Case report Factor XIII deficiency with intracranial haemorrhage Muzamil Ejaz, Ayesha Saleem, Nimrah Ali, Fizza Tariq Pediatrics, Dow Medical College, Dow University of Health Sciences, Dr Ruth KM Pfau Civil Hospital, Karachi, Pakistan Correspondence to Professor Muzamil Ejaz, ​muzamilejaz08@​yahoo.​com Accepted 31 July 2019 Summary A 5-year-old girl presented to paediatric emergency with fever and seizures for a short duration. At first, meningitis was suspected and management was started empirically. There was no improvement in the clinical condition of the patient and investigations revealed spontaneous intracranial haemorrhage (ICH) secondary to factor XIII deficiency. The child was transfused cryoprecipitate and managed conservatively for ICH. She became asymptomatic and was kept on monthly cryoprecipitate transfusions. This case report summarises factor XIII deficiency in ICH which was not suspected initially, but diagnosed later on after CT scan head and factor XIII assay. This report also highlights events occurring during its management. Background © BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ. To cite: Ejaz M, Saleem A, Ali N, et al. BMJ Case Rep 2019;12:e228682. doi:10.1136/bcr-2018228682 Factor XIII deficiency is a rare genetic, autosomal recessive disorder affecting one in 2–5 million live births.1 Although rare, it has been observed frequently in many countries including Iran, Pakistan and India. It has been reported that Iran has the highest incidence of factor Xlll deficiency, almost one-third of the affected global population.2 Prevalence of factor XIII in Pakistan is variable. An earlier study conducted in north Pakistan screened individuals with bleeding disorders and found 5.3% of the population to be factor XIII deficient,3 whereas a recent report from the similar region showed 4.6% of cases of factor XIII deficiency among autosomal recessive inherited bleeding disorders.4 Factor XIII deficiency usually presents with umbilical cord bleeding in neonates and haematoma, miscarriages and menorrhagia in young women.5 Factor XIII deficiency can also be acquired by middle-aged or elderly individuals, and is associated with conditions such as severe liver disease, chronic renal failure, autoimmune disorders and myeloid leukaemia.6 Intracranial haemorrhage (ICH) is a critical complication of congenital bleeding disorders such as von Willebrand disease, haemophilia, factors II, V, VII, X and XIII deficiency, and afibrinogenemia. Acquired diseases like idiopathic thrombocytopenic purpura, chronic liver disease and kidney disease can also present with ICH.7 Factor XIII is more frequently associated with ICH, accounting for about 30% of cases and a mortality rate of 15%.8 Identification of new cases of this disease could be attributed to the increased prevalence of consanguineous marriages in Pakistan. In contrast, another recent study reported four novel mutations of genes involved in factor XIII deficiency from the data collected from seven unrelated families.9 Diagnosis of factor XIII is based on clinical presentation, family history and laboratory investigations. Here is a case of a 5-year-old girl, the product of a non-consanguineous marriage with a clinical presentation of spontaneous ICH secondary to factor XIII deficiency. Case presentation A 5-year-old girl, completely vaccinated and weighing 16 kg, presented to paediatric emergency with complaints of fever, headache and irritability for 2 days and a self-limiting episode of tonic seizure. It was followed by a loss of consciousness for a few minutes. There was no history of trauma. At the time of admission, the child was vitally stable with normal anthropometric measurements. There were no signs of bleeding like petechiae, haematoma, epistaxis or bleeding from the gums. Neurological examination revealed a Glasgow Coma Scale (GCS) of 15/15, bilateral equally reactive pupils with normal funduscopy. There were positive signs of meningeal irritation. Other systemic examinations were unremarkable, the respiratory system showed normal vesicular breathing. The cardiovascular system revealed normal heart sound, while the abdomen was non-tender with no visceromegaly. A provisional diagnosis of meningitis was made, considering the common prevalence of this infectious disease in the paediatric population of our country.10 Relevant investigations, including complete blood picture, serum electrolytes, urea, creatinine, serum calcium and random blood sugar were done but were unremarkable. Lumbar puncture was deferred by the attendant and, therefore, empirical therapy for meningitis was initiated. The patient was given intravenous injection ceftriaxone, 100mg/kg/day, two times daily, intravenous injection vancomycin, 60 mg/kg/day, 8-hourly and intravenous dexamethasone 0.15 mg/kg/dose, 8-hourly for suspected meningitis. GCS was 15/15 at the start of therapy and her clinical condition showed no improvement despite the initiated treatment but rather worsened in next 2 days with increased headache, irritability and a drop in GCS score to12/15. Therefore, a CT scan of the head was done showing ICH in the right occipital lobe. On further enquiring of her mother to gather any points that may have been missed in the clinical history, we learnt that the child had been admitted to the neonatal intensive care unit on the 7th day of her life due to excessive and protracted bleeding from the umbilical stump. At that time she had been transfused platelets and packed cells. Besides, the mother had also noticed infrequent, spontaneous, self-limiting bruising on her skin and mucous Ejaz M, et al. BMJ Case Rep 2019;12:e228682. doi:10.1136/bcr-2018-228682 1 BMJ Case Rep: first published as 10.1136/bcr-2018-228682 on 26 August 2019. Downloaded from http://casereports.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright. Rare disease Table 1 Bleeding and coagulation profile Test Result Normal ranges Bleeding time 5.06 min (1–7) Platelet function analysis (PFA-100)  Ristocetin (0.5 mg/mL) 3% (0–8)  Epinephrine (10 um) 56% (48–103)  Collagen (2 ug/mL) 78% (46–112)  ADP (10 um) 101% (50–110)  Ristocetin (1.25 mg/mL) 111% (53–103) Platelet count 178×109 (150–400)× 109  PT 11.2 s (9.1–13.0)  APTT 26.4 s (22.9–34.5) Factor XIII 16% (70–140)  Factor V 155% (62–150)  Factor VIII 183% (50–149) Coagulation profile Factor chromogenic assay APTT, activated partial thromboplastin time; PT, prothrombin time. membranes since birth, but no major bleeding had been observed. There was no family history of any bleeding disorders. Bleeding and coagulation profiles were found to be normal except for the plasma factor XIII level, which was determined by a chromogenic method using a factor XIII assay kit and Siemens Berichrome F13 and was found to be low at 16% (table 1). Hence, based on history, examination and investigations, factor XIII deficiency was confirmed as the cause of ICH in this patient. The treatment for meningitis was continued for 10 days. The report of low factor XIII came after 7 days and simultaneously conservative management with cryoprecipitate was started. Investigations A CT scan of the head showed a left lobe hypodense lesion that was interpreted as an arachnoid cyst, and a right occipital lobe bleed was also observed. (figure 1) Differential diagnosis A 5-year-old child presented with complaints of fever, headache and irritability for 2 days with an episode of tonic seizures Figure 1 CT scan of the head showed left lobe hypodense lesion that was interpreted as an arachnoid cyst, and a right occipital bleed was also observed. 2 followed by a loss of consciousness. The examination revealed positive signs of meningeal irritation and upper motor neuron lesions. A common diagnosis of meningitis was suspected initially and the patient was managed accordingly; but later, GCS deteriorated. Other possible reasons for the findings included intracranial bleeding secondary to congenital bleeding disorders and vascular malformations. Workup was done showing normal haematological profile (platelet, PT, APTT) and ICH on CT scan of the head. Therefore, considering the normal haematological profile, factor XIII deficiency was suspected and it was confirmed on investigation. Treatment ICH was managed conservatively. Initially fresh frozen plasma was given, followed by cryoprecipitate 1 unit/10 kg transfusion every 4 weeks.11 Screening of family members revealed factor XIII deficiency in the younger female sibling also. Her levels were 10%, but she was asymptomatic, and therefore the family was counselled regarding the nature and mode of inheritance of the disease, its management and prognosis. Outcome and follow-up The patient is receiving cryoprecipitate transfusions, 1unit/10 kg monthly. She did not develop any neurological deficit secondary to the pressure effects of ICH and there was no other episode of ICH or bleeding from any other site at 10 months. Discussion Coagulation factors are one of the vital requirements for the maintenance of optimal haemostasis in the body. Factor XIII, also known as, fibrin stabilising factor, participates in the last step of the coagulation cascade. It stabilises the clot by crosslinking the fibrin mesh.12 Factor XIII deficiency is a rare bleeding disorder. It can be congenital or acquired. Congenital cases are present at the time of birth and have an autosomal recessive pattern of inheritance. On the other hand, some cases of factor XIII deficiency can be acquired secondary to chronic liver disease, chronic kidney disease, inflammatory bowel disease or certain malignancies such as myeloid leukaemia.13 Factor XIII deficiency clinically presents in many ways. It can present as early as in the neonatal stage. Almost 80% of cases present with prolonged bleeding from the umbilical cord.14 Other presentations include recurrent mucosal bleeding, ecchymoses, haemarthrosis and prolonged bleeding following trauma whereas ICH is a common fatal complication.15 Here, we present a case of a girl with ICH secondary to factor XIII deficiency. Our case is comparable to an earlier case report which also showed factor XIII deficiency with intraparenchymal haemorrhage in the right temporal-occipital region16 whereas, in our patient haemorrhage was (also) in the right occipital region without the involvement of the temporal region. Diagnosis of factor XIII is often missed, resulting in potentially fatal complications. The diagnosis is confirmed by decreased plasma levels of factor XIII with normal PT and APTT. Genetic mutation studies are a more reliable test for diagnosis but not available in many countries.17 Only a small quantity of template DNA is required in automated sequencing techniques. If a mutation in a family or a close relative is detected, diagnosis of patients or carriers can be simply done by PCR followed by sequencing of the amplified fragment or restriction enzyme digestion (PCR-restriction fragment length polymorphism (RFLP)) wherever the mutation creates a restriction enzyme site.18 Management is done with replacement therapy with factor XIII concentrate. If it is not available, fresh Ejaz M, et al. BMJ Case Rep 2019;12:e228682. doi:10.1136/bcr-2018-228682 BMJ Case Rep: first published as 10.1136/bcr-2018-228682 on 26 August 2019. Downloaded from http://casereports.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright. Rare disease Patient’s perspective I am surprised to know that my child is suffering from such a rare disease. My daughter’s doctor told me about the issues that may occur due to the illness and I need to get her transfused cryoprecipitate regularly and monitor her for bleeding from any site. Learning points ►► Rare congenital bleeding and coagulation disorders should always be considered when managing intracranial haemorrhage in the paediatric population. ►► Detailed history and conclusive clinical examination play a pivotal role in the early diagnosis and management of the life-threatening disease. ►► Screening of asymptomatic siblings should be done in factor XIII deficiency. frozen plasma or cryoprecipitates can also be used. Clinical trials have also shown the efficacy of purified plasma-derived factor XIII concentrate and recombinant factor XIII-A2 in treating these patients.19 Acknowledgements Authors would like to thank the family of the patient, doctors and paramedical staff of pediatrics department for their support in reporting this case. Contributors ME: written, reviewed, edited and final approval. AS: workup, literature search, writing of manuscript. NA and FT: literature search, writing of manuscript. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent for publication Parental/guardian consent obtained. Provenance and peer review Not commissioned; externally peer reviewed. References 1 Gober-Wilcox J, Crookston K. Factor XIII deficiency. http://www.​pathologyoutlines.​ com/​topic/​coag​ulat​ionfa​ cto​rXIIIdef.​html (Accessed 14 Mar 2019). 2 Dorgalalelh.A ASER, Tabiban.S SS, et al. Diagnosis, clinical manifestation and management of rare bleeding disorders in Iran. Hematology 2017;4:224–30. 3 Anwar M, Iqbal M, Ayyub M, et al. Prevalence of factor XIII deficiency in patients presenting with a bleeding disorder in Pakistan. J Thromb Haemost 2003;1:2693–4. 4 Naz.A JMY, Amnat.S DU. I, et al. Autosomal recessive inherited bleeding disorders in Pakistan; a cross-sectional study from selected regions, Orphanet. J.Rare Disease 2017;12:66. 5 Borhany M, Shamsi T, Fatima N, et al. Rare bleeding disorders are not so rare in Pakistan. J Hematol Thromb Dis 2013;2:122. 6 Inabal A. Factor XIII Deficiency - NORD (National Organization for Rare Disorders). 2019. https://​rarediseases.​org/​rare-d​ iseases/​factor-​xiii-​deficiency;​accessed 7 Tabibian S, Motlagh H, Naderi M, et al. Intracranial hemorrhage in congenital bleeding disorders. Blood Coagul Fibrinolysis 2018;29:1–11. 8 Alavi SER, 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. 9 Borhany M, Handrkova H, Cairo A, et al. Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations. Haemophilia 2014;20:568–74. 10 Ali M, Chang BA, Johnson KW, et al. Incidence and aetiology of bacterial meningitis among children aged 1-59 months in South Asia: systematic review and metaanalysis. Vaccine 2018;36:5846–57. 11 Bansal D, Oberoi S, Marwaha RK, et al. Approach to a child with bleeding in the emergency room. Indian J Pediatr 2013;80:411–20. 12 Coagulation-cascade-The-extrinsic-and-intrinsic-pathways-serve-to-activatecoagulation. 2018. https://www.r​ esearchgate.​net/​figure 13 NORD (National Organization for Rare Disorders), NORD (National Organization for Rare Disorders). Factor XIII Deficiency. 2018. https://​rarediseases.​org/​rare-​diseases/​ factor-​xiii-​deficiency/ (Accessed Oct 2018). 14 Vahid Golpayegani M, Behnia H, Akhgar Araghi M, et al. Factor XIII Deficiency, Review of the Literature and Report of a Case. J Compr Ped 2016;7:e30303. 15 Hartung HD. Pediatric Factor XIII Deficiency: clinical presentation. 2019. https://​ emedicine.​medscape.​com/​article/​960515-​treatment (Accessed Mar 2019). 16 Sawlani KK, Chaudhary SC, Roy A, et al. Factor XIII deficiency presenting with intracerebral bleed. BMJ Case Rep 2013;2013:bcr2012007303. 17 Karimi M, Peyvandi F, Naderi M, et al. Factor XIII deficiency diagnosis: Challenges and tools. Int J Lab Hematol 2018;40:3–11. 18 Dorgalaleh A, Tabibian S, Hosseini MS, et al. Diagnosis of factor XIII deficiency. Hematology 2016;21:430–9. 19 Jain S, Acharya SS. Management of rare coagulation disorders in 2018. Transfus Apher Sci 2018;57:705–12. Copyright 2019 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit https://www.bmj.com/company/products-services/rights-and-licensing/permissions/ BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission. Become a Fellow of BMJ Case Reports today and you can: ►► Submit as many cases as you like ►► Enjoy fast sympathetic peer review and rapid publication of accepted articles ►► Access all the published articles ►► Re-use any of the published material for personal use and teaching without further permission Customer Service If you have any further queries about your subscription, please contact our customer services team on +44 (0) 207111 1105 or via email at support@bmj.com. Visit casereports.bmj.com for more articles like this and to become a Fellow Ejaz M, et al. BMJ Case Rep 2019;12:e228682. doi:10.1136/bcr-2018-228682 3 BMJ Case Rep: first published as 10.1136/bcr-2018-228682 on 26 August 2019. Downloaded from http://casereports.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright. Rare disease