Single-Center Use of Prothrombin Complex Concentrate in Pediatric Patients

Abstract

Coagulation disturbances frequently occur in critically ill children. Four-factor prothrombin complex concentrate (4F-PCC) may have a potential role in managing these patients while avoiding concerns associated with fresh frozen plasma. However, data on this product in critically ill children is scarce. We retrospectively identified 24 critically ill pediatric patients who received 4F-PCC. The primary indication was to correct coagulopathy and control bleeding in the trauma or surgical setting. 4F-PCC effectively decreased the international normalized ratio level, a surrogate marker of hemostasis. Further study is warranted to identify efficacy, indications, optimal dosing, and adverse effects in the critically ill pediatric patients.

Introduction

Coagulation disorders are commonly encountered in critically ill children admitted to the pediatric intensive care unit (ICU) and are caused by various etiologies. ^{1 2} Current treatment pathways for coagulation disturbances include reversal of the underlying cause and, when indicated, transfusion of blood products including fresh frozen plasma (FFP) to replenish coagulation factors. However, the administration of FFP has several potential limitations including the time required to prepare and transfuse it, risk of transfusion reactions, as well as increased incidence of secondary infections, organ failure, and mortality. ^{3 4 5 6 7 8} Recombinant factor VIIa (rFVIIa) has been suggested as a potential adjunct to FFP transfusion in managing coagulopathy but the cost has limited its use. ^{9 10 11} Hence, additional adjuncts to treat coagulopathy in critically ill children are necessary. To further understand the use of four-factor prothrombin complex concentrate (4F-PCC) in critically ill children, we retrospectively reviewed our institution's experience with 4F-PCC.

Methods

The pharmacy database was searched for all patients who received 4F-PCC either in the emergency department (ED), operating room (OR), or ICU between 2015 and 2019 at the Nationwide Children's Hospital in Columbus, OH. No patients were excluded from the analysis. Data regarding demographics, clinical information, laboratory and radiographic results, administered blood products, 4F-PCC doses, thromboembolic complications, and survival outcomes were collected from the electronic health records. This project was approved by the Institutional Review Board at Nationwide Children's Hospital.

Results

The study cohort included 24 patients ( Table 1 ). The median age was 13 years (range from 2 months to 23 years) and the median weight was 45.2 kg (range from 4 to 76.3 kg). Thirteen were female (54.2%) and 11 were male. Only two patients were receiving anticoagulant medications at home prior to admission, one receiving warfarin and the other enoxaparin. The most common clinical scenario for 4F-PCC use was in trauma patients including severe traumatic brain injury, constituting 45.8% of the patients who received 4F-PCC. All trauma patients, except patient 6, had intracranial hemorrhage. All trauma patients, excluding patient 3, received neurosurgical interventions including decompressive craniectomy, hematoma evacuation, insertion of external ventricular drain, and/or placement of an intracranial pressure monitoring device. Patient 3 received 4F-PCC in preparation for neurosurgical intervention but her clinical status deteriorated and was not stable enough to receive surgical intervention.

Table 1. Demographic data of patients who received 4F-PCC.

Patient	Age (y)	Sex	Ethnicity	Weight (kg)	Home anticoagulant	Clinical scenario
1	13	M	White	49.2	None	Severe TBI
2	5	M	White	20.0	None	Polytrauma, severe TBI
3	2	F	Multi	13.2	None	Severe TBI, CPA
4	2	M	AA	11.0	None	Severe TBI, CPA
5	3	M	White	15.0	None	Polytrauma, severe TBI
6	2	F	Unknown	13.5	None	Severe TBI
7	3	M	White	17.0	None	Severe TBI
8	15	M	White	74.3	None	Polytrauma, severe TBI
9	12	F	Multi	36.0	None	Polytrauma, severe TBI
10	15	M	Multi	40.0	None	Polytrauma, severe TBI
11	15	M	White	66.4	None	Polytrauma, severe TBI
12	18	F	AA	53.0	None	Post-liver transplant
13	23	M	White	56.2	Warfarin	GI bleed, hemorrhagic shock
14	2 mo	M	White	4.0	Enoxaparin	Persistent hemorrhage postcardiac surgery
15	9	F	White	50.6	None	Septic shock, acute liver failure
16	12	F	White	41.1	None	AML, ICH
17	17	M	White	38.5	None	Bacterial meningitis, cerebral edema
18	18	F	AA	76.3	None	Liver failure
19	17	F	White	61.4	None	Lymphoblastic lymphoma, ICH
20	16	F	White	57.6	None	Vasogenic edema, elevated intracranial pressure
21	17	F	AA	57.7	None	Toxic megacolon, MODS, persistent hemorrhage after abdominal surgery, ICH
22	3 mo	F	White	4.35	None	Volvulus, necrotic bowel, DIC
23	12	F	Multi	70.9	None	Persistent hemorrhage post pelvic mass resection
24	20	F	White	74.4	None	Abdominal surgery, VP shunt externalization

Abbreviations: 4F-PCC, four-factor prothrombin complex concentrate; AA, African American; AML, acute myeloid leukemia; CPA, cardiopulmonary arrest; DIC, disseminated intravascular coagulation; F, female; ICH, intracranial hemorrhage; M, male; MODS, multiple organ dysfunction syndrome; TBI, traumatic brain injury; VP, ventriculoperitoneal.

A total of 29 doses of 4F-PCC were administered to the 24 patients ( Table 2 ). The median dose was 27 units/kg (range from 16 to 54 units/kg). Three patients received more than one dose of 4F-PCC. Patient 10 and 22 received two doses within 24 and 48 hours, respectively, and patient 21 received four doses within 72 hours. Of the 29 doses, 23 (79.3%) were given in the ICU, 5 (17.2%) in the OR, and 1 (3.4%) in the ED. Many had more than one reason for 4F-PCC administration and the most common indication was perioperative and periprocedural correction of coagulopathy (75.9%) followed by hemorrhage with refractory coagulopathy (27.6%). Only one patient received 4F-PCC for urgent reversal of vitamin K antagonist in the setting of hemorrhagic shock from gastrointestinal bleeding. Twenty patients (83.3%) received FFP, two patients received tranexamic acid (TXA), one patient received rFVIIa, and one patient received epsilon-aminocaproic acid (EACA) within 24 hours before and/or after 4F-PCC.

Table 2. Indications and dosing of 4F-PCC, INR levels before and after 4F-PCC, and adjunctive therapies.

Patient	PCC dose (units/kg)	Indication for 4F-PCC	INR		Coagulation adjuncts
			Pre	Post
1	22	Urgent surgery	1.73	1.37	None
2	50	Hemorrhage control and urgent surgery	2.23	1.43	FFP
3	37	Urgent surgery	5.72	1.13	FFP
4	25	Urgent surgery	1.63	1.22	FFP
5	37	Urgent surgery	2.07	1.37	FFP
6	26	Urgent surgery	1.69	1.27	None
7	30	Urgent surgery	2.32	1.19	FFP
8	53	Hemorrhage control and urgent surgery	1.7	1.21	FFP, TXA, EACA
9	25	Urgent surgery	1.84	1.59	FFP
10	25	Urgent surgery	1.63	1.41	FFP, TXA
	25		1.41	1.22	None
11	54	Urgent surgery	1.64	1.43	FFP
12	39	Urgent procedure	2.23	2.65	FFP
13	36	Urgent warfarin reversal	5.91	1.46	None
14	25	Hemorrhage with refractory coagulopathy	3.17	2.15	FFP
15	28	Coagulopathy and volume restriction	2.59	1.13	FFP
16	25	Hemorrhage with refractory coagulopathy	1.99	1.56	FFP
17	26	Urgent surgery	1.84	1.67	FFP
18	29	Coagulopathy and volume restriction	4.58	2.03	FFP
19	27	Worsening ICH and volume restriction	1.15	1.09	FFP
20	54	Urgent surgery	1.57	1.18	None
21	22	Hemorrhage with refractory coagulopathy and urgent surgery	1.89	1.55	FFP
	29		1.98	1.79	FFP
	29		1.1	1.19	FFP, rFVIIa
	30	Urgent surgery	1.18	1.2	FFP, rFVIIa
22	18	Hemorrhage with refractory coagulopathy and urgent surgery	3.05	1.92	FFP
	18		1.64	1.29	None
23	16	Hemorrhage with refractory coagulopathy	1.56	1.13	FFP
24	25	Urgent surgery	1.71	1.38	FFP

Abbreviations: 4F-PCC, four-factor prothrombin complex concentrate; EACA, epsilon-aminocaproic acid; FFP, fresh frozen plasma; ICH, intracranial hemorrhage; INR, international normalized ratio; rFVIIa, recombinant factor VIIa; TXA, tranexamic acid.

The median international normalized ratio (INR) prior to the first dose of 4F-PCC was 1.87 (range from 1.15 to 5.91) and the median time for rechecking INR after 4F-PCC was 125 minutes (range from 15 to 1,653 minutes). Twenty-one patients (87.5%) had an INR > 1.6 prior to the first dose of 4F-PCC and all patients had improvement in their INR to ≤ 1.6 with one patient requiring an additional dose of 4F-PCC. Rotational thromboelastometry (ROTEM; TEM International GmbH, Munich, Germany) was ordered in eight patients prior to receiving 4F-PCC. All showed prolonged extrinsic thromboelastometry coagulation time, which is a sign of coagulation factor deficiency, with two patients initially having borderline prolonged coagulation time. One patient did not have a repeat test after 4F-PCC and six patients showed improvement in EXTEM coagulation time after receiving 4F-PCC. The overall survival rate was 62.5% ( Table 3 ). Five patients (20.8%) were diagnosed with deep venous thrombosis (DVT). All DVT cases were central line-associated and located in the femoral vein. Median time from 4F-PCC administration to diagnosis of DVT was 10 days (range from 6 to 30 days). No patients developed pulmonary embolism.

Table 3. Risk factors, diagnosis of thrombotic disease, and survival outcome.

Patient	Coexisting past medical problems or family history of clotting risk	Location of central venous access including PICC	Venous thromboembolism		Survival outcome
			Location	Post-PCC (d)
1	None	Femoral	Pericatheter	6	Survived
2	None	Subclavian	None		Survived
3	None	Femoral	None		Deceased
4	Sickle cell disease	Femoral	Pericatheter	15	Deceased
5	None	Femoral	Pericatheter	10	Survived
6	None	Femoral	None		Survived
7	None	Femoral	None		Deceased
8	None	Subclavian	None		Deceased
9	None	Femoral	None		Deceased
10	None	Femoral	None		Survived
11	Family history of DVT	Femoral	Pericatheter	6	Survived
12	Liver failure	IJ	None		Survived
13	CCD, CKD, cardiac thrombi	None	None		Survived
14	CCD, cardiac thrombi	Femoral	None		Deceased
15	None	IJ	None		Survived
16	None	IJ, basilic	None		Survived
17	None	IJ	None		Deceased
18	Autoimmune hepatitis	IJ, basilic	None		Deceased
19	Lymphoblastic lymphoma	IJ	None		Deceased
20	None	Subclavian, brachial, IJ	None		Survived
21	None	IJ, femoral	Pericatheter	30	Survived
22	None	Femoral	None		Survived
23	PCOS	Brachial	None		Survived
24	None	Brachial	None		Survived

Abbreviations: CCD, congenital cardiac disease; CKD, chronic kidney disease; IJ, internal jugular; PCOS, polycystic ovary syndrome; PICC, peripherally inserted central catheter.

Discussion

Critically ill children with coagulation disorders are commonly encountered in the pediatric ICU. The etiology of coagulation disorders can be multifactorial including trauma, sepsis, surgery, dilutional, and cardiopulmonary bypass (CPB). ^{1 2} The primary therapy for coagulation disorders is to treat the underlying cause of the coagulopathy, but when indicated such as in scenarios of urgent surgical interventions, transfusion of FFP to replenish coagulation factors may be necessary. However, the transfusion of FFP has specific disadvantages, especially in critically ill patients. The preparation time for plasma transfusion including cross-matching, thawing, and the duration of the transfusion is time consuming, which can negatively impact patients especially in time-sensitive situations. Plasma transfusion is associated with risks of transfusion reactions such as transfusion-related acute lung injury and transfusion-associated circulatory overload. Additionally, it can cause an increase in risk of mortality, multiple organ failure, and infections. ^{3 4 5 6 7 8} Thus, the search for an effective adjunctive therapy to treat coagulopathy in critically ill children continues.

4F-PCC, which contains plasma-derived vitamin K-dependent coagulation factors (II, VII, IX, and X), is an appealing adjunct to FFP and has several advantages over FFP ( Table 4 ). ¹² Adult studies have also demonstrated that 4F-PCC reduces the total blood product requirements including pack red blood cells and FFP with improvements in clinical outcomes. ^{13 14 15 16 17 18 19} Although these advantages of 4F-PCC over FFP may be pertinent for pediatric patients, the optimal indications, dosing, frequency, and adverse effects in children are unknown due to limited experience. ^{20 21 22 23}

Table 4. Postulated benefits of 4F-PCC over FFP.

1. Volume required to correct INR level is significantly less. 2. Preparation administration time is significantly shorter. 3. More rapid correction of coagulation parameters. 4. No association with transfusion-related infection. 5. No risk of transfusion-related infectious diseases or reactions such as TRALI and TACO.

Abbreviations: 4F-PCC, four-factor prothrombin complex concentrate; FFP, fresh frozen plasma; INR, international normalized ratio; TACO, transfusion-associated circulatory overload; TRALI, transfusion-related acute lung injury.

Noga et al reported a retrospective experience in a cohort of 16 pediatric patients who received 4F-PCC to treat coagulation disturbances related to cardiac surgery and CPB or due to the administration of vitamin K antagonists. ²² Compared with this study, our patient population was unique because the main indication for 4F-PCC administration was perioperative coagulopathy, primarily secondary to trauma, and medical disorders rather than coagulopathy following CPB or from the administration of vitamin K antagonists. We also identified two patients who were above the age of 18 years. We included these patients because as a tertiary care children's hospital, we frequently care for patients in their early 20s, and we do not believe that the pathophysiology of these patients is strikingly different from adolescent patients. Our study is also unique because we were able to obtain INR data from all our patients and ROTEM data in a few patients, including the timing of blood sample collection, and demonstrated that 4F-PCC administration corrects the INR level and coagulation time on ROTEM. The quickest correction of INR level occurred in 15 minutes after 4F-PCC administration. In the seven patients who had ROTEM data before and after 4F-PCC, six showed an improvement in coagulation factor deficiency after 4F-PCC administration. The one patient that did not show improvement had active blood loss for approximately 3 hours between 4F-PCC administration and the repeat ROTEM, which may have altered the results.

In adults, the dosing recommendation for vitamin K antagonist reversal is based on body weight and pretreatment INR level. The recommended dose is 25 units/kg (10 mL/kg; maximum 2,500 units), 35 units/kg (12 mL/kg; maximum 3,500 units), and 50 units/kg (15 mL/kg; maximum 5,000 units) for pretreatment INR levels of 2 to <4, 4 to 6, and > 6, respectively. ¹² The dosing for off-label use in adults remain controversial and may not be based on the above-mentioned INR guidelines. In majority of our patients, because 4F-PCC was used for off-label indications, dosing did not follow the above-mentioned guidelines. Thus, several of our patients did not have an INR > 2 prior to receiving 4F-PCC and did not receive dosing based on the pretreatment INR level. Additionally, they received coagulation adjuncts including FFP, TXA, EACA, and/or rFVIIa prior to the INR and ROTEM values that we report, making the dosing decision more complex. 4F-PCC was administered in these settings because of active hemorrhage, clinical concerns for high risk of hemorrhage with ongoing coagulopathy, a necessity for volume restriction, and/or the need to rapidly normalize the INR and ROTEM values prior to performing invasive procedures. The dosing was based on the clinical situation and the physician's clinical judgment rather than the pretreatment INR level. As with other coagulation adjuncts, our clinical dosing generally started with the lower end of the dosing scheme (25–35 units/kg) with the plan to give additional doses if the initial dose did not result in the desired clinical outcome. The lower dose also limits the cost and potential of adverse effects (thrombosis) until additional clinical experience has been gained with this novel product. Patients that received doses above 50 units/kg or doses below 25 units/kg had their doses adjusted to the nearest available vial size to limit waste of the product.

In general, coagulation adjuncts such as 4F-PCC are theoretically contraindicated in DIC. Patient 22 of our cohort received 4F-PCC in the setting of a diagnosis of DIC. Although the management for DIC is to treat the underlying cause, FFP can be considered in situations of active bleeding. Despite receiving multiple blood products and surgical intervention, this patient continued to have intra-abdominal bleeding with an unstable hemodynamic state and fluid overload. Given the combination of these clinical findings, the decision was made to administer 4F-PCC. No adverse effects including DVT were noted.

The association of 4F-PCC administration and risk of thrombosis remains unknown in critically ill children. The incidence of thrombotic events for our cohort was five of 24 patients or 20.8% (36.7% in trauma patients and 7.7% in nontrauma patients). For patients that survived, the overall incidence of thrombosis was 26.7% (50% in trauma patients and 11.1% in nontrauma patients). Previous pediatric studies focusing on the rate of thrombosis in critically ill children reported that the incidence in severely injured patients can be as high as 13.8% with a significantly lower incidence in nontrauma patients. ^{24 25 26 27 28} Compared with these previous reports, the DVT rate in our cohort was high, but no sequelae of the localized thrombotic event such as pulmonary embolism was noted. Since this is a retrospective study with a small cohort, it would be difficult to determine if there is a causal relationship between the use of 4F-PCC and the high DVT incidence. Our cohort had a high mortality rate of 37.5%, with many affected by severe sepsis or traumatic injury. Therefore, the high severity of illness of our cohort may have impacted the higher DVT incidence. Additionally, the thrombotic issues were noted in association with central venous catheters, which is a known risk factor. Although we do not have an institutional protocol for DVT surveillance for patients with central venous catheters, ultrasound imaging is frequently performed if there are any clinical concerns of DVT, including extremity swelling, tenderness, or fever of unknown origin. We speculate that the frequent use of ultrasound may have also increased the incidence of DVT identification in our population. While there could be an associated causal factor with 4F-PCC administration, this would conflict with the published literature in adult patients. ^{14 15 19} In addition, two patients that received two doses of 4F-PCC, which both survived, did not develop DVT. The risk of DVT in 4F-PCC use remains a question that requires further investigation.

There were several limitations to our study. First, this was a retrospective study with a small sample size. The cohort size was small and heterogeneous in demographics as well as in the primary disease process making a case–control design difficult to perform. Second, as a retrospective study, dosing, time to repeat INR check, and use of ROTEM were not rigorously controlled and hence there was significant clinical variation. Third, we were not able to identify the clinical decision-making process behind the administration of other coagulation adjuncts including TXA, EACA, and rFVIIa. These factors potentially limit our ability to assess the true efficacy of 4F-PCC to rapidly correct INR and coagulation time on ROTEM. Fourth, although we were able to demonstrate the potential effect of 4F-PCC in reversing laboratory values, we were not able to objectively assess the clinical effects on hemostasis, which is another limitation of a retrospective study. This is important because the clinical significance of bleeding risk for INR > 1.6 compared with INR ≤ 1.6 is not well established. Fifth, the use of 4F-PCC at our institution is reserved for significantly critically ill patients and this may have impacted the thrombosis and mortality rate. Finally, we did not collect data on the cost for 4F-PCC, overall transfusion requirements, and length of ICU stay as there was no control group against which to compare these outcomes.

The cost–benefit of 4F-PCC also remains equivocal. Joseph et al previously noted that in adult trauma patients, PCC and FFP use was associated with a higher cost of therapy ($1,470 ± 845 vs. 1,171 ± 949; p  = 0.01) but a lower overall cost of transfusion ($7,110 ± 1,068 vs. 9,571 ± 1,524; p  = 0.01) compared with FFP therapy alone. ¹⁵ In the United States, 4F-PCC is available in vials containing 500 units and 1000 units and the average wholesale price is $1.76/unit, making a 500-unit vial and 1,000-unit vial cost $880 and $1,760, respectively. The cost may limit its universal use outside of specific clinical indications.

In our study, 4F-PCC was administered mainly for off-label purposes to a heterogeneous cohort of pediatric patients with variable pathophysiology and indications. Given these limitations, 4F-PCC may have the potential to rapidly improve INR and ROTEM results in critically ill children at risk of bleeding or those requiring emergent surgical interventions. Given the retrospective nature of the study, we were not able to assess the true clinical effect on hemostasis, incidence of DVT, and cost efficacy. With these caveats in mind, given its advantages over FFP especially in critically ill patients where rapid correction of coagulation disturbances may be indicated and the potential for adverse effects with FFP is high, future randomized trials in critically ill children are warranted to identify the indications, optimal dosing, clinical efficacy, adverse effects, and cost–benefit of 4F-PCC.