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Introduction: In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2‐antiplasmin (α2AP) deficiency. Aim: To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). Methods: A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. Results: We included 158 consecutive patients; mean ISTH‐BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5–79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97–131) and median α2AP activity of 112% (IQR = 103–119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH‐BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH‐BAT scores. Conclusion: In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value. [ABSTRACT FROM AUTHOR]

The prevalence and clinical significance of heterozygous factor XIII (FXIII) deficiency has long been debated, with controversial reports emerging since 1988. In the absence of large epidemiologic studies, but based on a few studies, a prevalence of 1 per 1,000 to 5,000 is estimated. In southeastern Iran, a hotspot area for the disorder, a study of more than 3,500 individuals found an incidence of 3.5%. Between 1988 and 2023, a total of 308 individuals were found with heterozygous FXIII deficiency, of which molecular, laboratory, and clinical presentations were available for 207 individuals. A total of 49 variants were found in the F13A gene, most of which were missense (61.2%), followed by nonsense (12.2%) and small deletions (12.2%), most occurring in the catalytic domain (52.1%) of the FXIII-A protein and most frequently in exon 4 (17%) of the F13A gene. This pattern is relatively similar to homozygous (severe) FXIII deficiency. In general, heterozygous FXIII deficiency is an asymptomatic condition without spontaneous bleeding tendency, but it can lead to hemorrhagic complications in hemostatic challenges such as trauma, surgery, childbirth, and pregnancy. Postoperative bleeding, postpartum hemorrhage, and miscarriage are the most common clinical manifestations, while impaired wound healing has been rarely reported. Although some of these clinical manifestations can also be observed in the general population, they are more common in heterozygous FXIII deficiency. While studies of heterozygous FXIII deficiency conducted over the past 35 years have shed light on some of the ambiguities of this condition, further studies on a large number of heterozygotes are needed to answer the major questions related to heterozygous FXIII deficiency. [ABSTRACT FROM AUTHOR]

Acquired factor FXIII (FXIII) deficiency can be immune- or non-immune mediated and may cause severe bleeding symptoms. The incidence of acquired FXIII deficiency and its etiology in patients with multiple myeloma (MM) are poorly understood. To assess FXIII levels and the balance of fibrinolysis in newly diagnosed, untreated MM and monoclonal gammopathy of undetermined significance (MGUS) patients. FXIII activity, mixing studies, FXIII-A 2 B 2 antigen, total FXIII-B antigen were measured in platelet-poor plasma from 17 untreated MM patients, 33 untreated MGUS patients, and 30 age and sex-matched healthy controls. Besides routine laboratory measurements, the balance of coagulation and fibrinolysis was evaluated using quantitative fibrin monomer (FM) test, thrombin-antithrombin assay, α2-antiplasmin activity, plasmin-α2-antiplasmin (PAP) complex, D-dimer, plasmin generation assay, clot lysis assay, and ClotPro-TPA test. FXIII-A 2 B 2 levels were significantly lower in MM patients compared to controls [median (IQR):14.6 (11.2–19.4) vs. 21.8 (17.1–26.4) mg/L, p = 0.0015], whereas total FXIII-B did not differ between groups. Decrease in FXIII activity was parallel to the decrease in FXIII-A 2 B 2. An immune-mediated inhibitory mechanism was ruled out. Free/total FXIII-B was significantly higher in MM patients compared to MGUS and healthy controls, suggesting an etiology of FXIII-A consumption. In MM and MGUS patients, FM, D-dimer, and PAP complex were significantly elevated compared to controls, indicating hypercoagulability and ongoing fibrinolysis. Low FXIII levels due to consumption were observed in MM patients at diagnosis. Hypercoagulability and ongoing fibrinolysis were detected in MM and MGUS, indicating that a disturbed hemostasis balance is already present in the latter benign condition. • Causes of acquired FXIII deficiency: immune-mediated inhibition, non-immune-mediated consumption, or decreased synthesis. • Low FXIII levels, as a result of FXIII consumption, were found in newly diagnosed MM patients. • Hypercoagulability and disturbed fibrinolytic balance were detected in MM and in MGUS. • In MM and MGUS, hemostasis alterations are already evident at presentation, calling for awareness during monitoring. [ABSTRACT FROM AUTHOR]

Despite the early discovery of factor XIII (FXIII) in 1944, the diagnosis of FXIII deficiency was not made until 1960, after all the other coagulation factor deficiencies, most likely due to the normality of routine coagulation testing in FXIII deficiency. Although the first case was detected by the clot solubility test and this test has long since been used to detect FXIII deficiency, the test is no longer recommended by experts. Over the past 60 years, knowledge about FXIII deficiency has expanded considerably, between 1992, when the first variant was identified, and 2022, 197 mutations have been reported. Almost all missense mutations have a similar effect on FXIII, leading to instability and faster degradation of mutant FXIII protein. Therapeutic options have evolved from historical fresh frozen plasma (FFP), old plasma, whole blood, and cryoprecipitate, to plasma-derived and recombinant FXIII concentrates, respectively available since 1993 and 2012. These concentrate products were respectively approved by the Food and Drug Administration in 2011 and 2013. This historical review covers various aspects of FXIII related disorders, including the discovery of the FXIII, associated disorders, molecular basis, diagnosis, and treatment of FXIII deficiency. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify clinical factors associated with progressive facial swelling after orthognathic surgery. Patients diagnosed with jaw deformities and undergoing orthognathic surgery were retrospectively evaluated, and those with surgical site infection, Le Fort I osteotomy, or genioplasty only were excluded. Facial swelling volume was calculated by comparing facial volume preoperatively and three days postoperatively using 3D images and image analysis software (VECTRA H2). FXIII was measured within three days after surgery in only patients with unexplained postoperative bleeding or hematoma. The correlation between facial swelling volume and clinical factors was statistically analyzed. Facial swelling volume was examined in 78 patients. Univariate analysis showed a significant difference between facial swelling volume (mean = 41.6 cm3) and operation time (mean = 209.3 min, r = 0.283, p = 0.012), ΔHb level (mean = 1.18 g/dL, r = 0.235, p = 0.039), as well as decreased factor XIII activity (mean = 75.3%, p = 0.012). Multivariate analysis showed a significant difference between facial swelling volume and FXIII deficiency (standard error = 6.44, p = 0.031).Progressive facial swelling immediately after orthognathic surgery may be due to factor XIII deficiency. [ABSTRACT FROM AUTHOR]

Factor XIII participates in the final stage of coagulation. It is made up of two components: two catalytic A subunits, and two carrier B subunits, it is activated in the presence of the fibrin, thrombin and Ca2 clot, giving rise to the cross-linking of fibrin fibers. Patients with congenital FXIII deficiency present bleeding hours or days after suffering the traumatic event. The objective is to present the clinical course of a neonate with massive hemorrhage from the umbilical cord due decreased factor XIII activity. This clinical case is about full-term male, son of parents without consanguinity, who at 8 days of life was admitted with hypovolemia and severe anemia due to profuse bleeding from the umbilical cord. His basic coagulation profile was normal. Factor XIII activity was found to be decreased, so fresh frozen plasma was transfused to control the bleeding. It is a rare disease. It is characterized by umbilical cord bleeding, depending on the level of factor XIII activity, will be the intensity of bleeding. Molecular biology has identified about 150 mutations, between chromosomes 6 p25-25 and 1 q32-32. Substitution treatments is with FXIII concentrates. It is presence must be considered in the presence of a neonate with umbilical cord bleeding and normal coagulation tests. Determine Factor XIII activity, antigenic levels and molecular biology. [ABSTRACT FROM AUTHOR]

Purpose: The study aimed to explore the molecular defects underlying FXIII deficiency. Materials and Methods: Sixteen unrelated cases were enrolled based on the indication of the urea clot solubility test and Factor XIII-A antigen levels. Cases were further subjected to targeted next-generation sequencing (custom gene panel: F7, F8, VWF, F9, F13A1, F13B). The pathogenic/likely pathogenic variants were validated by Sanger sequencing in the patients and family members. Results: Mean age of referral to our center was 27.2 years (8 week-67 years). Consanguinity was found in only one of the 16 cases and 9 cases presented in infancy. The most common symptoms were skin bleeds (69%) and umbilical cord bleed (50%). The clot solubility test was positive in 12, inconclusive in 1, and normal in 3. Mean FXIII-A levels were 15.7 IU/dL (range 0.6 to 49.5 IU/dL). Pathogenic/likely pathogenic variants in F13A1 were found in 11 (69%). Nine cases (82%) were homozygous, and two were compound heterozygous. Total eleven variants were found of which four were missense (c.1226G>A; c.998C>T; c.631G>C; c.2134A>C); three deletion (c.521delG; c.742delA; c.1405_1408delCAAA); two nonsense (c.1112G>A; c.1127G>A) and two splice site (c.1909-1G>C; c.2045G>A). No probably pathogenic variant was found in the F13B. Conclusion: Inherited FXIII deficiency with bleeding is associated with genetic defects in predominantly the F13A1 gene. A variety of variants were seen in this cohort. A nonsense variant c.1127G>A found in three of our cases seems to be recurrent. This data will contribute to designing functional studies and antenatal testing in affected families. [ABSTRACT FROM AUTHOR]

Pediatric stroke can be either hemorrhagic or ischemic, with ∼5% of hemorrhagic strokes being caused by genetic coagulopathies. We report an 8 mo old presenting with a hemorrhagic stroke caused by severe Factor XIII deficiency (OMIM # 613225) in whom rapid whole-genome sequencing identified a novel variant in the F13A1 gene c.1352_1353delAT (p.His451ArgfsTer29).

Japanese Brown cattle are the second most popular Wagyu breed, and the Kumamoto sub‐breed shows better daily gain and carcass weight. One of the breeding objectives for this sub‐breed is to reduce genetic defects. Chondrodysplastic dwarfism and factor VIII deficiency have been identified as genetic diseases in the Kumamoto sub‐breed. Previously, we detected individuals in the Kumamoto sub‐breed with causative alleles of genetic diseases identified in Japanese Black cattle. In the current study, 11 mutations responsible for genetic diseases in the Wagyu breeds were analyzed to evaluate the risk of genetic diseases in the Kumamoto sub‐breed. Genotyping revealed the causative mutations of chondrodysplastic dwarfism, factor XI deficiency, and factor XIII deficiency and suggested the appearance of affected animals in this sub‐breed. DNA testing for these diseases is needed to prevent economic loses in beef production using the Kumamoto sub‐breed. [ABSTRACT FROM AUTHOR]

Abstract Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60–70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.

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.

Factor XIII deficiency is a rare, potentially life-threatening bleeding disorder. While congenital disease is inherited in an autosomal recessive manner, acquired factor deficiency can be associated with autoimmune disease or malignancy. Clinical spectrum may range from mucocutaneous bleeding to intracerebral bleeding. This case describes a 21-year-old woman who initially presented with low grade fever and cervical lymphadenopathy. In two weeks’ time she developed bilateral spontaneous subdural haemorrhages along with bilateral small and large joint arthritis. Investigations revealed an acquired factor XIII deficiency, positive antinuclear antibodies (ANA) titer and Coomb’s positive autoimmune hemolytic anaemia and was subsequently diagnosed to have systemic lupus erythematosus. Intracerebral bleeding due to acquired factor XIII deficiency is a rare initial presentation of systemic lupus erythematosus in literature.

Background: Factor XIII (FXIII) deficiency is a rare yet profound coagulopathy. FXIII plays a pivotal role in hemostasis, and deficiencies in this factor can precipitate unchecked or spontaneous hemorrhaging. Immunological assays for detecting FXIII inhibitors are indispensable for diagnosing acquired FXIII deficiency; however, the availability of suitable testing facilities is limited, resulting in prolonged turnaround times for these assays., Case Summary: In this case study, a 53-year-old male devoid of significant medical history presented with recurrent intracranial hemorrhages and a hematoma in the right hip. Subsequent genetic analysis revealed a homozygous mutation in the ACE gene, confirming the diagnosis of acquired FXIII deficiency., Conclusion: This case underscores the significance of considering acquired deficiencies in clotting factors when evaluating patients with unexplained bleeding episodes., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60–70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency. [ABSTRACT FROM AUTHOR]

Background: Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder with defects in the F13A1 or F13B genes. Here, we report a case of congenital FXIII deficiency patient who presented with traumainduced intramuscular hemorrhage accompanied with transient platelet dysfunction with increased endogenous thrombin potential (ETP). Methods: FXIII antigen and activity, F13A1 gene sequencing, and thrombin generation assay were measured. Results: The diagnosis of FXIII deficiency was confirmed by a double heterozygous mutation of the F13A1 gene and decreased levels of FXIII antigen and activity. Platelet dysfunction caused by an antiplatelet drug was revealed in both platelet aggregation test and PFA-100. After a bleeding event, the PFA-100 results returned to normal and the thrombin generation assay in patient's plasma showed a higher ETP than normal. Conclusions: This increase in ETP may protect against bleeding and may explain why some patients show only a mild bleeding tendency despite undetectable FXIII activity. [ABSTRACT FROM AUTHOR]

Factor XIII (FXIII) deficiency is a rare but serious coagulopathy. FXIII is critical in blood coagulation, and FXIII deficiencies can lead to uncontrolled or spontaneous bleeding. FXIII deficiencies can be congenital or acquired; acquired FXIII deficiency can be categorized as autoimmune and non-autoimmune. Immunological tests to measure FXIII inhibitors are required to diagnose acquired FXIII deficiency; however, appropriate test facilities are limited, which increases the turnaround time of these tests. In the case of critical bleeding, delayed test results may worsen prognosis due to delayed treatment. Here, we report a case of acquired FXIII deficiency, followed by a review of FXIII deficiency cases in Japan. We performed a systematic review to investigate the present conditions of the diagnosis and treatment of FXIII deficiency, including the measurement of FXIII inhibitors in Japan. FXIII inhibitor testing was only performed in 29.7 of acquired FXIII deficiency cases. Clinical departments other than internal medicine and pediatrics were often involved in medical treatment at the time of onset. Therefore, it is important for doctors in clinical departments other than internal medicine and pediatrics to consider FXIII deficiency and perform FXIII inhibitor testing when examining patients with prolonged bleeding of unknown cause or persistent bleeding after trauma. [ABSTRACT FROM AUTHOR]

Ana Marco,1,2 Pascual Marco1– 3 1Thrombosis and Hemostasis Department, Hematology Service, University General Hospital in Alicante, Alicante, Spain; 2Biomedical Health Research Institute, University General Hospital in Alicante, Alicante, Spain; 3Department of Clinical Medicine, Miguel Hernández University, Alicante, SpainCorrespondence: Ana MarcoUniversity General Hospital in Alicante, Pintor Baeza 12, Alicante, 03010, SpainTel +34 965913863Fax +34 965913869Email marco_anaric@gva.esAbstract: Autoimmune acquired factor XIII (FXIII) deficiency is a rare disorder characterized by severe spontaneous hematomas and autoantibodies against FXIII. High mortality rates have been reported (18% within a year of diagnosis). We present a 70-year-old patient with recurrent muscular hematomas. The basic hemostasis study and the coagulation factors were within normal ranges. The aggregation platelet study was also normal and von Willebrand disease was excluded. Bearing in mind the recurrent bleeding history and the described laboratory results, we considered a FXIII deficiency, that was confirmed (FXIII< 10%). In addition, we suspected an acquired FXIII deficiency since the patient did not report a personal or family history of bleeding and FXIII gene sequencing study was normal. Non-immune causes were ruled out, and plasma autoantibodies against FXIII were detected. Immunosuppression was rapidly initiated to eradicate inhibitor as was hemostatic treatment to obtain bleeding control. Currently, the patient is asymptomatic, but a low level of FXIII inhibitor remains.Keywords: acquired disease, autoantibodies, factor XIII deficiency, hematoma, spontaneous

BACKGROUND: Congenital FXIII deficiency is a rare genetic bleeding disorder that is inherited in an autosomal recessive pattern with a frequency of 1/2 million individuals in the human population. Deficiency of FXIII is associated with significant bleeding disorders. AIMS: This study aimed to evaluate the demographic parameters, clinical presentations, and outcome of patients who were diagnosed with congenital factor XIII deficiency. SUBJECTS AND METHODS: A retrospective descriptive study of patients who were diagnosed with congenital FXIII deficiency over a period from August 2008 to August 2016 was conducted. The study included patients who were diagnosed by having bleeding tendency and normal standard coagulation tests (normal platelet count, normal prothrombin time; normal partial thromboplastin time, and normal bleeding time) and the diagnosis was confirmed by clot solubility test in 5M urea. The diagnosis was made in the Hemophilia Ward, Children Welfare Teaching Hospital, Medical City, Baghdad. RESULTS: There were 111 cases of other coagulation factors' deficiency (rare bleeding disorders) registered in the center, congenital FXIII deficiency represented 24 (22%) of them. Males represented 14 (58.3%) and females 10 (41.7%) of patients. Most of the patients (41.7%) had their symptoms during the 1st year of life. Positive consanguinity was found in 100% of patients and 14 (58.3%) patients had a family history of FXIII deficiency. Umbilical cord bleeding and gum bleeding were present in 37.5% and 20.8%, respectively, and they were the most common first presenting symptoms of FXIII-deficient patients, while muscle hematoma (28.5%) and joint bleeding (24.7%) were the most common presenting symptoms in follow-up visits. The majority of the patients (79.1%) did not develop complications, the complications were developed in 3 (12.4%) patients, which were intracranial bleeding in 2 (8.3%) patients and liver hematoma in 1 (4.1%) patient. One patient (4.1%) developed recurrent abortion and one patient (4.1%) developed hepatitis C. No death was reported during the study period. CONCLUSIONS: FXIII deficiency founded to be a more common rare bleeding disorder among Iraqi patients, with a high rate of consanguineous marriage. Umbilical cord bleeding and gum bleeding were the most common presenting symptoms for FXIII deficiency. There was a considerable delay in the diagnosis of FXIII deficiency in the majority of patients.

Abstract Background Factor 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 presentation We 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. Conclusion We 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.

Introduction and Importance: Factor XIII (FXIII) deficiency, a rare coagulation disorder resulting from F13A1 gene mutations, can lead to severe bleeding episodes, especially in infants. The authors' case study featuring a 16-year-old female with a history of this deficiency revealed intracranial hemorrhage necessitating immediate medical intervention. The text emphasizes the importance of understanding the epidemiology and genetics of FXIII deficiency, as well as the challenges in diagnosis and management., Case Presentation: A 16-year-old female with FXIII deficiency presented to the Emergency Department (ER) after a fall, experiencing weakness on her right side, headache, seizures, and altered consciousness. Neurological examination showed weakness and increased tone on the right side of the body. Computed tomography (CT) scan revealed an intracranial subdural hemorrhage overlying the superior parietal lobe. Treatment included IV fluids, sodium valproate, antibiotics, fresh frozen plasma, and mannitol. Serial neurological assessments were normal, and the patient remained stable. MRI later confirmed hemorrhage. Upon discharge, she was prescribed medication and physiotherapy, leading to significant improvement at the 6-month follow-up., Clinical Discussion: The prevalence of FXIII deficiency, a rare disorder, is higher in populations with consanguineous marriages, particularly in regions like Pakistan, India, Tunisia, Finland, and Iran due to specific genetic mutations. Diagnosis involves thorough evaluation and specific lab tests, with varied clinical symptoms including prolonged bleeding, especially in newborns. FXIII deficiency can also develop in association with conditions like hepatic failure and leukemia, complicating diagnosis. Treatment options include blood products and recombinant FXIII, with management of intracranial bleeding requiring a multidisciplinary approach., Conclusion: The case underscores the critical need for early identification and specialized care for individuals with FXIII deficiency to mitigate life-threatening complications like intracranial hemorrhage, promoting tailored treatment approaches and improved patient outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Disorders of the fibrin stabilizing and fibrinolytic pathway should be considered in patients with excessive postsurgical bleeding with normal screening tests of hemostasis. History, clinical assessment of the timing and severity of bleeding along with utilization of advanced tests such as global hemostasis assays and appropriate coagulation factor assays (especially FXIII) will aid in the diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Disorders of the fibrin stabilizing and fibrinolytic pathway should be considered in patients with excessive postsurgical bleeding with normal screening tests of hemostasis. History, clinical assessment of the timing and severity of bleeding along with utilization of advanced tests such as global hemostasis assays and appropriate coagulation factor assays (especially FXIII) will aid in the diagnosis.

Background: Factor XIII deficiency is a rare disorder that may be congenital or acquired and is considered if a coagulation disorder is suspected, but the initial laboratory investigations are normal. Clinical Description: A 10-year-old boy presented with a scrotal swelling and pain following minor trauma. Local examination showed redness of overlying scrotal skin with tenderness on palpation. Management: Initial laboratory investigations for coagulation (prothrombin time/activated partial thromboplastin time/thrombin time) were normal. The diagnosis of factor XIII deficiency was clinched by abnormal clot solubility test. Child was treated with fresh-frozen plasma. Conclusion: Scrotal hematoma is a rare site for bleeding in factor XIII deficiency, which must be suspected if clinical suspicion of coagulation disorder is high and initial laboratory tests for coagulation are normal.

For infants that present with intracranial hemorrhage in the setting of suspected abusive head trauma (AHT), the standard recommendation is to perform an evaluation for a bleeding disorder. Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder associated with intracranial hemorrhages in infancy, though testing for FXIII is not commonly included in the initial hemostatic evaluation. The current pediatric literature recognizes that trauma, especially traumatic brain injury, may induce coagulopathy in children, though FXIII is often overlooked as having a role in pediatric trauma-induced coagulopathy. We report an infant that presented with suspected AHT in whom laboratory workup revealed a decreased FXIII level, which was later determined to be caused by consumption in the setting of trauma induced coagulopathy, rather than a congenital disorder. Within the Child Abuse Pediatrics Research Network (CAPNET) database, 85 out of 569 (15 %) children had FXIII testing, 3 of those tested (3.5 %) had absent FXIII activity on qualitative testing, and 2 (2.4 %) children had activity levels below 30 % on quantitative testing. In this article we review the literature on the pathophysiology and treatment of low FXIII in the setting of trauma. This case and literature review demonstrate that FXIII consumption should be considered in the setting of pediatric AHT. [ABSTRACT FROM AUTHOR]

Pierpaolo Di Micco,1 Gualberto Gussoni,2 Filippo Pieralli,3 Mauro Campanini,4 Francesco Dentali,5 Andrea Fontanella1 1Department of Internal Medicine and Emergency Room, Fatebenefratelli Hospital of Naples, Naples, Italy; 2Centro Studi FADOI, Milan, Italy; 3Department of Medicine, Hospital Careggi, Florence, Italy; 4Department of Internal Medicine, Ospedale Maggiore, Novara, Italy; 5Department of Internal Medicine, University of Insubria, Varese, ItalyCorrespondence: Pierpaolo Di MiccoDepartment of Internal Medicine and Emergency Room, Fatebenefratelli Hospital of Naples, Naples, ItalyEmail pdimicco@libero.itAbstract: Factor XIII deficiency may be inherited or acquired. Inherited deficiency is associated with signs and symptoms of minor bleeding from a young age, and possible major bleeding complications, in particular during pregnancy. On the other hand, acquired factor XIII deficiency is usually associated with severe symptoms of major bleeding, in particular during surgery. In this paper, we report an interesting case of recurrent major bleeding with subsequent fatal bleeding in an adult man diagnosed with acquired factor XIII deficiency.Keywords: factor XIII deficiency, acquired haemophilia, blood disorders, bleeding, fatal bleeding

Factor XIII deficiency is an autosomal recessive disorder with an incidence of 1 in 1-5 million. On activation factor XIII stabilizes clot formation by cross-linking fibrin strands. Deficiency is characterized by severe bleeding due to impairment in clot formation. We describe a case of a child presenting with drowsiness following a trivial fall and trauma to the head. An emergency CT scan of the brain was suggestive of acute on chronic (recurrent) hemorrhage. Intraoperatively he was noted to have an intraparenchymal multiloculated cystic cavity with a thinned out cortex in the right frontal region. The child underwent right frontal craniotomy and decompression of an intracerebral hemorrhage. He was subsequently diagnosed to have factor XIII deficiency. He is presently on monthly cryoprecipitate prophylaxis with which he has not experienced a recurrence of a similar episode.

Introduction: Factor XIII (FXIII) deficiency may cause bleeding under certain clinical circumstances. Therapeutic plasma exchange (TPE) may lead to a transient deficiency. Objectives: To describe the clinical evolution of patients with acquired FXIII deficiency secondary to TPE. Methods: We respectively studied a cohort of consecutive patients from 2014 to 2019 who were treated with TPE with FXIII levels <50%. The FXIII was measured after the start of the TPE course, on days between the TPE sessions, due to suspected acquired deficiency. All TPE were performed using continuous flow cell separator. In all cases, the initial replacement fluid applied was albumin. Apheresis procedures were held at 24to 48 hours intervals. Results: Eighteen patients were included, 13 of them were recipients of kidney transplants. The main TPE prescription was humoral rejection. Median FXIII at diagnosis (measured on days between sessions of the TPE course) was 19%(IQR17‐25). The median of apheresis procedures before measurement of FXIII was 3(IQR2‐4). Among the total cohort, 10 patients suffered hemorrhages. None of the patients without history of kidney transplants had bleeding (n = 5), however, 10/13 with kidney transplants did. Five kidney transplant patients received therapy with FXIII concentrate because of life‐threatening bleeding. In all cases, the bleeding stopped within the first 24 hours. All patients had their FXIII levels measured again after finishing the TPE course, with normal results. Conclusions: TPE is an under‐diagnosed cause of acquired FXIII deficiency since routine coagulation tests remain unaltered. It might cause major bleeding, particularly in patients with a recent history of surgery like kidney transplants. [ABSTRACT FROM AUTHOR]

Postpartum hemorrhage (PPH) is a major cause of maternal mortality, which is a common clinical manifestation in women with rare bleeding disorders. In this study, we compare PPH and its complications in heterozygote factor XIII (FXIII) deficient women with healthy women. In this cross sectional case study, 50 women with heterozygote FXIII deficiency and 50 healthy women are evaluated. Data were initially collected by interviewing the women who were receiving FXIII replacement therapy after their childbirths. Data were analysed using SPSS (Version 22) and a P -value of less than.05 was considered statistically significant. The mean age in the patient and control groups were 31.2 and 32.5 years respectively. The occurring rate of PPH in the patient group was significantly higher than the control group (34% vs 2%) (P -value <.0001). None of the confounding variables such as maternal age, gestational age, numbers, and types of delivery in women with PPH showed any significant differences between the control and patient groups. According to the results of this study, the risk of PPH (early and late), miscarriage, and menorrhagia in women who are heterozygous for FXIII deficiency is significantly higher than healthy women. However, the effect of other factors such as maternal age, gestational age, number, and type of delivery require further studies to delineate any confounding factors. [ABSTRACT FROM AUTHOR]

Haematological abnormalities are a common finding in Systemic Lupus Erythematosus (SLE) patients. The wide spectrum includes anaemia, cytopenias, thrombosis as well as bleeding. Among the bleeding disorders, qualitative coagulation defects can be rarely encountered because of clotting factor inhibitors. More uncommon is the occurrence of quantitative clotting factor deficiencies. Here, we describe a rare cause of abdominal pain in a patient with SLE who developed perinephric and colonic sub mucosal haematomas owing to a rare association with acquired factor XIII deficiency which was diagnosed on quantitative assays and effectively treated with cryoprecipitate and fresh frozen plasma.

Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder (RBD) with estimated prevalence of one per 2 million in the general population. The disorder causes different clinical manifestations such as intracranial hemorrhage (ICH), recurrent miscarriage, umbilical cord bleeding, etc. High incidence of the disorder might be due to founder effect. To assess founder effect, haplotype analysis is an important step. For this purpose, suitable and reliable genetic markers such as microsatellites (Hum FXIIIA01 and HumFXIIIA02) and single nucleotide polymorphisms (SNP) are suggested. In the present study we tried to describe evaluation of founder effect in patients with congenital FXIII deficiency via haplotype analysis using suitable genetic markers. [ABSTRACT FROM AUTHOR]

We report two cases of acquired factor XIII deficiency with bleeding events during veno-venous extracorporeal membrane oxygenation (ECMO). Case 1: A 76-year-old man diagnosed with aspiration pneumonia after near-drowning was started on ECMO. Later, the patient presented with hemoptysis and anemia. Blood tests showed a decreased factor XIII activity of 29%. Although the patient recovered after receiving 1200 International Units of factor XIII concentrate, the patient had another episode of decreased factor XIII activity and bloody stool and was treated again with factor XIII concentrate. Case 2: A 48-year-old female diagnosed with pneumonia was started on ECMO. Soon after, she presented with hemoptysis and anemia. Blood tests showed a decreased factor XIII activity of 39%. The patient was treated with 720 IU of factor XIII concentrate with good recovery. Acquired factor XIII deficiency cannot be detected by routine coagulation tests, therefore it may be under-diagnosed in the ICU. Detection of acquired factor XIII deficiency is essential when treating a bleeding ECMO patient. [ABSTRACT FROM AUTHOR]

Background: Factor XIII deficiency is one of the most severe congenital bleeding disorders with high rate of lifethreatening bleeding including central nervous system bleeding, umbilical cord bleeding, and recurrent miscarriages. Due to the highest global incidence of the disorder in Iran, this study aimed to design a premarital screening program in Iran. Methods: This descriptive study was performed on 30 couples with a positive family history of factor XIII deficiency. Underling F13A gene mutation was determined in the family members, and all the selected couples underwent molecular testing mutations by polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP), tetra primer-amplification refractory mutation system-PCR (T-ARMS-PCR), and sequencing. Results: The probability of affected childbirth existed for ten couples. Three couples decided not to marry, while seven got married and three of them decided to have a baby. The genotypes of the fetuses were determined and revealed that none of them was a homozygote for the F13A gene mutation. Conclusions: Because of the importance of factor XIII deficiency diagnosis, it can be helpful to control the incidence of factor XIII deficiency by implementing preventive programs such as premarital screening. [ABSTRACT FROM AUTHOR]

Background: Congenital factor XIII (FXIII) deficiency is one of the rarest bleeding disorders with a prevalence of one per 2 million in the general population. The disorder is accompanied by a high rate of life-threatening bleeding. Due to normal results of routine coagulation tests, diagnosis of the disorder is challenging, but molecular methods can be used for precise diagnosis. Direct mutation detection is the standard method for confirmation of the disorder, but indirect molecular diagnosis can be used as a fast and cost-benefit choice. In the present study, we described indirect molecular methods for molecular diagnosis of congenital FXIII deficiency. Materials and Methods: For this study, a comprehensive literature review was performed on PubMed, Embase, Web of Science, and Scopus databases using the following keywords: "indirect molecular diagnosis" with "rare bleeding disorder", "coagulation factor XIII/13 deficiency", "prenatal diagnosis" "rare bleeding disorder", "molecular diagnosis", "factor XIII/13 deficiency", "indirect molecular diagnosis" "carrier detection", and "factor XIII/13". These words were used separately and in combination with each other. Results: A total of 293 papers were founded, among them 67 papers were selected for the study. Indirect molecular diagnostic approach can be done using candidate microsatellites and single nucleotide polymorphisms (SNP). This method can be used for prenatal diagnosis and carrier detection, especially in the areas with low economic resources. Polymorphic genetic markers associated with F13 gene like HumFXIII01, HumFXIIIA02, HumFXIIIB, rs7740009, and rs3024405 SNPs can be used for indirect molecular diagnosis of congenital FXIII deficiency. Finally, by comparing patient's polymorphic markers with healthy individuals, diagnosis can be made. Conclusion: It seems that indirect molecular diagnosis is a relatively reliable and cost-effective method for diagnosis of congenital FXIII deficiency in the areas with low economic resources. [ABSTRACT FROM AUTHOR]

Background: Factor XIII (FXIII) deficiency is a bleeding disorder and it inherited in an autosomal recessive manner. in areas where consanguineous marriage is common, it has high prevalence. Iran as a Middle East country comprise the high rate of consanguinity in nearly half of patients with severe congenital FXIII deficiency (FXIIID). The most common mutation in Iranian population is Trp187Arg. In these patients occure life- threatening bleeding including central nervous system (CNS) bleeding, umbilical cord bleeding and recurrent miscarriage that have high rate of morbidity and mortality. The aim of this study was to investigate morbidity and mortality rate among these patients and the reasons for it. Materials and Methods:In this systematic review we studied all published paper in the field of FXIIID factor deficiency in Iran until 2015 via searching in databases and search engine such as Sciencedirect, scientific information database (SID), PubMed and Google scholar. Results: Among 308 patients with FXIIID, 108 cases had experienced CNS bleeding (CNSB) that in 23 cases had associated with rebleeding. in 72 patients have occured different types of neurological complications after central nervous system bleeding. A total of 63 recurrent miscarriages were observed in 30 women and 21 deaths were registered due to umbilical cord bleeding or mucosal bleedings. Conclusion: Due to high rate of morbidity and mortality among patients with FXIIID, early diagnosis of disease, prophylaxis treatment and intensive health care should be considered among these patients.

ABSTRACT Objective: This study aims to give information about the relationship between different types of factor deficiencies and maternal/obstetric outcomes. Methods We retrospectively reviewed the medical records of eight women with factor deficiency disorders. The demographic and clinical features of the patients after their last pregnancies were registered retrospectively. Results: There were 29 pregnancies among the 8 patients. The spontaneous abortion rate was relatively high in two patients with factor XIII deficiency (80% and 57.1%) compared with the other factor deficiency groups. There were 16 births, which included 1 set of twins, and 2 deaths (1 stillbirth and 1 postpartum exitus occurred in the same patient). Intrauterine growth restriction was noted in five cases; four of these occurred in factor X deficiency cases. The mean decrease in hemoglobin level of all patients after birth was 1.7 g/dL (range, 0.2-3.6 g/dL). Red blood cell transfusion was required only in one case of factor XIII deficiency. Conclusions: There is currently no consensus on the pregnancy management of women with factor deficiencies because of the limited knowledge due to the rarity of such disorders. Labor should be managed in a dedicated unit with a team consisting of an obstetrician, a hematologist, an anesthesiologist, a midwife, and a pediatrician to minimalize the complications.