Treatment of Congenital Afibrinogenemia in a Neonate With Critical Pulmonary Stenosis

Abstract

Fibrinogen deficiencies in neonates can lead to bleeding complications. In this report, we describe a case of congenital afibrinogenemia in a newborn with critical pulmonary stenosis who presented with bilateral cephalohematomas after an uncomplicated delivery. The initial use of cryoprecipitate was followed by administration of fibrinogen concentrate. We estimated a half-life of 24 to 48 hours with the concentrate product. This patient received fibrinogen replacement and had a subsequent successful cardiac repair. The drug's shorter half-life in this neonate contrasts with prior reports of longer half-life in older patients and is important to note in treating future neonatal patients with this diagnosis.

Introduction

Fibrinogen is a liver-synthesized key substrate to establish the fibrin network that is the end result of the coagulation cascade and serves as scaffolding for platelet aggregation. Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete deficiency of fibrinogen. This disorder has an estimated prevalence of 1:1,000,000 and it manifests clinically with bleeding that most often presents in the neonatal period. Paradoxically, thrombosis can also be associated with this disorder.¹ Treatment is provided on demand with bleeding episodes, and, in certain scenarios, prophylaxis has been administered. When available, treatment consists of fibrinogen concentrate replacement to avoid exposure to cryoprecipitate owing to risks of increased immunogenicity, potential for viral transmission, and increased potential for thromboembolic events. Because of the infrequency of these cases, treatment guidelines are individualized to the clinical scenario, using the rare literature available on fibrinogen concentrate pharmacokinetics. Decisions about treatment frequency have been guided by the clinical scenario. We present here the management approach to a patient with a congenital heart defect requiring interventions and with bleeding in the neonatal period. The calculated half-life of the fibrinogen concentrate in this case of a neonate with a bleed and the management outcome with procedures can help future clinicians estimate treatment frequency in similar patient scenarios.

Case Report

The patient was admitted to our institution after being noted to have a murmur at birth after a normal pregnancy and an atraumatic, unmanipulated vaginal delivery. The birth weight was 3.35 kg at gestational age 39 weeks and 3 days. Echocardiogram at birth showed critical pulmonary stenosis and hypertrophy of the right ventricle; therefore, umbilical arterial and venous lines were placed, prostaglandin therapy was started, and the patient was intubated and transferred to our tertiary care center. On arrival, he underwent balloon dilation for critical pulmonary stenosis, without complication; a decrease in saturation levels was noted, so a ductus arteriosus (PDA) stent was placed and small-dose aspirin (20.5 mg, ~6 mg/kg/day) was started to maintain stent patency.

Bilateral cephalohematomas was noted despite the patient's atraumatic delivery; and on preoperative laboratory screening, he had an undetectable fibrinogen activity (by Clauss method) and prolonged activated partial thromboplastin time (aPTT) at >100 seconds. Initial complete blood count was significant for a hemoglobin of 17.9 g/dL, hematocrit 52%, and platelets 190 K/μL, which are normal values for age. Prior to initial pulmonary stenosis balloon dilation, fresh frozen plasma was given, with partial correction in aPTT and improvement in fibrinogen to 45 mg/dL. The procedure did not incur any noted bleeding or thrombotic complications. Initially the low fibrinogen activity was presumed by the primary medical team to be due to consumption in the setting of cephalohematomas, so fibrinogen replacement was commenced with cryoprecipitate. He was given doses of 3.8 to 14.5 mL/kg (ordered as 1 to 2 units) of cryoprecipitate. After the first week postoperatively, fibrinogen and coagulation measures were not routinely checked. A repeated check in the subsequent week showed low fibrinogen activity again, and hematology was consulted. Umbilical arterial catheter and umbilical venous catheter were removed as per protocol in the first week of life without any bleeding or thrombotic complications.

At the time of hematology consultation when the patient had not received cryoprecipitate for 1 week, testing showed prolonged reptilase time (92 seconds) and thrombin time (39.3 seconds). Thromboelastometry was not available. Genetic testing was sent and revealed homozygous mutation in the FGA gene for a sequence variant designated c.510+1G>T, which has been reported to be pathologic for congenital fibrinogen deficiency.²

The patient received therapy with lyophilized fibrinogen concentrate when this diagnosis was confirmed; he received a total of 9 doses of fibrinogen concentrate (Human) (RiaSTAP, CSL Behring LLC, Kankakee, IL) intravenous at 70 mg/kg/dose in a 25-day period (see Figure for doses and subsequent fibrogen activity concentrations). This product was used because it was the product on formulary. The second cardiac intervention was performed with the safeguard of fibrinogen concentrate (concentration of 96 mg/dL morning of procedure) at 1 month of life with a second balloon dilation and closure of the PDA. Aspirin was discontinued at that time. Ultrasonography for cephalohematomas was followed by significant improvement at week 5 but with calcified rims noted that corresponded to ongoing bony prominences. Fibrinogen concentrate was then changed to be given less frequently to maintain a concentration >30 mg/dL for the remainder of the patient's hospitalization given low concern for ongoing bleeding (Figure). A peripherally inserted central catheter was placed for administration of repeated intravenous medications without complication at the time of discharge.

Figure.

Patients' fibrinogen concentration over time with therapy. The arrows identify administration of cryoprecipitate and fibrinogen concentrate. These data may be helpful for those with a similar clinical scenario to help guide frequency of monitoring of fibrinogen concentrations after use of either cryoprecipitate or fibrinogen concentrates.

No thrombotic complications were noted in this patient throughout the course and cephalohematomas resolved (to a level possible with ongoing calcified rims). In the setting of this patient's history of cephalohematomas, the use of secondary prophylaxis was discussed with the family. As an outpatient he subsequently transitioned to weekly prophylaxis therapy with fibrinogen concentrate for secondary prophylaxis while in infancy and with known cardiac condition. As of age 7 months, he has been stable on this regimen without bleeding or thrombotic complications.

Discussion

Early diagnosis and appropriate treatment of congenital afibrinogenemia decrease bleeding complications. Identification of this rare disorder requires a high index of suspicion while monitoring coagulation parameters. Congenital afibrinogenemia presents with bleeding most often in the neonatal period, although later presentations can occur with menorrhagia, splenic rupture, hemoperitoneum from rupture of the corpus luteum, and first trimester miscarriage. In a patient born via an unmanipulated birth, large bilateral cephalohematomas should trigger evaluation for underlying bleeding diathesis. Fortunately, this patient received preoperative coagulation testing given his cardiac defect, which showed a prolonged prothrombin and aPTT. Because each of these tests requires the function of the common pathway in the coagulation cascade, testing of entities of the common pathway may be indicated when both are prolonged.

Initial testing for fibrinogen abnormalities is performed by measurement of fibrinogen activity through the Clauss method. Thrombin time and reptilase time are also sensitive to deficiencies in fibrinogen activity and were also prolonged in this patient.³ Fibrinogen antigen values can also be checked and obtained when testing for dysfibrinogenemia via immunoassay. In our patient's case, antigen values were concordantly low, confirming the diagnosis of afibrinogenemia.

Replacement of low fibrinogen was initially performed with cryoprecipitate, a blood product with a minimum amount of fibrinogen required by standards of the American Association of Blood Banks.⁴ There is wide variability (range, 120–796 mg) in the amount of fibrinogen per bag.⁵ This variability makes treatment dosing difficult and also exposes the patient to the risks of blood product administration. Fibrinogen concentrate [Human] (RiaSTAP) is 1 of 2 fibrinogen concentrate products available in the United States (the other being fibrinogen [Human] [Fibryga, Octapharma, Vienna, Austria US License No. 1646]) that are indicated for the treatment of bleeding episodes in patients with afibrinogenemia. In published pharmacokinetic studies, the elimination half-life of biological fibrinogen is 100 hours.⁶ The median elimination half-life of fibrinogen concentrate [Human] (RiaSTAP) previously reported is roughly 78.7 ± 18.13 hours for fibrinogen activity (69.9 ± 8.54 hours for patients younger than 16 years and 82.3 ± 20.04 hours for patients older than 16 years).⁷ To our knowledge, there are no published pharmacokinetic profiles available for infants. A case report of a neonate with bleeding and this diagnosis describes the use of cryoprecipitate for treatment.⁸ The youngest age group in published pharmacokinetic studies for fibrinogen concentrates consists of 8-year-olds.⁹ In one case report, the estimated elimination half-life with use of fibrinogen concentrate in a neonate was also shorter than reported in adults, estimated to approximate 48 hours.¹⁰ Based on the available fibrinogen concentrations collected for our patient, the estimated elimination half-life was 24 to 48 hours. Because a pharmacokinetic sample was not drawn, the elimination half-life was extrapolated from the time it took for the fibrinogen concentration to decrease approximately by half after fibrinogen concentrate [Human] (RiaSTAP) dose. Fibrinogen [Human] (Fibryga) half-life ranges from 45.6 hours to 157 hours (45.6–67 hours in children younger than 6 years, 57.7–91.6 hours in children 6–12 years of age, and 40–157 hours in adults). In pharmacokinetic studies, there was no difference in the pharmacokinetics of fibrinogen [Human] (Fibryga) between adults and adolescents (12–17 years of age). However, when compared with adults, studies did show that children 1 to 12 years of age experienced a shorter half-life.^11,12 Thus, similarly to Fibryga, fibrinogen concentrate [Human] (RiaSTAP) may have a higher clearance in pediatric patients; therefore, the need for higher or more frequent dosing.

Once we determined the drug's half-life in our patient we were able to choose a timeline for consistent administration of the fibrinogen replacement product for secondary prophylaxis. The review by Peyvandi et al¹³ suggests that while there is variation in secondary prophylaxis use for congenital fibrinogen deficiency, the majority of use occurred in patients with a previous history of central nervous system bleeding with primarily fibrinogen concentrate dosed weekly.

In addition, this report outlines the successful use of fibrinogen replacement for cardiac catheterization procedures in a patient with congenital afibrinogenemia. While fibrinogen replacement has been reported for other cardiac procedures, this is the first report in a patient with this rare underlying diagnosis. Of note, the patient also had a short period of concurrent aspirin therapy while he had a stent in place. The concurrent use of aspirin therapy may have increased bleeding risk with this patient's underlying afibrinogenemia, which was not diagnosed at that time, but fortunately, no bleeding was noted.

Conclusion

This case report documents the need for frequent redosing of fibrinogen concentrate in a patient with congenital afibrinogenemia with bilateral cephalohematomas. We estimated a fibrinogen elimination half-life for our patient that was shorter than previously reported. Our patient received cardiac catheterizations for congenital pulmonary stenosis with the safeguard of concentrate as well. Although an exact fibrinogen concentrate half-life could not be reported owing to insufficient pharmacokinetic data, future management of neonatal patients diagnosed with afibrinogenemia may benefit from this vignette, which describes frequency of need for concentrate in a dynamic, evolving clinical situation.

ABBREVIATIONS

aPTT

activated partial thromboplastin time;

PDA

ductus arteriosus

Funding Statement

Dr Balasa has served on Advisory Boards and received speaker honoraria from CSL, SanofiGenzyme, and Takeda.