aPTT (31.7 vs 30.3; P = .137), PT (14 vs 13.7; P = .366), or INR (1.28 vs 1.26; P = .337). A description of types of TEC identified is summarized in Table 7.
Table 6.
Outcomes.
| Characteristic | No TEC (N = 278) | TEC (N = 55) | P value |
|---|---|---|---|
| In hospital mortality, n (%) | 73 (26.3) | 13 (23.6) | .685 |
| Hospital LOS, days | 5.6 (2.9-10.3) | 10.8 (6.2-21.8) | <.001 |
| Post-aPTT | 31.7 (28.6-35.3) | 30.3 (26.3-32.8) | .137 |
| Post-PT | 14 (12.6-16.5) | 13.7 (12.5-16.1) | .366 |
| Post-INR | 1.28 (1.17-1.51) | 1.26 (1.16-1.5) | .423 |
| Repeat INR < 2 | 263/279 (94.3) | 68/70 (97.1) | .337 |
Table 7.
Description of TECs.
| Type of TEC | Number* |
|---|---|
| Lower extremity VTE | 29 |
| Below the knee VTE | 19 |
| Above the knee VTE | 12 |
| Upper extremity VTE | 10 |
| Pulmonary embolism | 1 |
| Acute myocardial infarction | 5 |
| Ischemic stroke | 11 |
| Mesenteric vein thrombosis | 1 |
| Ischemic colitis | 1 |
| LV thrombus | 2 |
Patients may have had more than 1 type of TEC.
Discussion
Anticoagulation reversal is a necessary treatment for patients with life-threatening bleeding. One complication of anticoagulation reversal with PCC is TEC, such as DVTs, PEs, and ischemic stroke. In our study, we found a rate of TEC of 16.5%, which is comparable to previous studies.5-12 Comparing patients who developed TEC versus those who did not, there were 3 main differences observed. The first was a higher rate of rivaroxaban use in the patients who developed TEC compared with those who did not. While this has not been described in the literature, it could be hypothesized that because rivaroxaban only inhibits factor Xa, administration of PCC, which contains 4 factors (II, VII, IX, and X), could increase the possibility of clot development. 1 Interestingly, this was not seen among patients who received apixaban, another factor Xa inhibitor. However, the difference may have been due to the low numbers in the study. The second factor was PCC administration in patients who were anticoagulated for a previous TEC. While only new TEC were counted, the likelihood of a patient who had previously developed a TEC having additional clots seems likely. Lastly, more patients who received more than 1 dose of PCC developed TEC. However, this increase was not driven by a significantly higher cumulative dose. While patients in the TEC group were noted to have a lower baseline GCS than those who did not develop TEC (9 vs 14), this finding may be due to the fact that these patients were more severely injured or critically ill.
Our study is the first to report specifically on TEC for both reversal of OAC as well as in patients who were not receiving OAC. Based on institutional guidelines, patients may receive a dose of PCC for reversal of warfarin, a DOAC, or no anticoagulant in the setting of life-threatening bleeding. Our institution also allows additional doses of PCC if bleeding is not controlled with the initial dose or the goal INR is not obtained. Because of the variety of practice patterns, we have noted a wide range of patients that have not been reported on in previous studies.
This study has several limitations that must be noted. First, due to the retrospective design of the study, cause and effect cannot be shown. The retrospective data collection within the electronic health record may have led to missing or incomplete data. Factors that increase a patient’s hypercoagulable risk were unable to be collected in this study (such as cancer, oral contraceptive use, smoking, etc.). The doses were given at the discretion of each provider and all of the patient specific factors may not have been documented. Additionally, some units conduct DVT screening in asymptomatic patients. This may have overestimated the rates of symptomatic DVTs. Finally, the variability in dosing may not make the results of this study applicable in institutions with stricter use criteria and guideline adherence.
Despite the limitations of this study, the results provide a direction for future studies. Additional studies that evaluate PCC for reversal of life-threatening bleeding should consider an in-depth review of the TEC. Providers must weigh patient specific factors that increase the likelihood of developing a TEC with the necessity of PCC treatment.
The results of this study bring to light the side effects of treatment of life-threatening bleeding in those who receive PCC for anticoagulation reversal. In emergent situations where PCC is considered, often, little thought is given to what may ensue after the dose is administered. However, the results of this study bring a couple of patient populations forward as being at a higher rate of developing TEC. First, those who are receiving PCC for rivaroxaban reversal. Additionally, those who are on an anticoagulant for a thromboembolic indication also appear to be at higher risk of developing a TEC. Finally, those who receive more than 1 dose are at a higher likelihood of developing TECs.
Footnotes
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Emily J. Owen and Gabrielle A. Gibson are on speakers bureau for Portola Pharmaceuticals, LLC.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Emily J. Owen 
https://orcid.org/0000-0002-6095-4805
References
- 1. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. [DOI] [PubMed] [Google Scholar]
- 2. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(suppl 2):e152S-e184S. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Kcentra(R) [package insert]. Kankakee, IL: CSL Behring LLC. http://labeling.cslbehring.com/PI/US/Kcentra/EN/Kcentra-Prescribing-Information.pdf. Published February 2017. Accessed January 06, 2020. [Google Scholar]
- 4. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6(4):622-631. [DOI] [PubMed] [Google Scholar]
- 5. Young H, Holzmacher JL, Amdur R, Gondek S, Sarani B, Schroeder ME. Use of four-factor prothrombin complex concentrate in the reversal of warfarin-induced and nonvitamin K antagonist-related coagulopathy. Blood Coagul Fibrinolysis. 2017;28(7):564-569. [DOI] [PubMed] [Google Scholar]
- 6. Arshad F, Ickx B, van Beem RT, et al. Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial. BMC Surg. 2013;13:22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Milling TJ, Jr, Refaai MA, Goldstein JN, et al. Thromboembolic events after vitamin K antagonist reversal with 4-factor prothrombin complex concentrate: exploratory analyses of two randomized, plasma-controlled studies. Ann Emerg Med. 2016;67(1):96-105.e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Harrison NE, Gottlieb M. Comparison of fresh frozen plasma with prothrombin complex concentrate for warfarin reversal. Ann Emerg Med. 2017;69(6):777-779. [DOI] [PubMed] [Google Scholar]
- 9. Barton CA, Johnson NB, Case J, et al. Risk of thromboembolic events after protocolized warfarin reversal with 3-factor PCC and factor VIIa. Am J Emerg Med. 2015;33(11):1562-1566. [DOI] [PubMed] [Google Scholar]
- 10. Kuroski JE, Young S. Comparison of the safety and efficacy between 3-factor and 4-factor prothrombin complex concentrates for the reversal of warfarin. Am J Emerg Med. 2017;35(6):871-874. [DOI] [PubMed] [Google Scholar]
- 11. Felton D, Foley EM, Traub SJ, Vodonos A, Ganetsky M. Risk of venous thromboembolism after receiving prothrombin complex concentrate for warfarin-associated intracranial hemorrhage. J Emerg Med. 2016;50(1):1-6. [DOI] [PubMed] [Google Scholar]
- 12. Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15(6):566-573. [DOI] [PubMed] [Google Scholar]
- 13. Cruz JL, Moss MC, Chen SL, Hansen KM, Amerine LB. Retrospective evaluation of the clinical use of prothrombin complex concentrate for the reversal of anticoagulation with vitamin K antagonists. Blood Coagul Fibrinolysis. 2015;26(4):378-382. [DOI] [PubMed] [Google Scholar]
- 14. Joseph R, Burner J, Yates S, Strickland A, Tharpe W, Sarode R. Thromboembolic outcomes after use of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal in a real-world setting. Transfusion. 2016;56(4):799-807. [DOI] [PubMed] [Google Scholar]
- 15. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62-69. [DOI] [PMC free article] [PubMed] [Google Scholar]