In Vivo Effects of Fibrinogen Concentrate (FC) Versus Cryoprecipitate on the Neonatal Fibrin Network Structure After Cardiopulmonary Bypass (CPB)

This primary aim of this study is to compare the in vivo effects of fibrinogen concentrate and cryoprecipitate on the neonatal fibrin network after surgery with cardiopulmonary bypass to develop effective and safe strategies for managing coagulopathies in neonates.

Study Overview

• Status: Completed
• Conditions: Hemostasis
• Intervention / Treatment: Drug: Fibrinogen Concentrate (FC); Drug: Cryoprecipitate

Detailed Description

This study is a prospective, randomized control trial comparing two different sources of fibrinogen on clot kinetics (degradation and structure) in post-CPB coagulopathy in neonates undergoing cardiac surgery. The two sources of fibrinogen include the blood product, cryoprecipitate, and a blood product alternative, fibrinogen concentrate. Cryoprecipitate is an allogenic blood product that requires cross-matching and thawing prior to administration and is associated with immunologic reactions and possible pathogen transmission. Fibrinogen concentrate, a blood product alternative, is a purified form of fibrinogen, which undergoes a pasteurization process to minimize the risk of immunologic and allergic reactions. The primary aim of this study is compare the in vivo effect of post-CPB administration of FC, a blood product alternative, to cryoprecipitate on neonatal clot properties and clinical outcomes.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta (CHOA), Egleston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 month (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Full term neonates (36-42 weeks gestational age)
2. Infants =< 30 days of age at time of surgery
3. APGAR score of 6 or greater at 5 minutes after delivery
4. Neonates undergoing elective cardiac surgery requiring CPB at Children's Healthcare of Atlanta
5. Parents willing to participate and able to understand and sign the provided informed consent

Exclusion Criteria:

1. Preterm neonates (less than 36 weeks gestation)
2. Patients undergoing an emergent procedure or surgery not requiring CPB
3. Patients with personal or family history of a coagulation defect or coagulopathy
4. Parents unwilling to participate or unable to understand and sign the provided informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fibrinogen Concentrate (FC); Neonates undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB) who are randomized to receive platelets and FC after separation from bypass. The dose of fibrinogen concentrate will be calculated to achieve a level of 300mg/dL after drug administration. If a patient in either arm continues to have post-bypass bleeding, the anesthesiologist will use point of care testing and the transfusion thresholds outlines in the transfusion algorithm to determine appropriate products for transfusion.	Drug: Fibrinogen Concentrate (FC); The dose of fibrinogen concentrate will be calculated to achieve a level of 300mg/dL after drug administration.; Other Names: RiaSTAP
Active Comparator: Cryoprecipitate; Neonates undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB) who are randomized to receive platelets and cryoprecipitate. Standard transfusion algorithm includes two units of cryoprecipitate, which result in a median post-operative fibrinogen level of 286mg/dL (based on findings by Downey et al., published in Anesthesia and Analgesia in 2020). If a patient in either arm continues to have post-bypass bleeding, the anesthesiologist will use point of care testing and the transfusion thresholds outlines in the transfusion algorithm to determine appropriate products for transfusion.	Drug: Cryoprecipitate; The standard transfusion algorithm includes two units of cryoprecipitate, which result in a median post-operative fibrinogen level of 286mg/dL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clot Degradation at 24 Hours Post-operatively	Blood samples were obtained from an arterial line that was required for the planned surgical procedure. Samples were centrifuged to yield platelet poor plasma (PPP), stored at -80 degrees Celsius and utilized for the clot analysis. Clot degradation was determined by degradation kinetic study. Blood samples were collected at four time points:1) baseline sample within 24 hours of surgery and after induction of anesthesia prior to CPB; 2) after termination of CPB and transfusion of platelets and either cryoprecipitate or fibrinogen (within 1 hour of separation from bypass; 3) upon arrival to the ICU; 4) 24 hours post-operatively. The primary outcome is to examine differences in clot degradation between study arms at 24 hours post-surgery.	From induction of anesthesia to 24 hours postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interoperative Transfusion Requirement	Blood product transfusion requirements were obtained from electronic medical records. An increased transfusion requirement indicates increased interoperative bleeding, thus, lower values are preferable.	During surgery (up to 6 hours)
Transfusion Requirements Within the First 24 Hours After Surgery	Transfusion requirements within the first 24 hours of surgery were obtained from electronic medical records.	24 hours postoperatively
Amount of Post-operative Bleeding	Post-operative bleeding was recorded by 24 hour chest tube output. Higher values indicate greater post-operative bleeding.	Up to 24 hours postoperatively
Mechanical Ventilation Time	Mechanical ventilation time was obtained from medical records. Higher values indicate increased need for mechanical ventilation.	Time of extubation (up to 2 weeks)
Length of ICU Stay	Length of ICU stay was obtained from medical records. A shorter ICU stay indicates a favorable state of health.	At discharge from ICU (typically up to 21 days)
Length of Hospital Stay	Length of hospital stay was obtained from medical records. A shorter hospital stay indicates a favorable state of health.	At discharge from hospital (up to 150 days)
Number of Adverse Events	Adverse events within seven days of surgery were obtained from medical records.	Within seven days of surgery
Clot Strength	Blood samples will be obtained from an arterial line that is required for the planned surgical procedure. They will be centrifuged to yield platelet poor plasma (PPP), stored at -80 degrees Celsius and utilized for the clot analysis. Strength will be assessed by rheology and atomic force microscopy (AFM).	From induction of anesthesia to 24 hours postoperatively
Clot Polymerization Kinetic	Blood samples will be obtained from an arterial line that is required for the planned surgical procedure. They will be centrifuged to yield platelet poor plasma (PPP), stored at -80 degrees Celsius and utilized for the clot analysis. Polymerization will be determined by thrombin-initiated turbidity/absorbency curves.	From induction of anesthesia to 24 hours postoperatively
Fibrin Fiber Alignment	Clot structure is assessed by examination of images of clot fibrin fiber alignment. Quantification of clot fiber alignment was achieved through the application of an automated algorithm based on a fast Fourier transform that measures the alignment of the fibers, as well as visual inspection. A reference range has not been established for neonates, however, higher values indicate more dense clot structure.	From induction of anesthesia to 24 hours postoperatively

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Events of Postoperative Thrombosis	The number of events of clinically significant postoperative thrombosis that required treatment were obtained from medical records.	Within the first 24 hours of surgery
Fibrinogen Plasma Level	Blood samples were obtained from an arterial line that was required for the planned surgical procedure. The samples were centrifuged to yield platelet poor plasma (PPP), stored at -80 degrees Celsius and utilized for the clot analysis. ELISA was used to measure coagulation factors at each time point. Normal fibrinogen plasma values are between 0.5 to 15 mcg/mL.	From induction of anesthesia to 24 hours postoperatively
Thrombin Plasma Level	Blood samples were obtained from an arterial line that was required for the planned surgical procedure. The samples were centrifuged to yield platelet poor plasma (PPP), stored at -80 degrees Celsius and utilized for the clot analysis. ELISA was used to measure coagulation factors at each time point. The reference range for thrombin plasma level is 0.000313 to 0.02 mcg/mL.	From induction of anesthesia to 24 hours postoperatively
FXIII Plasma Level	Blood samples were obtained from an arterial line that was required for the planned surgical procedure. The samples were centrifuged to yield platelet poor plasma (PPP), stored at -80 degrees Celsius and utilized for the clot analysis. ELISA was used to measure coagulation factors at each time point. The reference range for FXIII plasma level is 0.000469 to 0.03 mcg/mL.	From induction of anesthesia to 24 hours postoperatively
Von Willebrand Factor Plasma Level	Blood samples were obtained from an arterial line that was required for the planned surgical procedure. The samples were centrifuged to yield platelet poor plasma (PPP), stored at -80 degrees Celsius and utilized for the clot analysis. ELISA was used to measure coagulation factors at each time point. Lower values may indicate an increased risk of excessive bleeding.	From induction of anesthesia to 24 hours postoperatively

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Laura Downey, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2019
• Primary Completion (Actual): April 9, 2021
• Study Completion (Actual): November 16, 2021

Study Registration Dates

• First Submitted: April 3, 2019
• First Submitted That Met QC Criteria: April 28, 2019
• First Posted (Actual): April 30, 2019

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Cardiopulmonary Bypass; Transfusion; in vivo; Cryoprecipitate; Fibrinogen Concentrate; FC; Open-heart surgery; Fibrin Network Structure
• Other Study ID Numbers: IRB00109310

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices), will be shared.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal to achieve aims in the approved protocol. Proposals should be directed to laura.ansley.downey@emory.edu. To gain access, data requestors will need to sign and obtain a data use agreement. The data will be available for five years in the investigator's Emory's data warehouse.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No