Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://www.cardiologyres.org

Review

Volume 13, Number 1, February 2022, pages 18-26

Prothrombin Complex Concentrates to Treat Coagulation Disturbances: An Overview With a Focus on Use in Infants and Children

**Table 1.** Factor Composition of Various Coagulation Adjuncts and Concentrates
Factor concentrate	Brand names	Composition
PCC: prothrombin complex concentrate.
Three-factor PCC	Profilnine^® SD, Bebulin^®	Factors II, IX and X
Four-factor PCC	Beriplex^®, Kcentra^®, Confidex^®, Octaplex^®, and Prothromblex^®	Factors II, VII, IX and X; protein C, protein S, and heparin
Activated PCC	FEIBA-NF™	Factors II, VIIa, IX, Xa; protein C
Recombinant factor VIIa	Novoseven^®	Factor VIIa
Fibrinogen concentrate	RiaSTAP^®	Plasma derived fibrinogen concentrate (factor I)

Table 1. Factor Composition of Various Coagulation Adjuncts and Concentrates

Factor concentrate

Brand names

Composition

PCC: prothrombin complex concentrate.

Three-factor PCC

Profilnine^® SD, Bebulin^®

Factors II, IX and X

Four-factor PCC

Beriplex^®, Kcentra^®, Confidex^®, Octaplex^®, and Prothromblex^®

Factors II, VII, IX and X; protein C, protein S, and heparin

Activated PCC

FEIBA-NF™

Factors II, VIIa, IX, Xa; protein C

Recombinant factor VIIa

Novoseven^®

Factor VIIa

Fibrinogen concentrate

RiaSTAP^®

Plasma derived fibrinogen concentrate (factor I)

**Table 2.** Selected Reports of PCC Use in Adults With Traumatic Injury
Author and reference	Study design and cohort	Outcomes
PCC: prothrombin complex concentrate; INR: international normalized ratio; FFP: fresh frozen plasma; rFVIIa: recombinant activated factor VII; TBI: traumatic brain injury.
Joseph et al [29]	Retrospective study including 85 TBI patients in a level-1 trauma center who received PCC (64 patients) or rFVIIa (21 patients).	Mortality rate was lower in the PCC group compared with rFVIIa. PCC was an effective treatment for coagulopathy, reducing the resources needed and costs when compared to rFVIIa.
Joseph et al [30]	Retrospective study with propensity-scoring matching of 252 trauma patients with INR ≥ 1.5 over a 2-year period, divided in two groups: PCC and FFP versus FFP alone.	PCC use was associated with a more rapid correction of the INR, reduction in requirement for packed red blood cells and FFP, and decreased mortality (23% vs. 28%; P = 0.04) when compared to FFP alone.
Zeeshan et al [31]	Retrospective review using propensity-score matching analysis in a cohort of 250 patients to compare the efficacy of 3F-PCC versus 4F-PCC in coagulopathy following trauma.	4F-PCC compared to the 3F-PCC was associated with a more rapid INR reversal and reduction in transfusion requirements without increasing the risk of thromboembolic events or increasing the hospital cost.
Joseph et al [32]	Four-year retrospective analysis of 88 patients with devastating gunshot wounds to the brain. Thirteen patients had coagulation disturbances at the time of admission.	Ten patients received PCCs. Mean INR before PCC administration was 2.01 ± 0.7 and decreased to 1.1 ± 0.7 after administration. Correction of coagulopathy was attained in seven of 10 patients (70%). Of these seven patients, consent for donation was obtained in six, resulting in 19 solid organs being procured.
Joseph et al [33]	Propensity score matching of a cohort of 22 patients with TBI and coagulopathy who received PCC (25 IU/kg) and FFP or FFP alone.	Patients who received PCC and FFP therapy had faster time to craniotomy compared with patients who received FFP therapy alone (average time of 231 versus 485 minutes). The mortality rate was also lower in patients who received PCC and FFP.

Table 2. Selected Reports of PCC Use in Adults With Traumatic Injury

Author and reference

Study design and cohort

Outcomes

PCC: prothrombin complex concentrate; INR: international normalized ratio; FFP: fresh frozen plasma; rFVIIa: recombinant activated factor VII; TBI: traumatic brain injury.

Joseph et al [29]

Retrospective study including 85 TBI patients in a level-1 trauma center who received PCC (64 patients) or rFVIIa (21 patients).

Mortality rate was lower in the PCC group compared with rFVIIa. PCC was an effective treatment for coagulopathy, reducing the resources needed and costs when compared to rFVIIa.

Joseph et al [30]

Retrospective study with propensity-scoring matching of 252 trauma patients with INR ≥ 1.5 over a 2-year period, divided in two groups: PCC and FFP versus FFP alone.

PCC use was associated with a more rapid correction of the INR, reduction in requirement for packed red blood cells and FFP, and decreased mortality (23% vs. 28%; P = 0.04) when compared to FFP alone.

Zeeshan et al [31]

Retrospective review using propensity-score matching analysis in a cohort of 250 patients to compare the efficacy of 3F-PCC versus 4F-PCC in coagulopathy following trauma.

4F-PCC compared to the 3F-PCC was associated with a more rapid INR reversal and reduction in transfusion requirements without increasing the risk of thromboembolic events or increasing the hospital cost.

Joseph et al [32]

Four-year retrospective analysis of 88 patients with devastating gunshot wounds to the brain. Thirteen patients had coagulation disturbances at the time of admission.

Ten patients received PCCs. Mean INR before PCC administration was 2.01 ± 0.7 and decreased to 1.1 ± 0.7 after administration. Correction of coagulopathy was attained in seven of 10 patients (70%). Of these seven patients, consent for donation was obtained in six, resulting in 19 solid organs being procured.

Joseph et al [33]

Propensity score matching of a cohort of 22 patients with TBI and coagulopathy who received PCC (25 IU/kg) and FFP or FFP alone.

Patients who received PCC and FFP therapy had faster time to craniotomy compared with patients who received FFP therapy alone (average time of 231 versus 485 minutes). The mortality rate was also lower in patients who received PCC and FFP.

**Table 3.** Selected Reports of PCC Use in Infants and Children
Author and reference	Study design and cohort	Outcomes
PCC: prothrombin complex concentrate; INR: international normalized ratio; DVT: deep vein thrombosis; CVC: central venous catheter; FFP: fresh frozen plasma; ROTEM: rotational thrombo-elastogram.
Karube et al [41]	The study cohort included 24 patients, ranging in age from 2 months to 23 years. Only two patients were receiving chronic therapy with anticoagulant medications (warfarin or enoxaparin).	Twenty-nine doses of 4F-PCC at a median dose of 27 units/kg. The primary indication for PCC administration was perioperative/procedural correction of coagulopathy. 4F-PCC decreased the INR, corrected abnormalities on the ROTEM, and controlled bleeding. Thrombotic complications (DVT) were noted in five patients (20.8%) in association with a femoral CVC.
Noga et al [42]	Retrospective study of 16 infants and children, ranging in age from 23 days to 16 years.	PCCs administered to control postoperative bleeding or for reversal of vitamin K antagonists (n = 11). Dosing based on an institutional guideline that included both weight and the presenting INR. Nine patients receiving PCC for vitamin K antagonist reversal had a rapid and marked improvement in the INR.
Rech et al [43]	A 5-month-old infant with shock and liver failure following non-accidental trauma.	Due to bleeding during a laparotomy related to coagulopathy, unresponsive to platelet and FFP transfusions, PCC (30 IU/kg) was administered. The authors reported a cessation of bleeding and a decrease of the INR from 2.9 to 1.5.
Fuentes-Garcia et al [44]	A 6-week-old infant with an intracerebral hemorrhage who did receive vitamin K prophylaxis at birth.	PCC 50 IU/kg reversed coagulopathy in the setting of life-threatening bleeding.

Table 3. Selected Reports of PCC Use in Infants and Children

Author and reference

Study design and cohort

Outcomes

PCC: prothrombin complex concentrate; INR: international normalized ratio; DVT: deep vein thrombosis; CVC: central venous catheter; FFP: fresh frozen plasma; ROTEM: rotational thrombo-elastogram.

Karube et al [41]

The study cohort included 24 patients, ranging in age from 2 months to 23 years. Only two patients were receiving chronic therapy with anticoagulant medications (warfarin or enoxaparin).

Twenty-nine doses of 4F-PCC at a median dose of 27 units/kg. The primary indication for PCC administration was perioperative/procedural correction of coagulopathy. 4F-PCC decreased the INR, corrected abnormalities on the ROTEM, and controlled bleeding. Thrombotic complications (DVT) were noted in five patients (20.8%) in association with a femoral CVC.

Noga et al [42]

Retrospective study of 16 infants and children, ranging in age from 23 days to 16 years.

PCCs administered to control postoperative bleeding or for reversal of vitamin K antagonists (n = 11). Dosing based on an institutional guideline that included both weight and the presenting INR. Nine patients receiving PCC for vitamin K antagonist reversal had a rapid and marked improvement in the INR.

Rech et al [43]

A 5-month-old infant with shock and liver failure following non-accidental trauma.

Due to bleeding during a laparotomy related to coagulopathy, unresponsive to platelet and FFP transfusions, PCC (30 IU/kg) was administered. The authors reported a cessation of bleeding and a decrease of the INR from 2.9 to 1.5.

Fuentes-Garcia et al [44]

A 6-week-old infant with an intracerebral hemorrhage who did receive vitamin K prophylaxis at birth.

PCC 50 IU/kg reversed coagulopathy in the setting of life-threatening bleeding.

**Table 4.** Selected Reports of PCC Use in Infants and Children Undergoing Cardiac Surgery
Author and reference	Study design and cohort	Outcomes
PCC: prothrombin complex concentrate; CPB: cardiopulmonary bypass; rFVIIa: recombinant activated factor VII; AT-III: anti-thrombin III; FFP: fresh frozen plasma; FC: fibrinogen concentrate.
Giorni et al [47]	Retrospective study cohort of 14 patients, ranging in age from 8 to 67 days, compared to 11 case-matched controls.	PCCs administered after CPB. PCC patients had lower chest tube output in the first 24 postoperative hours and decreased transfusion requirements although these did not reach statistical significance.
Navaratnam et al [48]	Five patients, ranging in age from 7 to 23 years, for combined liver-heart transplantation.	PCCs used as part of their perioperative management protocol following large volume transfusions (1-3 blood volumes). Four of the five patients also received an antifibrinolytic agent and rFVIIa.
Rybka et al [49]	Prospective cohort of 15 children, 9 months to 3 years of age. PCC dosing of 30-50 IU/kg.	Clinical bleeding after heparin reversal with protamine. Clinical hemostasis was achieved in 13 of 15 patients.
Jooste et al [50]	Retrospective cohort of five neonates and one infant.	3F-PCC used in conjunction with rFVIIa (four patients) and AT-III replacement if level was less than 70%. Thrombotic complications noted in two patients.
Sisti et al [51]	Cohort of patients for heart transplantation, being supported preoperatively with a ventricular assist device.	Anticoagulation reversed with PCC or FFP. Patients who received PCC had decreased transfusion requirements.
Velik-Salchner et al [52]	Propensity score matching of 210 children who received FC and PCC compared to standard treatment with FFP.	FC/PCC was well tolerated and provided effective clinical hemostasis. Outcomes were non-inferior to FFP.

Table 4. Selected Reports of PCC Use in Infants and Children Undergoing Cardiac Surgery

Author and reference

Study design and cohort

Outcomes

PCC: prothrombin complex concentrate; CPB: cardiopulmonary bypass; rFVIIa: recombinant activated factor VII; AT-III: anti-thrombin III; FFP: fresh frozen plasma; FC: fibrinogen concentrate.

Giorni et al [47]

Retrospective study cohort of 14 patients, ranging in age from 8 to 67 days, compared to 11 case-matched controls.

PCCs administered after CPB. PCC patients had lower chest tube output in the first 24 postoperative hours and decreased transfusion requirements although these did not reach statistical significance.

Navaratnam et al [48]

Five patients, ranging in age from 7 to 23 years, for combined liver-heart transplantation.

PCCs used as part of their perioperative management protocol following large volume transfusions (1-3 blood volumes). Four of the five patients also received an antifibrinolytic agent and rFVIIa.

Rybka et al [49]

Prospective cohort of 15 children, 9 months to 3 years of age. PCC dosing of 30-50 IU/kg.

Clinical bleeding after heparin reversal with protamine. Clinical hemostasis was achieved in 13 of 15 patients.

Jooste et al [50]

Retrospective cohort of five neonates and one infant.

3F-PCC used in conjunction with rFVIIa (four patients) and AT-III replacement if level was less than 70%. Thrombotic complications noted in two patients.

Sisti et al [51]

Cohort of patients for heart transplantation, being supported preoperatively with a ventricular assist device.

Anticoagulation reversed with PCC or FFP. Patients who received PCC had decreased transfusion requirements.

Velik-Salchner et al [52]

Propensity score matching of 210 children who received FC and PCC compared to standard treatment with FFP.

FC/PCC was well tolerated and provided effective clinical hemostasis. Outcomes were non-inferior to FFP.

**Table 5.** Potential Benefits of PCC Compared to Standard Allogeneic Blood Products
PCC: prothrombin complex concentrate.
1. General efficacy even in refractory coagulation disturbances
2. No need for specific type and cross matching of product
3. Rapid preparation time
4. Low volume with short administration time
5. Rapid preparation time and rapid administration time lead to rapid correction of coagulation disturbances
6. Limited risk of adverse effects which may be seen with allogeneic blood products including:
a. Viral disease transmission
b. Transfusion-associated circulatory overload
c. Transfusion-related acute lung injury
d. Hemodynamic effects due to effects on ionized calcium
e. Immune and non-immune-mediated transfusion reactions

Table 5. Potential Benefits of PCC Compared to Standard Allogeneic Blood Products

PCC: prothrombin complex concentrate.

1. General efficacy even in refractory coagulation disturbances

2. No need for specific type and cross matching of product

3. Rapid preparation time

4. Low volume with short administration time

5. Rapid preparation time and rapid administration time lead to rapid correction of coagulation disturbances

6. Limited risk of adverse effects which may be seen with allogeneic blood products including:

a. Viral disease transmission

b. Transfusion-associated circulatory overload

c. Transfusion-related acute lung injury

d. Hemodynamic effects due to effects on ionized calcium

e. Immune and non-immune-mediated transfusion reactions