|Year : 2022 | Volume
| Issue : 2 | Page : 113-116
Factor XIII deficiency in a mother-baby dyad
Shalini Thangaraj, Karthikeyan Kadirvel, Rathisharmila Ramar, Anandhi Chandramohan
Department of Pediatrics, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, India
|Date of Submission||15-Mar-2022|
|Date of Decision||20-Apr-2022|
|Date of Acceptance||02-May-2022|
|Date of Web Publication||30-May-2022|
Dr. Anandhi Chandramohan
of Pediatrics, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Puducherry
Source of Support: None, Conflict of Interest: None
Background: Factor XIII deficiency is a rare autosomal recessive coagulation disorder with varied presentations including prolonged bleeding from the umbilical cord stump, defective wound healing, recurrent miscarriages, or life-threatening intracranial hemorrhage. Clinical Description: A male baby was born at term gestation to a fourth gravida mother with a history of two abortions in the past. He was born out of a third-degree consanguineous marriage, with smooth perinatal transition, but developed multiple episodes of seizures associated with poor feeding and lethargy after 24 h of life. Management: On evaluation, septic screen, metabolic screen (serum electrolytes, calcium, and blood sugar), and coagulation assays were normal. Ultrasonogram revealed a hyperechoic lesion restricted to the left cerebral hemisphere, suggestive of an intraparenchymal hemorrhage. Magnetic resonance imaging brain showed left intraparenchymal hemorrhage with significant mass effect and midline shift. In view of intracranial bleed with normal coagulation assay and other causes being ruled out, factor XIII clot solubility assay was sent and found to have undetectable levels. Factor XIII levels of the mother were also found low (5.5%) though the levels in the father were normal. The baby was managed conservatively with supportive measures in the form of anticonvulsant and anti-edema measures. He recovered successfully and is under close follow-up. Conclusion: A high index of suspicion of factor XIII deficiency should be kept in any neonate presenting with intraparenchymal hemorrhage and recurrent abortions in the mother. This case is being reported to highlight factor XIII deficiency in recurrent pregnancy loss and neonatal intracranial bleeding. Prenatal screening for factor XIII deficiency in these circumstances will help in effective management of future pregnancies.
Keywords: Factor XIII deficiency, intracranial bleeding, neonate, recurrent pregnancy loss
|How to cite this article:|
Thangaraj S, Kadirvel K, Ramar R, Chandramohan A. Factor XIII deficiency in a mother-baby dyad. Indian Pediatr Case Rep 2022;2:113-6
|How to cite this URL:|
Thangaraj S, Kadirvel K, Ramar R, Chandramohan A. Factor XIII deficiency in a mother-baby dyad. Indian Pediatr Case Rep [serial online] 2022 [cited 2023 Sep 26];2:113-6. Available from: http://www.ipcares.org/text.asp?2022/2/2/113/346264
Bleeding in a newborn can be caused by many heterogeneous causes and requires a systematic approach to arrive at a diagnosis. Plenty of clues can be discerned from the history and examination which gives direction to the investigative plan. For example, if the bleeding baby is sick, the common differentials include sepsis, necrotizing enterocolitis, disseminated intravascular coagulation, or liver disease, whereas in a well neonate with bleeding, diagnoses such as immune-mediated thrombocytopenia, Vitamin K deficiency, qualitative platelet defects, or deficiencies of various clotting factor should be considered. Similarly, neonates presenting with petechiae or small mucosal bleeds are usually due to platelet disorders, while the more voluminous spontaneous umbilical stump, intracranial, or gastrointestinal hemorrhage is more commonly associated with disorders of coagulation. The common coagulation disorders in a neonate include Hemophilia A and B and von Willebrand disease and rarely severe deficiencies of fibrinogen and factors VII, X, and XIII.
Factor XIII deficiency is a coagulopathy that has an autosomal recessive inheritance and thus more commonly observed in populations with a high rate of consanguineous marriages. The prevalence is estimated to be one in 2–5 million live births. Factor XIII deficiency often gets missed in a bleeding neonate until a detailed history and complete clinical evaluation is done. The clinical presentation is varied, and besides manifestations that range from prolonged bleeding from the umbilical cord stump to life-threatening intracranial hemorrhage, it can also cause defective wound healing and recurrent miscarriages. The prevalence of intracranial bleed is around 30%, which is much higher than that reported in other coagulation disorders.
We report a mother–baby dyad with factor XIII deficiency who presented with recurrent miscarriages in the undiagnosed mother and intracranial hemorrhage in the 2-day-old baby.
| Clinical Description|| |
A baby boy was brought to the emergency department on day 2 of life with seizures, refusal to feed, and poor activity that had started after 24 h of life. The baby had passed urine and stools after birth. The first manifestation was a multifocal tonic-clonic seizure lasting for 2 min that occurred within 24 h of life. Subsequently, the baby had three more seizures over the next 4 h, before we received him in our emergency. There was no history of progressive pallor, jaundice, bleeding from any site, appearance of bluish patches, or rashes.
He was born of a third-degree consanguineous marriage to a fourth gravida mother with an uneventful antenatal period. Quickening had been perceived at 20 weeks of gestation. There was no history of any maternal drug intake during pregnancy, apart from the routine iron and calcium supplementation. The baby was delivered via spontaneous vaginal delivery at term gestation. There was no history of any febrile illness, leaking per vaginum, or repeated vaginal examinations before delivery. The birth weight was 2.6 kg, and the APGAR scores were normal. The baby had received intramuscular Vitamin K (1 mg) after birth. He was discharged after 18 h of life, once breastfeeding had been established. There was no family history of recurrent bleeding or poor wound healing in the mother, the elder 12-year-old sibling, or any other family member. The second and third pregnancies had ended as abortions at 12 and 6 weeks of gestation, respectively.
At admission, the baby was lethargic, normothermic, with a heart rate of 160 beats per minute, respiratory rate of 56 breaths per minute, no retractions, SpO2 of 90% in room air that increased to 97% with oxygen, and normal capillary filling time. His weight was 2.4 kg, length 47 cm, and head circumference 32.5 cm, all of which were between 0 and − 2 standard deviation for age. General physical examination revealed a normal-sized, nonbulging anterior fontanelle. The sutures and posterior fontanelle were normal. The spine was normal, and there were no gross congenital anomalies. There was no cyanosis, pallor, jaundice, bruises, petechiae, or purpura. The cry was weak, and the spontaneous limb movements were decreased but symmetrical. The tone in all four limbs was reduced. Both pupils were equal in size but sluggishly reacting to light. There was no cranial nerve involvement. The examination of the cardiovascular and respiratory systems was normal, and no organomegaly was appreciated. Based on the clinical phenotype of a sick baby with seizures and nonrespiratory hypoxemia, the differential diagnoses considered included hypoglycemia, dyselectrolytemia, neonatal sepsis with meningitis, congenital anomalies involving the central nervous system (CNS) with compromised respiratory drive, and inborn errors of metabolism (IEM) with CNS and possibly cardiac involvement. Investigations were planned accordingly.
| Management and Outcome|| |
The baby was immediately started on maintenance intravenous (IV) fluids and oxygen by prongs (at 2 l/min). The blood sugar at admission was 112 mg/dl. He was shifted to the neonatal intensive care unit (NICU) where he was started on anticonvulsant drugs (phenobarbitone) and IV antibiotics (cefotaxime 150 mg/kg/day and amikacin 15 mg/kg/day). The results of the hemogram, electrolytes, sepsis screen, and coagulation profile were within normal limits [Table 1]. The neurosonogram detected a hyperechoic lesion restricted to the left cerebral hemisphere, suggestive of considerable intraparenchymal hemorrhage. Therefore, we deferred getting a metabolic screen for IEM and instead planned a magnetic resonance imaging (MRI) brain. This revealed left intraparenchymal hemorrhage with significant mass effect and midline shift in the left temporal lobe and subfalcine, tentorial, and uncal herniation [Figure 1]. The baby was started on anti-edema measures (3% saline). A neurosurgery opinion was sought, and we were advised to continue conservative management. Since the baby had intraparenchymal bleed in the setting of normal coagulation profile and normal platelets, the possibility of factor XIII deficiency was considered and the specific semiquantitative clot solubility assay was performed.
|Figure 1: Magnetic resonance imaging of the brain (a) on day 2 of life: Heterogeneous area in the left temporal region (white arrow) suggestive of an intraparenchymal hemorrhage, causing significant mass effect, obliteration of adjacent left lateral ventricle, and midline shift toward right. (b) At 5 months of age: Complete resolution of the previously noted hemorrhages. Significant gliotic changes and encephalomalacia are seen in the left temporal lobe and part of the left parietal lobe leading to significant volume loss|
Click here to view
There were no further episodes of seizures, the baby did not require oxygen to maintain saturation, and the sensorium had started to improve 3 days after admission. Nasogastric feeding was initiated and slowly increased, until the baby was able to exclusively breastfeed by the 8th day of life. The umbilical stump fell off by the end of the first week, and there was no prolonged bleeding from the site. The baby was discharged on oral phenobarbitone from NICU on day 13 of life with a diagnosis of left intracranial hemorrhage with probable factor XIII deficiency. At discharge, the child was breastfeeding and cry, activity, and tone had improved. The anterior fontanelle and head circumference (33 cm) were normal. Danger signs were explained to the parents, and he was advised regular follow-up in our high-risk newborn clinic.
The report of the factor XIII assay became available by his first follow-up visit and was found to be undetectable, confirming the diagnosis. Taking into consideration the autosomal recessive inheritance of factor XIII deficiency, parental consanguinity, and significant history of recurrent abortions, factor XIII levels were sent for both parents as well. The mother's reports revealed very low levels of factor XIII (<5.5%), whereas the father's levels were normal. Molecular testing was advised but deferred for later due to financial constraints. Thus, the final diagnosis was factor XIII deficiency with left intracranial hemorrhage. The parents were counseled about the nature of the disease, precautions to be taken prior to any possible piercing, surgical intervention, or dental extraction, the need for regular follow-up, the screening of the elder sibling, and the option of prenatal diagnosis if the planned another pregnancy.
The last visit was when the infant was 5 months old. He was asymptomatic with no recurrence of seizures on anticonvulsant drugs, no history of bruising or bleeding from any site, and absence of any focal neurological deficits. His developmental milestones were appropriate for age, and the head circumference growth curve plotted was following the normal trajectory. A follow-up MRI brain was done, which showed near-complete resolution of the hemorrhages. However, there was significant encephalomalacia involving the left temporal lobe and part of the left parietal lobe.
| Discussion|| |
Factor XIII is a tetramer belonging to the transglutaminase family. It is made up of two catalytic A subunits and two regulatory B subunits. Once activated, the A subunit cross-links alpha- and gamma-fibrin chains, thus increasing clot strength and fibrinolytic resistance and also playing a crucial role in the coagulation cascade. Since factor XIII helps in the cross-linking of fibrin with fibronectin, it has an important role in helping in the attachment of the placenta to the uterus. That is the reason why factor XIII deficient women have spontaneous detachment of the placenta leading to recurrent miscarriages. It is well known that pregnancy is a hypercoagulable state per se. An analysis of antenatal women with normal course of pregnancy showed that factor XIII levels decrease during the second and third trimesters and in the immediate postnatal period for a normal woman. Thus, in factor XIII deficient women, this expected decrease reaches much lower nadir, increasing the predisposition to miscarriages and preterm delivery. Factor XIII concentrate has to be administered every 7–10 days, beginning from 5 weeks of gestation once for deficient women to maintain the necessary factor levels for the maintenance of pregnancy. Recently, treatment options with recombinant factor XIII substitutes have shown promising results with successful pregnancy and neonatal outcomes as well.
The diagnosis of factor XIII deficiency is often missed due to normal coagulation test results. Once suspected, a variety of specialized laboratory tests are required to confirm the diagnosis. These include in vitro tests such as clot solubility assay, factor XIII activity assay, factor XIII antigen assay, factor XIII inhibitor assay, and molecular diagnosis by identifying the genetic mutations of A or B subunit. Once the parents are screened and the molecular mutation is identified, the prenatal diagnosis for the targeted mutation can be performed. This can be done by polymerase chain reaction with restriction fragment length polymorphism using noninvasive methods like obtaining cell-free fetal DNA from the mother or by extraction of DNA by chorionic villous sampling. Genetic analysis in a large cohort has revealed a high heterogeneity in the nature of mutations and showed that the mutations were mainly due to subunit A of factor XIII. Hence, screening of the affected family members helps in the prenatal diagnosis of the subsequent pregnancies. Treatment of factor XIII deficiency includes fresh frozen plasma, cryoprecipitate, or replacement with recombinant factor XIII. Indications for replacement therapy include those neonates who develop bleeding in congenital factor XIII deficiency, as prophylaxis for children with severe deficiency, and throughout the pregnancy of affected women to prevent miscarriages. The dose for routine prophylaxis is 35 IU/kg of recombinant factor XIII A monthly. In a child with intracranial bleed initial dose of 30 IU/kg for 4 days followed by 10 IU/kg for 10 days should be given. This should be followed by routine prophylaxis.
This report emphasizes that subclinical factor XIII deficiency should be considered among women with history of recurrent pregnancy loss and in a newborn with intracranial bleeding and normal coagulation assay. This can prevent further pregnancy losses, aid in prenatal diagnosis, and prevent life-threatening hemorrhages in the newborn.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dorgalaleh A, Naderi M, Shamsizadeh M. Morbidity and mortality in a large number of Iranian patients with severe congenital factor XIII deficiency. Ann Hematol 2016;95:451-5.
Alavi SE, Jalalvand M, Assadollahi V, et al
. Intracranial hemorrhage: A devastating outcome of congenital bleeding disorders-prevalence, diagnosis, and management, with a special focus on congenital factor XIII deficiency. Semin Thromb Hemost 2018;44:267-75.
Sharief LT, Lawrie AS, Mackie IJ, et al
. Changes in factor XIII level during pregnancy. Haemophilia 2014;20:e144-8.
Abdel-Samad N. Treatment with recombinant factor XIII (Tretten) in a pregnant woman with factor XIII deficiency. Am J Case Rep 2017;18:436-9.
Karimi M, Peyvandi F, Naderi M, et al
. Factor XIII deficiency diagnosis: Challenges and tools. Int J Lab Hematol 2018;40:3-11.
Motlagh H, Dorgalaleh A, Tabibian S, Naderi M, Zaker F. Noninvasive prenatal diagnosis of congenital factor XIII deficiency in Iran. Blood Coagul Fibrinolysis. 2022 Jan 3. doi: 10.1097/MBC.0000000000001121. Epub ahead of print. PMID: 34980832.
Shanbhag S, Ghosh K, Shetty S. Genetic basis of severe factor XIII deficiency in a large cohort of Indian patients: Identification of fourteen novel mutations. Blood Cells Mol Dis 2016;57:81-4.
Shanthi S, Clotting factor replacement therapy Indian J Pract Pediatr Hematol Oncol 2020;22:298-311.
Dasari P, Mangolngnbi Chanu S, Gadipudi LP. Prenatal diagnosis of factor 13 deficiency and its recurrence. BMJ Case Rep 2020;13:e236365.