Factor XIII deficiency, a rare coagulopathy: case reports

intracraniana, sangramento do cordão umbilical no nascimento, hematoma, abortos espontâneos e menometrorragia. Objetivo: Ressaltar as particularidades desse distúrbio hemostático, assim como o manejo preconizado. Relato de caso: Os autores descrevem dois casos de deficiência de FXIII com diferentes manifestações hemorrágicas. O Caso 1 apresentou extenso hematoma espontâneo na coxa direita, enquanto o Caso 2 apresentou sangramento do cordão umbilical ao nascer e hemorragia intracraniana, necessitando de suporte hemoterápico. Ambos os pacientes apresentavam resultados normais nos testes laboratoriais de triagem para distúrbios de coagulação. As dosagens séricas de fatores de coagulação e de diagnóstico identificaram deficiência leve do Fator XIII no Caso 1 e grave no Caso 2. O paciente do Caso 1 está sob controle e acompanhamento regular, enquanto o paciente do Caso 2 está em regime profilático mensal com infusão de FXIII. Conclusão: O diagnóstico de Deficiência de FXIII em pacientes com sangramento importante deve ser considerado se os testes de coagulação de triagem forem normais. O Comitê Científico e de Padronização da Sociedade Internacional de Trombose e Hemostasia estabeleceu um algoritmo para o diagnóstico laboratorial e identificação de diferentes formas de deficiência FXIII. A determinação quantitativa da atividade do FXIII, ensaios antigênicos e estudos moleculares são necessários.


INTRODUCTION
2][3] Data from the Ministry of Health publication indicates that Brazil had 96 cases of FXIIID registered in 2022, a value that corresponds to a 2.97 % prevalence of rare coagulopathies in the country. 4In the previous year (2021), Brazil had 90 cases of FXIIID documented, representing a prevalence of 3.02% for rare coagulopathies in the country. 5It is crucial to underscore that, in this calculation, individuals diagnosed with hemophilia and von Willebrand disease have been excluded.FXIIID can present significant hemorrhagic manifestations -intracranial hemorrhage (IH), umbilical cord bleeding, hematoma, hemarthrosis, menorrhagia or minor bleeding, whose severity is inversely proportional to the individual plasma level of FXIII and determines repeat abortions. 62][3] FXIII-A is produced in the bone marrow, while FXIII-B is produced by hepatocytes. 1 Activated FXIII promotes stabilization and protection of newly formed fibrin against premature fibrinolysis, with an extremely relevant role in hemostasis, pregnancy maintenance, wound healing, and angiogenesis. 2,6IIID is due to a mutation in the gene that encodes the A subunit of FXIII or the B subunit.FXIII-A deficiency is more frequent and severe. 2 Over 200 genetic mutations have been recognized since the initial instance of inherited FXIII deficiency was documented.A newly discovered and probably pathogenic mutation in the F13A1 gene was reported, expanding the range of gene mutations associated with inherited FXIII deficiency. 7e diagnosis of FXIIID is difficult and complex, characterized by the normality of all screening coagulation tests (fibrinogen, prothrombin Time -PT, activated thromboplastin time -aPTT, thrombin time -TT, and bleeding time-TS) regardless of the severity of the hemorrhage, since FXIII acts in the final phase of fibrin formation and routine laboratory evaluation does not detect changes in the final phase of coagulation.The clinical hypothesis for FXIIID includes a well-detailed anamnesis with family history and physical examination, in addition to a healthcare professional familiar with rare bleeding disorders. 6,8Diagnostic confirmation is performed with specific qualitative and quantitative FXIII tests, antigenic assays, and molecular and genetic tests. 6,9,10Immuno Sorbent Assay), for laboratory diagnostic purposes. 2,8e CST is a qualitative test and a method widely used to screen this pathology, which consists of verifying the stability of the clot, in the urea or monochloroacetic acid solutions: at adequate levels of FXIII, the clot becomes insoluble, but if the factor is deficient, the fibrin network dissolves.The dissolution time is directly proportional to the concentration of FXIII in the plasma. 13e CST, despite being a low-cost and easy-toimplement test, has low sensitivity and non-standardized methodology, which can lead to an erroneous or late diagnosis in heterozygous patients with mild to moderate mutations. 13e the need for greater efforts to establish accurate diagnoses and improve information systems worldwide 9 .In accordance with that, maintaining an updated registry of patients with coagulopathies is crucial to understand the prevalence of the disease, its clinical aspects, treatment, and epidemiological surveillance.
In Brazil, the computerized system Hemovida Web  Furthermore, there is a scarcity of large-scale studies addressing the mortality rate in congenital FXIII deficiency, and there is also a notable absence of longterm follow-up studies to evaluate treatment outcomes.
This situation contributes to the underdiagnosis of the condition and underscores the necessity for a better understanding of the primary manifestations of FXIII deficiency 2,7,8.

Figure 1 :
Figure 1: Brain Nuclear Magnetic Resonance from Case 2. Subacute intraparenchymal hematoma measuring 5.5x4.5 cm located in the subcortical white substance, promoting mass effect with the erasure of the cortical grooves, partial collapse of the left lateral ventricle and deviation of the midline structures to right by 0.6 cm.

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Coagulopathies was developed to systematize this information, contributing to the effective monitoring, and planning of the National Program for Hereditary Coagulopathies.Moreover, the use of this system allows obtaining information about the quantity of coagulation factors dispensed to these individuals.The adherence and appropriate use of this system by healthcare services are essential for the success of the program, providing valuable data for decision-making in the Unified Health System (SUS) and government control agencies.17

Nonetheless, it is
acknowledged that the scarcity of this condition, combined with the limited awareness among healthcare professionals and technical challenges in both pre-and post-analytical phases, presents a substantial impediment to achieving an early diagnosis.
14ter the diagnosis of pregnancy.In this case, FXIII levels should be mantained between 3 IU/dL and 10 IU/ dL.This corresponds to an approximate dose of 250 IU of FXIII concentrate per week in the first 22 weeks of gestation.From then on, the dose should be increased to 500 IU per week until delivery.At the time of delivery, aiming to prevent hemorrhagic complications, the recommended dose becomes approximately 1,000 IU.6An observational study assessed the efficacy and safety of rFXIII in Italian patients with varying degrees of FXIII deficiency over nearly four years.It confirmed its effectiveness and emphasized the importance of initiating prophylaxis in cases of severe FXIII deficiency at birth or upon diagnosis. 3 to report two cases of Hereditary FXIIID with different clinical features, highlighting the characteristics of the mild and severe forms and discussing the need for investigation of this pathology in patients with unusual hemorrhagic conditions.CASE REPORT HU Rev. 2023; 49:1-6.DOI: 10.34019/1982-8047.2023.v49.43058Rodriguesetal.Coagulopatias raras.athoroughassessmentby the healthcare service, no underlying coagulation disorders were identified in her.During the anamnesis, he denied being a descendant of consanguineous relationships.The patient reported post-trauma splenectomy at the age of 16 without bleeding and tooth extraction without complications.In September 2020, he presented with an extensive spontaneous hematoma on the right thigh, which was reported after a minor bruise incurred from incidental contact with furniture.It was a trauma of a magnitude that would not typically warrant such a presentation in the absence of hemostatic disorders.During the episode, a cryoprecipitate transfusion was deemed necessary.The patient's physical examination was normal.The results of the coagulation screening tests are described in Table2.Serology for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) were performed with non-reactive results.There was a suspicion of FXIIID, which was confirmed after the measurement of FXIII (12.7% result), and the diagnosis of the mild form was defined.braininjury in a mild automobile accident, which determined nystagmus, aphasia, motor incoordination, and headache with a diagnosis of IH (Figure1) with hematoma formation in the cerebellar region.Duckert et al 11 made the first report involving FXIIID in 1960 and described a seven-year-old boy admitted to an emergency department due to ICH.The boy was born to consanguineous parents and had a history of bleeding from the umbilical stump (after 12 days of delivery), bruises, and disproportionate bleeding.11There is in the literature a time window of approximately eight years until the next publication and, until then, less than 100 case reports of congenital FXIIID were described in the MedLine database, via PubMed, evidencing the scarcity of literature involving this rare topic and the importance of registering new cases that can enrich the literature.consanguineousparentswith a history of recurrent IH.13The siblings' laboratory tests including coagulation, liver, and kidney function tests with 24-hour insoluble Clot Solubility Test (CST) were normal.Genetic evaluation detected the homozygous variant c.2150A>G, p.H717R, of the F13A1 gene in both children.The clinical HU Rev. 2023; 49:1-6.DOI: 10.34019/1982-8047.2023.v49.43058Rodriguesetal.Coagulopatias raras.manifestationsandgeneticanalyses of the children confirmed the diagnosis of FXIIID subunit A. The CST showed values within the normal range, evidencing the low sensitivity of the test for diagnostic confirmation. 10erature data demonstrate that FXIIID can generate spontaneous or disproportionate bleeding due to mild trauma, as described by Xu PP et al 13 , due to instability of the fibrin network, as occurred in Case 2 presented, an adult with extensive spontaneous hematoma in the thigh.Ejaz M et al 14 report the case of a 5-yearold girl who was admitted to the pediatric emergency14The occurrence of IH in this age group, without other predisposing factors, as