Coagulation Factor XIII Deficiency Research Articles

A case of acquired coagulation factor XIII deficiency induced by inhibitor

A case of acquired coagulation factor XIII deficiency induced by inhibitor

Evaluation of the Effect of Regular Administration of Coagulant Factors on the Joint Pain Level and Dimensions of the Quality of Life of the Patients Suffering from Some Bleeding Disorders (BDs)

Background: Blood coagulation is a process that prevents blood loss. Lack of coagulation factors (inherited or acquired) disrupts this path. The prevalence of coagulant deficiency including VIII and XIII factors in Sistan and Baluchistan province is higher than in other parts of Iran. This study aimed to investigate the condition of patients suffering from some bleeding disorders (BDs) in terms of regular coagulant takes and their effects on quality of life.
 Methods: Our cross-sectional study was descriptive-analytical. Thirty-five BD patients suffering the blood coagulant deficiency enrolled, and were sorted into 5 groups.
 Results: The mean (±SD) age in the hemophilia A and B groups were (16.25 ± 8.15), and (8.14 ± 3.9), and other coagulation factor deficiencies including VWF, XIII, and IX were (15.1 ± 7.8), (15.5 ± 2.4), and IX (19.0 ± 11.5) respectively. The quality of life in group A (81.3 ± 14.9) compared to groups B (50 ± 0.25) and IX (47.5 ± 24.1) had a significant difference (p value < 0.05). In addition, there was a significant difference in group XIII (79.2 ± 29.2) compared to groups B (50 ± 0.25) and IX (47.5 ± 24.1) (p value < 0.05). Generally, the quality of life was higher in women (10 people) (72.5 ± 26.2) than in men (26 people) (61.1 ± 24.5). Furthermore, the Visual analog scale for pain in group A (1.3 ± 0.4) had a significant difference compared to group B (3.5 ± 0.43), IX (7.8 ± 0.9), XIII (0.4 ± 4.3) and VWF (3.2 ± 0.38) (p value < 0.05).
 Conclusion: In sum, patients with hemophilia A and coagulation factor XIII deficiency had low levels of joint pain and a high level of quality of life dimensions.

Gene diagnosis of a family with coagulation factor ⅩⅢ deficiency caused by large deletion of F13A1 gene

Gene diagnosis of a family with coagulation factor ⅩⅢ deficiency caused by large deletion of F13A1 gene

Coagulation factor XIII deficiency – Report of a newborn F13A1 Val34Leu polymorphism carrier

Coagulation factor XIII deficiency – Report of a newborn F13A1 Val34Leu polymorphism carrier

The Role of Different Matrixin Gene Expressions on Cerebral Bleeding among Patients with Deficiency of Coagulation Factor XIII.

Enzymes of the matrixin family could be seen as a critical determinant in the breakdown of the extracellular matrix, cell membrane, and tissue regeneration and are interned in the process of brain bleeding. On the other hand, coagulation factor XIII deficiency is a sporadic hemorrhagic disease with an estimated prevalence of 1 in 1-2 million people. Cerebral hemorrhage is the leading cause of death in these patients. This study investigated the relationship between the expression of matrix metalloproteinase 9 and 2 genes with cerebral hemorrhage in these patients. For this purpose, in this case-control study, by examining the clinical and general findings of the studied patients, the Q-Real-time RT-PCR method was used to quantitatively examine the mRNA levels of matrix metalloproteinase 9 and 2 in 42 patients with hereditary deficiency of coagulation factor XIII, including two groups with and without a history of cerebral hemorrhage (case and control groups, respectively). A comparative method (2-ΔΔCT) was used to check the expression level of the target genes. The GAPDH gene expression levels were used to standardize the expression of the measured matrix metalloproteinase genes. The results showed that bleeding from the umbilical cord was the most common clinical symptom among all patients. High levels of MMP-9 gene expression were observed in 13 patients of the case group (69.99%) and three patients of the control group (11.9%). which showed a significant difference (CI: 2.77-95.3, P=0.001) Patients with coagulation factor XIII deficiency show a wide range of clinical symptoms crucial in screening and diagnosing this group of patients. Based on the results of this study, it seems that the increased expression of the MMP-9 gene is due to polymorphism or inflammation related to the pathogenesis of cerebral hemorrhage in this category of patients. It may be conceivable to diminish this impact by utilizing MMP-9 inhibitors and offering assistance to diminishes these patients' hospitalization and passing rates.

Important roles of the human leukocyte antigen class I and II molecules and their associated genes in the autoimmune coagulation factor XIII deficiency via whole-exome sequencing analysis.

Autoimmune coagulation factor XIII deficiency is a bleeding disorder caused by the formation of autoantibodies against the coagulation factor XIII (FXIII); however, the molecular mechanism underlying this process is unknown. Therefore, in the present study, we aimed to elucidate this mechanism by performing whole-exome sequencing analysis of 20 cases of autoimmune FXIII deficiency. We identified approximately 21,788-23,916 variants in each case. In addition to their ability to activate T cells, present antigens, and immune tolerance, the candidate alleles were further narrowed down according to their allelic frequencies and the magnitude of damage caused by the substitution of amino acids. After selecting 44 candidate alleles, we investigated whether they were associated with the FXIII inhibitory titers and/or the anti-FXIII autoantibodies. We found that two polymorphisms whose variant allele frequencies were significantly lower in the patients tended to decrease FXIII inhibitory titers as the number of variant alleles increased. We also found that five polymorphisms whose variant allele frequencies were significantly higher in the patients tended to increase the levels of the anti-FXIII autoantibodies as the number of variant alleles increased. All of these polymorphisms were found in the human leukocyte antigen (HLA) class I and II molecules and their associated genes. In particular, the HLA class II molecule and its associated genes were found to be involved in the presentation of foreign antigens as well as the negative regulation of the proliferation of T-cells and the release of cytokines. Polymorphisms in the HLA class II molecules and the cytotoxic T lymphocyte antigen 4 have been reported to be associated with the development of autoantibodies in acquired hemophilia A. Therefore, we hypothesized that these polymorphisms may be associated with the development of autoantibodies in autoimmune FXIII deficiency.

Congenital Coagulation Factor XIII Deficiency Revealed by Convulsion: A Case Report

Factor XIII deficiency is a rare inherited disease, with a particularly high risk of intracerebral hemorrhage. We report the case of a newborn who was suspected to have a coagulation disorder at birth, due to an intracerebral hemorrhage. A quantitative dosage of factor XIII was requested but the usual coagulation tests (thromboplastin, thrombokinase, fibrinogen) were normal. Because of unavailability of specific treatment with factor XIII concentrate, the patient was treated with fresh frozen plasma. The initial dose was for normalizing factor XIII; subsequent monthly doses were designed for preventing the occurrence of serious bleeding.

A novel Cys328-terminator mutant implicated in severe coagulation factor XIII deficiency: a case report

BackgroundFactor XIII (FXIII) deficiency is an extremely rare bleeding disorder that is commonly due to mutations in the FXIIIA subunit gene (F13A1), and it has been reported to have a prevalence of one per 2 million. We describe a new genetic variant in the F13A1 gene that caused a patient to suffer from lifelong hemorrhagic diathesis.Case presentationWe evaluated a 20-year-old female with umbilical cord bleeding after birth, an intracerebral hemorrhage at age 6, and other bleeding episodes, including hematuria and cephalohematoma, who suffered from a lifelong hemorrhagic diathesis. The clot solubility test showed that the clot of the patient was dissolved in urea solution at 10 h. Genetic testing identified a novel homozygous mutation, c.984C > A(p. Cys328stop), resulting in a premature stop codon in exon 8 of the F13A1 gene. The results obtained with ClusterX software showed that Cys328 of exon 8 in the F13A1 gene is highly conserved among species.ConclusionWe reported a novel homozygous mutation in the F13A1 gene in a factor XIII (FXIII)-deficient patient, which adds a new point mutation to the mutant library. In this paper, we discuss other aspects of the disease, including laboratory examination, homogeneous sequence alignment and molecular modeling.

Spontaneous intracranial hypotension complicated by refractory subdural hematomas in a patient with coagulation factor XIII deficiency

Abstract Spontaneous intracranial hypotension (SIH) is often secondary to an occult cerebrospinal fluid (CSF) leak in the neuroaxis. It is sometimes associated with chronic subdural hematomas (SDH). The authors present the case of a 61 year-old male who presented with SIH from an occult CSF leak and complicated by refractory SDH. The patient underwent treatment for SIH with multiple epidural blood patches, hydration and bed rest. In addition, he underwent evacuation of his SDH twice, once via burr hole drainage and the second via craniotomy. Once the diagnosis of coagulation factor XIII (CFXIII) deficiency was made, the patient was treated with recombinant factor XIII followed by an epidural blood patch. He subsequently made a complete recovery. In this report, the authors propose management strategies for treating patients with SIH complicated by refractory SDH and coagulopathies by reviewing the literature.

繰り返す出血症状にも関わらず高齢で診断された血液凝固第XIII因子欠損症の1例(Undiagnosed coagulation factor XIII deficiency: an elderly case with repeated bleeding)

要旨血液凝固第XIII因子（Factor XIII: F XIII）欠損症は易出血性を呈する稀な疾患であるが，一般的なスクリーニング検査では正常を示すことが多い。F XIII活性測定でのみ診断可能なため，見落とされやすい。今回，筋肉内血腫の突然発症を契機に診断したF XIII欠損症の1例を報告する。68歳の女性。外傷などの誘因はなく左前胸部の腫脹・疼痛が突然出現した。CT検査で左大胸筋内血腫を認め，責任血管の塞栓術を施行した。患者は過去に，大量出血を繰り返す既往があったが，止血に関わるスクリーニング項目は正常で日常的な出血症状も認めないため，本症を診断されることなく未治療であった。今回我々は，過去の病歴から出血傾向を認識し精査することでF XIII欠損症を診断した。F XIII補充療法を開始し，以後再出血なく経過した。F XIII欠損症は致死的出血を来し得る疾患である。しかし出血傾向に気づけば，診断すること自体は難しくない。止血や出血予防にF XIII補充が著効するため，早期診断が望まれる。

Pathogenicity analysis of variations and prenatal diagnosis in a hereditary coagulation factor XIII deficiency family

ABSTRACTObjectives: Prenatal diagnosis (PND) procedure is urgent to be established for timely management and fatal consequence prevention of factor XIII deficiency (FXIIID), and variations data among Chinese are very scanty. We aimed to find a novel mutation among Chinese and establish a rapid and precise PND procedure with pathogenicity analysis to contribute to the prevention of postpartum hemorrhage in pregnant women and central nervous system bleeding in newborns.Methods: FXIIID was diagnosed by qualitative and quantitative tests of clot solubility test and enzyme-linked immunosorbent assay, respectively. Variations were detected by direct sequencing of F13A and F13B genes in the pedigree and the unborn fetus. Pathogenicity assessment of variations was based on American College of Medical Genetics and Genomics Guidelines.Results: Ten variants in the F13A gene including a novel missense mutation in exon 10, a nonsense mutation in exon 4, a missense mutation in exon 12, 2 missense mutations in exon 14, 3 polymorphisms in intron 10, 2 polymorphisms in intron 14 were detected. Two variants in the F13B gene including a polymorphism in 3’UTR and a synonymous mutation were detected. The compound heterozygous mutations of the nonsense mutation and a novel missense mutation of the F13A gene caused the deficiency in proband, and the fetus which was evaluated to be unaffected by PND was born successfully and the results were verified by follow-up visits.Discussion: We first established the PND procedure with pathogenicity assessment in FXIIID patients. The F13A gene mutations’ spectrum of the Chinese Han population was enriched.

Characterization of a novel large deletion caused by double-stranded breaks in 6-bp microhomologous sequences of intron 11 and 12 of the F13A1 gene.

Coagulation Factor XIII is a heterotetrameric protransglutaminase which stabilizes preformed fibrin clots by covalent crosslinking them. Inherited homozygous or compound heterozygous deficiency of coagulation Factor XIII (FXIII) is a rare severe bleeding disorder affecting 1 in 2 million individuals. Most of the patients with inherited FXIII deficiency described in the literature carry F13A1 gene point mutations (missense, nonsense and splice site defects), whereas large deletions (>0.5 kb in size) are underrepresented. In this article we report for the first time the complete characterization of a novel homozygous F13A1 large deletion covering the entire exon 12 in a young patient with a severe FXIII-deficient phenotype from France. Using primer walking on genomic DNA we have identified the deletion breakpoints in the region between g.6.143,016–g.6.148,901 caused by small 6-bp microhomologies at the 5´ and 3´ breakpoints. Parents of the patient were heterozygous carriers. Identification of this large deletion offers the possibility of prenatal diagnosis for the mother in this family who is heterozygous for this deletion.

Association between expression of MMP-2 and MMP-9 genes and pathogenesis of intracranial hemorrhage in severe coagulation factor XIII deficiency

BackgroundMatrix metalloproteinases (MMPs) play a key role in the degradation of basement membrane and extracellular matrix in tissue remodeling, and are involved in pathogenesis of intracranial hemorrhage (ICH). Despite replacement therapy, ICH is by far the main cause of bleeding-related death among patients with severe factor XIII deficiency (FXIIID). The aim of this study is to evaluate the association between MMP-2 and MMP-9 genes expression and ICH in these patients.Materials and methodsQuantitative real-time reverse transcription (RT)-PCR assay was used to quantify MMP-2 and MMP-9 mRNAs in 42 specimens of patients with FXIIID including 18 case and 24 control groups. The comparative method of relative quantification (2–Delta-Delta-cCt) was utilized to analyze the expression level of each target gene. The expression level of glyceraldehyde-3-phosphate dehydrogenase was used to standardize the expression levels of MMPs.ResultsUmbilical bleeding was the most common clinical manifestation among all patients. We found expression upregulation of MMP-9 gene in 13 patients (72.2%) in case and 3 patients (12.5%) in control group, indicating a significant difference between cases and controls for MMP-9 gene expression level (P = 0.001%)(CI 2.8–95.3).ConclusionsOur patients present with a wide spectrum of clinical symptoms, which are important in screening and diagnosis of patients with FXIIID. We hypothesized that the overexpression of MMP-9 due to polymorphisms or inflammation was associated with pathogenesis of ICH in FXIIID. This effect can be attenuated by nonspecific MMP inhibition to reduce hospitalization and death rates in these patients.

Association Between Val34Leu Polymorphism and Risk of Umbilical Cord Bleeding in Severe Congenital Coagulation Factor XIII Deficiency in Southeast of Iran

1Genetic Researcher Center in Non-Communicable Disease, Zahedan University of Medical Sciences, Zahedan, IR Iran2Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, IR Iran3Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations

Deficiency of coagulation factor XIII (FXIII) belongs to the rare bleeding disorders and its incidence is higher in populations with consanguineous marriages. The aims of this study were to characterize patients and relatives from seven families with suspected FXIII deficiency from Pakistan and to identify the underlying mutations. As a first indicator of FXIII deficiency, a 5M urea clot solubility test was used. Plasma FXIII A- and B-subunit antigen levels were determined by ELISA. FXIII activity was measured with an incorporation assay. Sequencing of all exons and intron/exon boundaries of F13A was performed, and a novel splice site defect was confirmed by RT-PCR analysis. Genetic analysis revealed six different mutations in the F13A gene. Two splice site mutations were detected, a novel c.1460+1G>A mutation in the first nucleotide of intron 11 and a previously reported c.2045G>A mutation in the last nucleotide of exon 14. Neither of them was expressed at protein level. A novel nonsense mutation in exon 4, c.567T>A, p.Cys188X, was identified, leading in homozygous form to severe FXIII deficiency. Two novel missense mutations were found in exons 8 and 9, c.1040C>A, p.Ala346Asp and c.1126T>C, p.Trp375Arg, and a previously reported missense mutation in exon 10, c.1241C>T, p.Ser413Leu. All patients homozygous for these missense mutations presented with severe FXIII deficiency. We have analysed a cohort of 27 individuals and reported four novel mutations leading to congenital FXIII deficiency.

The Massive Bleeding after the Operation of Hip Joint Surgery with the Acquired Haemorrhagic Coagulation Factor XIII(13) Deficiency: Two Case Reports

Two women, aged 81 and 61, became haemorrhagic after surgery. Their previous surgeries were uneventful with no unexpected bleeding observed. Blood tests prior to the current surgeries indicated normal values including those related to coagulation. There were no problems with the current surgeries prior to leaving the operating room. At 3 hours after the surgery, the 81-year-old patient had an outflow of the drain at 1290 grams and her blood pressure decreased. She had disseminated intravascular coagulation (DIC). The 61-year-old woman had repeated haemorrhages after her current surgery for a long time. Their abnormal haemorrhages were caused by a deficiency of coagulation factor XIII(13). The mechanism of haemorrhagic coagulation factor XIII(13) deficiency is not understood, and it is a rare disorder. The only diagnostic method to detect this disorder is to measure factor XIII(13) activity in the blood. In this paper, we used Arabic and Roman numerals at the same time to avoid confusion of coagulation factor XIII(13) with coagulation factor VIII(8) that causes hemophilia A.

Acquired deficiency of coagulation factor XIII—possible evidence for a new link between coagulation and infection from a case

Dear Editor,We would like to present a case with a parainfectious dropof factor XIII (FXIII) pointing to a so far not described linkbetween coagulation and infection. A 3-year-old girl wasadmitted to our clinic due to acute joint swelling and hae-matomas during an uncomplicated infection of the upperrespiratory tract lasting since 3 weeks. The child has so farhad a normal history with respect to alimentation and de-velopment and has had the usual vaccinations. On admis-sion, the patient had haematomas at her right cheek, rightelbow andabove both heels anda mild hepatosplenomegaly.By clinical evaluation and laboratory results (Table 1), aninfection of unknown origin was suspected, presenting witha mild acute phase reaction (elevated CRP, immunoglobu-lins and fibrinogen) and signs of a mild coagulation activa-tion (indicated by slightly elevated D-dimers). A screeningshowed that the patient has already had HHV-6, HSV 1,VZV and RSV infection (IgG positive, IgM negative) andprotection from vaccination against mumps, measles andrubella. An acute infection by CMV, adenovirus, RSV, my-coplasma, cocksackie, ECHO, enterovirus, Parvo B19,EBV, Yersinia, Borrelia, Salmonella and Streptococcus pyo-genes was excluded. FXIII was very low and was the onlysignificant deviation in the coagulation system (Table 1).After a few days, the patient’s condition improved undersymptomatic therapy and could be discharged. Two weekslater, a control check-up in the outpatients’ clinic showed agood clinical recovery and normalisation of the laboratoryresults. The usual causes for FXIII deficiencies like geneticdefects[1],inhibitors, andunderlying diseases like Henoch–Schoenlein purpura, Crohn’s disease or ulcerative colitis[2-4] can be excluded by the clinical and laboratory find-ings. No interventions had taken place, which would poten-tially explain the transient deficiency. Also, it seems lessprobable that a cut coagulation activation lead to consump-tion of FXIII, as D-dimers were only slightly elevated and

Hémorragie intracérébrale spontanée secondaire à un déficit congénital en facteur XIII

Deficiency of coagulation factor XIII is a rare anomaly. The risk of intracranial haemorrhage is particularly high at any age, either spontaneously or during minor trauma. We report a case of spontaneous intracerebral haemorrhage in a child carrying a known deficiency of factor XIII.

Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function

Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer. We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations. All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation. The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms.

Erfassung eines Faktor-XIII-Mangels mit der Thrombelastometrie

While undergoing Whipple's operation (pancreaticoduodenectomy) a patient developed diffuse bleeding and an unexpectedly high blood loss. An intraoperatively performed thrombelastometry with ROTEM (Pentapharm, Munich, Germany) showed an aprotonin-resistant mild fibrinolysis and suggested the presence of an isolated deficiency of coagulation factor XIII. This was confirmed by a second thrombelastometry, where no lysis was seen after in vitro substitution of factor XIII. After administration of 1250 IU factor XIII concentrate the diffuse bleeding ceased and further substitution of coagulation factor concentrates or fresh frozen plasma was not necessary. A postoperatively performed analysis confirmed the factor XIII deficiency (52%).