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International Journal of Clinical Pediatrics

Original Article

Volume 13, Number 1, May 2024, pages 8-13

Prothrombin Complex Concentrate to Treat Coagulation Disturbances in Pediatric Patients With Intracranial Pathology Including Traumatic Brain Injury

Coagulation disturbances and hemorrhage are common in critically ill pediatric patients especially those with intracranial pathology or traumatic brain injury (TBI). Various etiologies predispose these patients to bleeding diathesis including blood loss, large volume transfusions, shock, coagulation factor consumption, hypothermia, acidosis, and release of tissue factors from the injured brain [1]. Clinical management strategies include addressing the physiologic needs of the patient with correction of cardiovascular dysfunction, treatment of systemic infection, attention to the associated traumatic injury and resultant acquired coagulopathy, and correction of pre-existing anti-coagulant therapies or inherited disturbances of coagulation. Based on laboratory parameters, treatment pathways for the reversal of coagulation disturbances include transfusion of blood products including fresh frozen plasma (FFP), cryoprecipitate, and platelets [2]. However, the administration of blood products and FFP has several potential limitations including the time required to prepare, thaw, and transfuse it, the risk of transfusion reactions, and an increased incidence of secondary infections, organ failure, pulmonary complications, and even mortality [3, 4]. Furthermore, even with therapy directed by laboratory parameters, these blood products may fail to effectively correct the underlying coagulation defect. Delays in coagulopathy correction may result in delays in diagnostic or therapeutic interventions.

Recently, the anecdotal use of prothrombin complex concentrates (PCCs) has been increasingly reported in adults and children as therapy for the correction of refractory coagulation disturbances in various clinical scenarios [5, 6]. PCCs available for clinical use can be separated into three-factor PCCs (3F-PCCs), four-factor PCCs (4F-PCCs), and PCCs with activated factors such as factor eight inhibitor bypassing activity (FEIBA). Availability of the specific products for clinical use varies according to country of practice. The currently available 4F-PCCs contain coagulation factors II, VII, IX, and X in addition to proteins C and S and antithrombin III [7]. Four-factor PCCs were initially used in patients with hemophilia B or those with hemophilia A who had developed inhibitors to standard therapy with factor VIII products. Four-factor PCCs are now also considered first-line therapy for adults who are chronically receiving oral vitamin K antagonist who present with clinically significantly bleeding or require urgent/emergent surgical interventions [6, 8, 9]. We present our retrospective experience with the use of 4F-PCC in patients with neurosurgical conditions, intracranial pathology, and TBI.

This retrospective study was reviewed and approved by the IRB of Nationwide Children’s Hospital (Columbus, OH) and conducted in accordance with the guidelines of the Declaration of Helsinki. Given the retrospective nature of the study, the need for individual written informed consent was waived. The waiver of consent was based on the fact that the research involved no or minimal risk since it was limited to a retrospective chart review. To maintain patient confidentiality, only deidentified data were used for the purpose of this study. Data collected during this study were stored in a secure location and only the collaborators directly involved in this study have access. All electronic files were stored on a secure, password protected network. This study expands on our previously published work by focusing specifically on patients with associated intracranial pathology and by expanding the study database with a longer duration of the retrospective review [5]. The current study includes patients who were reported in our previous study if they had associated intracranial pathology.

Patients who received 4F-PCC (K-Centra^®, CSL Bering, King of Prussia, PA) were identified by the Pharmacy Services and the medication records of the hospital’s electronic medical record (EMR) database. The study cohort was limited to patients 0 - 18 years of age who have received 4F-PCC in the setting of TBI, intracranial pathology, or other central nervous system (CNS)-related neurosurgical disorders. The study period included a 13-year period spanning from January 2010 through December 2022. Data regarding demographics, surgical procedures, clinical information, laboratory and radiographic results, administered blood products before and after 4F-PCC, and 4F-PCC dosing were retrieved from the EMR. Clinical efficacy was judged by coagulation parameters, blood product use, and clinical bleeding before and after the administration of 4F-PCC. Adverse effects related to 4F-PCC including thromboembolic complications and survival outcomes were also collected.

Demographic and laboratory data are presented as mean ± standard deviation (SD) and the range. Dosing information is presented as mean and interquartile range (IQR). Statistical analysis included a paired t-test to compare coagulation parameters including prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) before and after the administration of 4F-PCC.

The study cohort included 47 patients, ranging in age from newborn to 18 years, who were diagnosed with TBI or other intracranial pathology (e.g., hemorrhage), and who received 4F-PCC. The demographic data are outlined in Table 1. The average patient was 8.97 ± 6.78 years of age with a range from newborn (1 day) to 18 years. The average patient weight was 35.4 ± 27.1 kg with a range of 3.2 to 96.5 kg. The primary etiology of the coagulation disturbance included intracranial hemorrhage (n = 24, 52%), increased intracranial pressure or hypoxic-ischemic encephalopathy (n = 13, 28%), TBI (n = 7, 15%), and hemorrhagic shock (n = 3, 6%) (Table 2). The primary clinical indications for 4F-PCC administration included the presence of or potential for ongoing bleeding with an associated coagulopathy in the setting of a neurosurgical procedure (n = 23, 49%), to prevent ongoing hemorrhage or mitigate the potential for expansion of an intracranial hemorrhage (n = 17, 36%), or the combination of the two (n = 7, 15%). Multiple patients (n = 32, 68%) in the current cohort received FFP within 6 h of the 4F-PCC dose. Additional blood products used around the time of 4F-PCC administration included packed red blood cells (n = 18, 38%), cryoprecipitate (n = 5, 11%), or platelets (n = 15, 32%).

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Table 1. Demographic Data of the Study Cohort

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Table 2. Primary Etiology of Coagulation Disturbance

A total of 71 doses of 4F-PCC were administered to the 47 patients in the study cohort. The dose ranged from 11 to 75 units/kg (median dose 26 units/kg; mean dose 30.4 ± 14.7 units/kg) (Table 3, Fig. 1). The majority of patients (n = 35, 75%) received one dose of 4F-PCC. The remaining 12 patients received multiple doses. Two doses were administered to seven patients (15%), three doses to two patients (4%), four doses to one patient (2%), five doses to one patient (2%), and seven doses to one patient (2%). Varied indications existed for the use of multiple doses including further correction of coagulation parameters, control of ongoing bleeding, or an anticipated or ongoing surgical procedure.

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Table 3. Dosing of 4F-PCC in the Study Cohort

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Figure 1. Histogram showing distribution of the 71 doses of 4F-PCC in the cohort of 47 patients with the dose in units/kg on the x-axis and the number of doses on the y-axis. 4F-PCC: four-factor prothrombin complex concentration.

Laboratory assessment of coagulation function generally improved after the administration of 4F-PCC. INR values decreased after the administration of 4F-PCC for 78% of doses, with 38% of INR values decreasing from an abnormally high value into the normal range (≤ 1.5) (Table 4). PT values decreased after 4F-PCC in 74% of doses; however, only 1.6% of PT values decreased from an abnormally high value into the normal range (≤ 15 s). PTT values decreased after 4F-PCC administration in 63% of doses with 16% decreasing from an abnormally high value into the normal range (≤ 35 s). The INR decreased from 2.4 ± 1.4 before 4F-PCC to 2.0 ± 1.5 after 4F-PCC. The PT decreased from 25 ± 11 s before 4F-PCC to 22 ± 11 s after 4F-PCC while no change was noted in the PTT. Thirty-one patients (66%) underwent a surgical procedure around the time that 4F-PCC was administered. The surgical procedures included craniectomy, craniotomy, burr hole placement, cranial decompression, and hematoma evacuations.

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Table 4. Laboratory Coagulation Parameters Before and After 4F-PCC

Adverse effects that may have been attributed to 4F-PCC were noted in three of 47 patients (6.4%). These adverse events, each occurring in one patient, included thrombotic complications of the common femoral and iliac veins, external iliac artery, or internal carotid artery. Overall, the severity of illness was significant with an overall patient mortality of 53% in this patient population related to coagulopathies, associated with immature hemodynamic stability, TBI, hemorrhages, or other neurosurgical disturbances.

TBI and intracranial pathologies associated with coagulopathy remain common causes of morbidity and mortality in critically ill infants and children. The primary etiologies of these coagulation disturbances are multi-factorial including blood loss, transfusion of blood products with dilution of coagulation factors, coagulation factor consumption, and the release of thrombogenic factors with TBI and intracranial pathology. The coagulation disturbances can be further accelerated by hypothermia, liver dysfunction, hypoperfusion, and metabolic acidosis [1]. Traditionally, FFP, cryoprecipitate, and platelet concentrates remain the primary method to treat and reverse coagulation disturbances with administration based on laboratory parameters [2]. However, in addition to potential adverse effects, additional limitations include treatment delays related to preparation time with cross-typing, thawing, and transfusion as well as ineffective correction of coagulation defects despite appropriate dosing [2-4]. Contemporary alternatives with anecdotal reports of success primarily in case series of trauma or cardiac surgical patients include single factor concentrates or more recently, PCCs [10-14].

The currently available 4F-PCCs contain coagulation factors II, VII, IX, and X in addition to proteins C and S and antithrombin III. In addition to their clinical indications in specific scenarios in patients with hemophilia, they are considered first-line therapy for adults who are chronically receiving oral vitamin K antagonists who present with clinically significantly bleeding or require urgent/emergent surgical interventions [8, 9]. Three-factor PCCs are generally used to treat hemophilia B. Outside of these scenarios, clinical experience with PCCs in children has generally focused on controlling bleeding following cardiopulmonary bypass and surgery for congenital heart disease [15-20]. Outside of the cardiac surgery population, there are a limited number of reports regarding the use of 4F-PCC in pediatric-aged patients. A unifying theme of some of the studies is a focus on preterm infants with the administration of PCCs as a means to control or limit the extent of intracranial hemorrhage related to prematurity or associated hypoxic-ischemic encephalopathy [21]. In a meta-analysis of these reports, Zeng and colleagues analyzed three randomized controlled trials, three non-randomized controlled trials, and two cohort studies [21]. The meta-analysis failed to find that PCC improved mortality or more effectively corrected hemostatic defects.

Our study expands upon the previous work of Karube et al, specifically focusing on patients with intracranial pathology and associated coagulation dysfunction [5]. We noted a correction of coagulation values when 4F-PCC was administered in pediatric patients presenting with coagulopathy related to TBI, intracranial pathologies, and neurosurgical disorders. When assessing routine coagulation parameters to judge efficacy, the response was variable. Overall, INR values decreased in 78% of patients, PT values decreased in 74% of patients, and activated PTT (aPTT) values decreased in 63% of patients; however, the change was a statistically significant decrease only when considering PT. Furthermore, given the variability in the dose and perhaps the lack of strict dosing guidelines, the majority of the laboratory values of coagulopathy did not correct to normal. Because of the severity of illness and limitations of controlling confounding variables in a retrospective study, additional information on the direct effects that 4F-PCC might have had on patient outcomes, including blood product utilization, was limited.

There were multiple limitations to the current study starting with a small, retrospective sample size. Although we attempted to focus on a specific population (intracranial pathology), there was still significant heterogeneity in our patients, the primary event responsible for the coagulation disturbances, the indication for PCC, and the dose. As in most pediatric studies, there was significant variation in patient age, weight, and ethnicity with a range of comorbid diseases. There were no specific guidelines regarding indication for 4F-PCC, blood product use prior to giving 4F-PCC, or interpretation of laboratory parameters before and after use. The confounding treatments limited the ability to objectively assess the sole effectiveness of 4F-PCC in the reversal of coagulopathies and hemorrhagic disturbances related to TBI. The circumstances regarding patient conditions varied greatly, with many doses of 4F-PCC being administered to critically ill patients in dire conditions, affecting the apparent efficacy of using 4F-PCC for the treatment of coagulopathies due to TBI. Many of these same confounders were present with the initial studies reporting the use of recombinant factor VIIa [22, 23]. These same limitations apply to identification of adverse effects. With a retrospective chart review, it is possible that adverse effects may not have been charted, may be missed during the review or a cause-effect relationship related to therapies may be difficult to determine.

Moving forward, patient care and research on this topic might be improved with internal guidelines regarding both indications for use and for initial and subsequent dosing parameters. To better analyze its efficacy, future studies could be conducted using randomized controlled trials in pediatric populations with TBI and intracranial pathologies to accurately identify indications, proper dosages, and potential adverse effects. The standardization of dosing and parameters within a homogenous population will allow direct analysis of the effectiveness of 4F-PCC. As noted in our study cohort, there was significant variation in dosing, ranging from 11 to 75 units/kg with a median dose of 26 units/kg. There are no specific dosing guidelines when 4F-PCC is used to correct generalized coagulopathy related to systemic illnesses. When used to reverse anticoagulation related to oral vitamin K antagonist, recommendations for dosing are based on the INR with a dose of 25 units/kg (maximum dose 2,500 units), 35 units/kg (maximum dose 3,500 units), or 50 units/kg (maximum dose 5,000 units) for an INR value of 2 - 4, 4 - 6 or more than 6, respectively.

Due to the severity of hemostatic disturbances in pediatric patients with intracranial pathologies, larger doses of PCC may be necessary to truly assess the clotting potential of the drug; however, adverse reactions, such as thromboembolic events, need to be monitored. There is also potential for more precise coagulation parameters with the use of thromboelastometry (ROTEM) and thromboelastography (TEG), along with traditional INR, PT, and aPTT to quantify total clotting capacity [24]. The cost-benefit analysis of 4F-PCC is uncertain due to the conflicting balance between cost of therapy (cost of 4F-PCC) and cost of transfusion including type and screen, blood acquisition and processing costs, and transfusion costs. Four-factor PCC, when compared to FFP may be associated with a higher cost of therapy when considering only the product, but possesses lower costs of overall therapy including additional costs involved with transfusion.

In conclusion, the current study found decreased coagulation values when 4F-PCC was administered in pediatric patients presenting with TBI, intracranial pathologies, and CNS neurosurgical disorders. However, due to the retrospective nature of the study, no direct conclusions were able to be established regarding the effects of 4F-PCC. Although small volumes, low immunogenicity, efficiency, and speed in correcting coagulopathy are attractive qualities of PCCs for pediatric practice, current evidence remains anecdotal. The main concerns are unknown dosing regimens, lack of an identified clinical means to monitor the effects of PCCs in real time, and the possibility of thrombotic complications. Future randomized controlled trials should be utilized to establish effective doses for PCC in pediatric patients based on clinical and laboratory parameters, identify optimal protocols to define indications for PCC, define optimal laboratory parameters to evaluate clinical efficacy, and monitor for adverse effects. The need for such trials is demonstrated by the increasing off-label use of PCCs over the past 4 years in pediatric patients, especially in critically ill patients with a high risk for mortality [25].

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Given the retrospective nature of the study, the need for individual written informed consent was waived.

Author Contributions

CR: chart review and preparation of manuscript; EAS: study design and review of the final manuscript; JDT: study design, manuscript preparation, review, and editing.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

1. Zhang J, Zhang F, Dong JF. Coagulopathy induced by traumatic brain injury: systemic manifestation of a localized injury. Blood. 2018;131(18):2001-2006.
   doi pubmed pmc
2. Ghadimi K, Levy JH, Welsby IJ. Perioperative management of the bleeding patient. Br J Anaesth. 2016;117(suppl 3):iii18-iii30.
   doi pubmed pmc
3. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113(15):3406-3417.
   doi pubmed
4. Marshall AL, Levine M, Howell ML, Chang Y, Riklin E, Parry BA, Callahan RT, et al. Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal. J Thromb Haemost. 2016;14(2):324-330.
   doi pubmed
5. Karube T, Andersen C, Tobias JD. Single-center use of prothrombin complex concentrate in pediatric patients. J Pediatr Intensive Care. 2020;9(2):106-112.
   doi pubmed pmc
6. Munlemvo DM, Tobias JD, Chenault KM, Naguib A. Prothrombin complex concentrates to treat coagulation disturbances: an overview with a focus on use in infants and children. Cardiol Res. 2022;13(1):18-26.
   doi pubmed pmc
7. Tanaka KA, Shettar S, Vandyck K, Shea SM, Abuelkasem E. Roles of four-factor prothrombin complex concentrate in the management of critical bleeding. Transfus Med Rev. 2021;35(4):96-103.
   doi pubmed
8. Costa-Lima C, Fiusa MM, Annichino-Bizzacchi JM, de Paula EV. Prothrombin complex concentrates in warfarin anticoagulation reversal. Rev Bras Hematol Hemoter. 2012;34(4):302-304.
   doi pubmed pmc
9. Sarode R, Milling TJ, Jr., Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-1243.
   doi pubmed pmc
10. Arnekian V, Camous J, Fattal S, Rezaiguia-Delclaux S, Nottin R, Stephan F. Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery. Interact Cardiovasc Thorac Surg. 2012;15(3):382-389.
    doi pubmed pmc
11. Ortmann E, Besser MW, Sharples LD, Gerrard C, Berman M, Jenkins DP, Klein AA. An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery. Anesth Analg. 2015;121(1):26-33.
    doi pubmed
12. Zeeshan M, Hamidi M, Feinstein AJ, et al. Four-factor prothrombin complex concentrate is associated with improved survival in trauma-related hemorrhage: A nationwide propensity-matched analysis. J Trauma Acute Care Surg. 2019;87(2):274-81
13. Joseph B, Aziz H, Pandit V, Hays D, Kulvatunyou N, Yousuf Z, Tang A, et al. Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? World J Surg. 2014;38(8):1875-1881.
    doi pubmed
14. Jehan F, Aziz H, O'Keeffe T, Khan M, Zakaria ER, Hamidi M, Zeeshan M, et al. The role of four-factor prothrombin complex concentrate in coagulopathy of trauma: A propensity matched analysis. J Trauma Acute Care Surg. 2018;85(1):18-24.
    doi pubmed
15. Noga T, Bruce AA, Blain H, Nahirniak S. Four-factor prothrombin complex concentrates in paediatric patients - a retrospective case series. Vox Sang. 2016;110(3):253-257.
    doi pubmed
16. Ashikhmina E, Said S, Smith MM, Rodriguez V, Oliver WC, Jr., Nuttall GA, Dearani JA, et al. Prothrombin complex concentrates in pediatric cardiac surgery: the current state and the future. Ann Thorac Surg. 2017;104(4):1423-1431.
    doi pubmed
17. Ashikhmina Swan E, Brinkman NJ, Lahr BD, Nemergut ME, Dearani JA, Stephens EH. Activated prothrombin complex concentrate in pediatric cardiac patients, our early experience. World J Pediatr Congenit Heart Surg. 2023;14(4):417-424.
    doi pubmed
18. Guzzetta NA, Williams GD. Current use of factor concentrates in pediatric cardiac anesthesia. Paediatr Anaesth. 2017;27(7):678-687.
    doi pubmed
19. Benson JW, Hraska V, Scott JP, Stuth EAE, Yan K, Zhang J, Niebler RA. Comparison of prothrombin complex concentrate with activated factor VII use for bleeding following cardiopulmonary bypass in children. World J Pediatr Congenit Heart Surg. 2023;14(3):282-288.
    doi pubmed
20. Harris AD, Hubbard RM, Sam RM, Zhang X, Salazar J, Gautam NK. A retrospective analysis of the use of 3-factor prothrombin complex concentrates for refractory bleeding after cardiopulmonary bypass in children undergoing heart surgery: a matched case-control study. Semin Cardiothorac Vasc Anesth. 2020;24(3):227-231.
    doi pubmed
21. Zeng L, Choonara I, Zhang L, Li Y, Shi J. Effectiveness of prothrombin complex concentrate (PCC) in neonates and infants with bleeding or risk of bleeding: a systematic review and meta-analysis. Eur J Pediatr. 2017;176(5):581-589.
    doi pubmed
22. Grounds RM, Seebach C, Knothe C, Paluszkiewicz P, Smith TS, Kasal E, Lecumberri R, et al. Use of recombinant activated factor VII (Novoseven) in trauma and surgery: analysis of outcomes reported to an international registry. J Intensive Care Med. 2006;21(1):27-39.
    doi pubmed
23. Felfernig M, Huepfl M. Experience of recombinant activated factor VII (NovoSeven) in the operating theatre and intensive care unit for the management of intracranial bleeding in nonhaemophilic patients. Clin Neurol Neurosurg. 2008;110(3):227-232.
    doi pubmed
24. Wikkelso A, Wetterslev J, Moller AM, Afshari A. Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. Cochrane Database Syst Rev. 2016;2016(8):CD007871.
    doi pubmed pmc
25. Lutmer JE, Mpody C, Sribnick EA, Karube T, Tobias JD. Prothrombin complex concentrate utilization in children's hospitals. J Pediatr Intensive Care. 2023;12(3):219-227.
    doi pubmed pmc

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International Journal of Clinical Pediatrics is published by Elmer Press Inc.