Acquired Factor XIII Deficiency Research Articles

A case of post-extraction bleeding due to chronic DIC associated with thoracic aortic aneurysm and acquired factor ⅩⅢ deficiency successfully treated with factor ⅩⅢ

A case of post-extraction bleeding due to chronic DIC associated with thoracic aortic aneurysm and acquired factor ⅩⅢ deficiency successfully treated with factor ⅩⅢ

Detection of factor XIII inhibitors in 33 patients with autoimmune factor XIII deficiency in Japan.

Autoimmune factor XIII (FXIII) deficiency (AiF13D) is a rare hemorrhagic disease. The anti-FXIII autoantibodies that cause this disease are classified into three types: type Aa inhibits the heterotetramer assembly and activation of FXIII, type Ab inhibits the enzymatic activity of activated FXIII, and type B enhances the elimination of FXIII from the blood. The former two are FXIII inhibitors and may be lethal if overlooked by conventional functional assays. To reliably detect both types of FXIII inhibitors, a new assay was developed by incorporating 5-(biotinamido)pentylamine (BAPA) into α2-plasmin inhibitor (PI-BAPA assay). This assay was tested on plasma samples from 128 participants, including 60 healthy controls, 35 patients with non-immune acquired FXIII deficiency, and 33 patients with AiF13D (29 with type Aa inhibitors and 4 with type Ab inhibitors). The PI-BAPA assay successfully detected type Aa and Ab inhibitors in 5-step dilution cross-mixing tests between patient and normal plasma. This assay also showed comparable or superior inhibition rates in the 1:1 mixing test compared to conventional ammonia release and amine incorporation assays. Receiver operating characteristic curve analysis confirmed the excellent specificity and sensitivity of this assay for determining inhibition rates, and the assay has already been used for AiF13D diagnosis.

Multiple Cerebral Infarctions after Treatment of Acquired Factor XIII Deficiency with Retroperitoneal Hematoma.

Multiple Cerebral Infarctions after Treatment of Acquired Factor XIII Deficiency with Retroperitoneal Hematoma.

PB0574 Severe Bleeding in an Acquired Factor XIII Deficiency in an Otherwise Healthy Patient

PB0574 Severe Bleeding in an Acquired Factor XIII Deficiency in an Otherwise Healthy Patient

Acquired Factor XIII Deficiency Is Common during ECMO Therapy and Associated with Major Bleeding Events and Transfusion Requirements.

Bleeding events are frequent complications during extracorporeal membrane oxygenation therapy (ECMO). To determine the rate of acquired factor XIII deficiency and its association with major bleeding events and transfusion requirements in adults undergoing ECMO therapy. A retrospective single centre cohort study. Adult patients receiving veno-venous or veno-arterial ECMO therapy during a 2-year period were analysed and screened for factor XIII activity measurements. Factor XIII deficiency was defined based on the lowest factor XIII activity measured during ECMO therapy. Among 84 subjects included into the analysis, factor XIII deficiency occurred in 69% during ECMO therapy. There were more major bleeding events (OR, 3.37; 95% CI, 1.16-10.56; p = 0.02) and higher transfusion requirements (red blood cells, 20 vs. 12, p < 0.001; platelets, 4 vs. 2, p = 0.006) in patients with factor XIII deficiency compared to patients with normal factor XIII activity. In a multivariate regression model, factor XIII deficiency was independently associated with bleeding severity (p = 0.03). In this retrospective single centre study, acquired factor XIII deficiency was observed in 69% of adult ECMO patients with a high bleeding risk. Factor XIII deficiency was associated with higher rates of major bleeding events and transfusion requirements.

Novel Immunochromatographic Test for Anti-factor XIII B Subunit Autoantibodies to Diagnose Autoimmune Acquired Factor XIII Deficiency.

Autoimmune factor XIII (FXIII) deficiency (AiF13D) is an acquired life-threatening bleeding disorder due to anti-FXIII autoantibodies (autoAbs). We previously established an immunochromatographic test (ICT) for detection of anti-FXIII-A subunit (FXIII-A) autoAbs. Conversely, the detection of anti-FXIII-B subunit (FXIII-B) autoAbs is currently performed in a limited number of medical facilities through time-consuming and expensive laboratory tests, such as dot-blotting analysis and enzyme-linked immunosorbent assay (ELISA). Accordingly, in this study, we generated eight rat monoclonal antibodies (mAbs) against human FXIII-B using the rat lymph node method. By employing an ELISA, two mAbs, 2G12B10 and 8H12B9, were selected considering the distance between the recognition regions of each mAb (the 6th and 9th-10th Sushi domain, respectively) and the strength of their reactivity. Using this mAb combination, we prototyped an ICT to detect anti-FXIII-B autoAbs and distinguish between AiF13D and "nonimmune" acquired FXIII deficiency (acF13D), and tested it with 22 healthy controls, 23 acF13D patients, 15 AiF13D patients without anti-FXIII-B autoAbs, and 8 AiF13D patients with anti-FXIII-B autoAbs. Receiver operating characteristic curve analyses of ICTs for anti-FXIII-B autoAbs were performed and revealed a precision similar to dot-blot analysis. Human anti-FXIII-A mAbs were also generated from a single patient with AiF13D using a new cDNA cloning method, and their binding properties were characterized. Consequently, anti-FXIII-A immunoglobulin G preparations were established as potentially permanent positive controls of ICT for anti-FXIII-A antibodies. Combining the previously developed ICT for anti-FXIII-A autoAbs and the novel ICT for anti-FXIII-B autoAbs may reduce false negatives and lead to appropriate diagnosis and treatment.

Factor XIII: More than just a fibrin stabilizer for the burn patient? A matched-pair analysis

Acquired factor XIII deficiency is an underestimated risk in patients with large surface burns, which potentially exposes these patients to prolonged bleeding and delayed wound healing if undetected. A retrospective matched-pair analysis of the burn registry of the Department of Plastic, Aesthetic, Hand, and Reconstructive Surgery of Hannover Medical School was performed from 2018 to 2023. A total of 18 patients were included. Acquired factor XIII deficiency was not statistically significant correlated with age, sex, or body mass index. Patients who developed acquired factor XIII deficiency had a significantly longer hospital stay (72.8 days) compared with those in the matched group (46.4 days), although burn depths, total body surface area, and Abbreviated Burn Severity Index were not statistically correlated with factor XIII deficiency. Little is known about acquired factor XIII deficiency in patients with burns. Factor XIII supplementation may improve hemostasis, wound healing, and general outcome while reducing the patient's exposure to blood products.

A case of acquired factor XIII deficiency secondary to plasmablastic lymphoma

Acquired factor XIII (FXIII) deficiency is an extremely rare and potentially fatal bleeding disorder. Immune-mediated FXIII deficiency is due to the development of anti-FXIII autoantibodies which may develop with concomitant conditions that cause immune dysregulation such as malignancies or autoimmune disorders. Clinical presentation includes delayed post-operative bleeding or spontaneous soft tissue hematomas and/or cerebral bleeding. Since screening coagulation laboratory tests (prothrombin time, activated partial thromboplastin time, and fibrinogen) are typically normal, acquired FXIII deficiency is likely to be overlooked and underdiagnosed. The management of immune-mediated FXIII deficiency is based on hemostatic therapy, autoantibody removal and eradication of the underlying etiology; however, no treatment guidelines are still available. Here we report a case of acquired FXIII deficiency associated with plasmablastic lymphoma, in order to raise awareness of this rare bleeding disorder and consent prompt life-saving management.

Systemic lupus erythematosus presenting as acquired factor XIII deficiency and spontaneous subdural haemorrhage

The Asian Journal of Internal Medicine is the official journal of the Sri Lanka College of Internal Medicine. It is an open access peer-reviewed journal which is currently published bi-annually. AJIM’s mission is to achieve the supreme standards of holistic patient care by dissemination of high quality scientific knowledge related to Internal Medicine in the whole of Asia and Sri Lanka.

Acquired factor XIII deficiency

Acquired factor XIII (FXIII) deficiency is a very rare haemostatic defect that can be either immune (rare development of an autoantibody targeting FXIII epitopes) or nonimmune (diminished synthesis or increased consumption of the same factor). The aim of this study is to review the symptomatology, the diagnostic method used, but above all to determine the most frequently used and potentially most effective treatment for acquired FXIII deficiency. PubMed, Medline, embase/Ovid databases were queried from 1 January 2012 to 3 April 2022. Data extraction was performed using the keywords ‘Acquired FXIII deficiency.’ The systematic search identified 474 records. After screening titles and abstracts, only 36 articles met the eligibility criteria. The mean age of all patients was 57.6 [range, 1–84] years. The male to female ratio was 35 : 25. The majority of cases described were due an autoimmune reaction with antibody production (24 manuscripts), only six manuscripts described consumption. The most prevalent symptoms were local haematoma (31). Six cases died, two from haemorrhagic shock, two from haemorrhagic stroke, one from respiratory distress, and 1 from septic shock. Given the patient outcomes, this review confirms that the most appropriate treatment consists of one of the following elements or a combination of several of these elements: FXIII concentrate, corticosteroids, cyclophosphamide, rituximab for autoimmune cases, and FXIII concentrate supplementation only in case of consumption.

Acquired Factor XIII Deficiency in Patients with Multiple Trauma

IntroductionFibrin stabilizing factor (FXIII) plays a crucial role in blood clotting, tissue repair, and immune defense. FXIII deficiency after trauma can lead to prolonged wound healing due to persistent infections or coagulation disorders.The aim of this study was to describe the prevalence of acquired FXIII deficiency after trauma and to provide a description of the time-course changes of important coagulation parameters in relation to FXIII activity. In this context, patient characteristics, laboratory data, and treatment modalities were examined with respect to their influence on FXIII activity. Furthermore, the effects of in vitro administration of FXIII on clot firmness and outcomes in patients with severe traumatic brain injury were investigated. Patients and MethodsTwo trauma cohorts (A and B) were examined prospectively in a two-center study, and another (cohort C) was examined retrospectively. In cohort A (trauma patients, n=880) routine laboratory tests were conducted, and FXIII activity was measured. In cohort B (polytrauma patients, n=26), additional clinical parameters were collected, and in-vitro FXIII administration and rotational thromboelastometry (ROTEM) analyses were performed. In cohort C (polytrauma patients with severe traumatic brain injury [sTBI], n=84), the impact of initially measured FXIII activity on clinical outcomes after sTBI was investigated using the modified Rankin Scale (mRS) at least 6 months after trauma. ResultsThe prevalence of FXIII activity <70% in cohort A was 12.4%, with significant differences in age, Hb, fibrinogen, and Hct levels, platelet count, aPTT, and INR (vs. prevalence of FXIII activity >70%). Cohort B showed a decrease in FXIII activity from 85% to 58% after 7 days. FXIII deficiency correlated with time after trauma, aPTT, and fibrinogen level, lactate, and Hb levels. In-vitro administration of FXIII showed a positive influence on clot firmness due to improved maximum clot firmness (MCF in FIBTEM) and reduced maximum lysis (ML in EXTEM). Finally, a significant difference in FXIII activity between patients after sTBI with good and poor clinical outcomes was observed 6 months after trauma. ConclusionWe demonstrated that trauma-associated FXIII deficiency is a common coagulation disorder, with FXIII deficiency increasing further in the first 7 days after trauma, the period of early surgical care. In vitro administration of FXIII was able to demonstrate significant clot stabilizing effects. For trauma patients with sTBI, FXIII activity could serve as a prognostic parameter, as it differed significantly between patients with good and poor clinical outcomes.

Acquired Factor XIII Deficiency Is Associated with High Morbidity and Mortality in Critically Ill Patients

Acquired Factor XIII Deficiency Is Associated with High Morbidity and Mortality in Critically Ill Patients

Measuring Factor XIII Inhibitors in Patients with Factor XIII Deficiency: A Case Report and Systematic Review of Current Practices in Japan.

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.

Successful treatment of intractable pseudomeningocele with FXIII deficiency by surgery and FXIII replacement therapy: A case report

Pseudomeningocele is an extradural cystic collection of cerebrospinal fluid (CSF) and is rare and typically asymptomatic. However, pseudomeningocele is sometimes associated with symptoms. Whether symptomatic pseudomeningocele is best treated conservatively or surgically remains controversial. Factor XIII (FXIII) is a blood coagulation factor that also promotes fibroblast proliferation during wound healing. Although treatment of postsurgical CSF leakage with FXIII has been reported, there have been no reports on surgical treatment and FXIII replacement therapy of pseudomeningocele with FXIII deficiency. We report a case of pseudomeningocele with FXIII deficiency that was successfully treated by surgery and FXIII replacement therapy. The patient presented with symptoms of intracranial hypotension syndrome that had started a few months after laminectomy for thoracic ossification of the ligamentum flavum 2 years earlier. Magnetic resonance imaging and delayed computed tomography myelography confirmed a diagnosis of pseudomeningocele. Epidural blood patch treatment was performed twice but did not result in improvement. Furthermore, the FXIII level decreased to 56%, so the patient was also diagnosed as having acquired FXIII deficiency. We elected to treat the patient by surgery with FXIII replacement therapy. The dural injury was repaired using an artificial dura mater patch, fibrin glue, and polyglycolic acid sheets. The FXIII level was 74%–135% during the perioperative period. The patient had a good postoperative course. Postoperative magnetic resonance images showed resolution of the pseudomeningocele. There was no recurrence during 6 months of follow-up. Perioperative FXIII replacement may be a useful treatment for pseudomeningocele with FXIII deficiency.

Plasma proteomics associated with autoimmune coagulation factor deficiencies reveals the link between inflammation and autoantibody development.

Autoimmune coagulation factor deficiency (AiCFD) is characterized by sudden excessive bleeding due to autoantibodies against coagulation factors. This occurs primarily in elderly patients with no family history or previous clotting issues. However, the detailed mechanisms underlying autoantibody development are not well understood. Here, we evaluated the plasma proteome in patients with AiCFD and compared it with that of 22 healthy controls and 17 patients with non-autoimmune acquired factor XIII deficiency (acF13D). We identified eighteen proteins whose plasma levels were higher in AiCFD than in either healthy controls or patients with acF13D. Most of these proteins were found to be acute-phase reactants or immunoglobulins. Patients with acF13D had lower levels of nine of these proteins and higher levels of the remaining nine compared to healthy controls. However, in all cases, these protein levels were much higher in patients with AiCFD than in those with acF13D. These results suggest that an inflammatory response independent of the acute inflammation caused by bleeding can occur, which may lead to the development of AiCFD. Therefore, we believe that severe and/or chronic inflammation, probably due to an underlying disease or aging, is the most important factor in autoantibody development.

Acquired Factor XIII Deficiency in a Patient with Metastatic Lung Cancer

Acquired factor XIII (FXIII) deficiency can result in life-long bleeding tendency and can be caused by enhanced consumption, impaired synthesis, or as an immune-mediated process. The latter can be related with solid neoplasms, through neutralizing or non-neutralizing antibodies. The relationship between FXIII activity and non-small cell lung cancer (NSCLC) is not well established. This case report is about a patient with NSCLC and acquired FXIII deficiency. Materials and Methods: Clinical records were obtained through the electronic process analysis, and the confidentiality of the patient was always assured. Results and Discussion: A 70-year-old male with no relevant past medical history and a recently diagnosed metastatic NSCLC was admitted for priapism. Five days later, a he developed a bleeding disorder, with slightly elevated coagulation times and normal fibrinogen levels and platelets count. FXIII level was found to be decreased (0.24 IU/mL) and FXIII plasma mixing studies did not confirm the presence of a neutralizing inhibitor. The FXIII level correction with standard plasma mixing studies was in favour of a non-neutralizing antibody. Despite treatment, haemorrhage control was not achieved and the patient died. Conclusion: This clinical report describes a rare case of a patient with metastatic NSCLC presenting a severe haemorrhagic event caused by FXIII deficiency immune-mediated by non-neutralizing antibodies and subsequent increased clearance.

Factor XIII and surgical bleeding.

Factor XIII (FXIII) is the final factor in the coagulation cascade. It converts soluble fibrin monomers into a stable fibrin clot, prevents premature degradation of fibrin, participates in wound healing, and helps prevent the loss of the endothelial barrier function. FXIII deficiency is believed to be rare, and this may explain why clinicians do not routinely take it into consideration. Congenital FXIII deficiency is a rare disease with a reported prevalence of 1 per million. However, the prevalence of acquired FXIII deficiency is much higher. Acquired forms have been described in patients with decreased hepatic or bone marrow synthesis, overconsumption and increased degradation by autoantibodies. This review offers guidance on how to suspect and diagnose FXIII deficiency in both the preoperative consultation and different surgical settings. We also analyze current scientific evidence in order to clarify when and why this clinical situation should be suspected, and how it may be treated.

Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database

Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database

Acquired FXIII Deficiency is Associated with High Morbidity.

A factor XIII (FXIII) level >30% is considered necessary to prevent spontaneous bleeding. Bleeding is also a risk in patients with acquired FXIII deficiency, but the hemostatic level of FXIII in this context remains to be determined. We retrospectively analyzed all patients diagnosed with acquired FXIII deficiency at a large hospital over 3 years (study ID NCT04416594, http://www.clinicaltrials.gov) and assessed clinical data to identify the best cut-off point for FXIII activity to distinguish between low and high risk of major bleeding in a mixed medical and surgical population. Of the 97 patients who experienced bleeding despite a normal coagulation test, 43.2% had FXIII activity <70%. FXIII activity was significantly lower in surgical patients and patients admitted to the intensive care unit (ICU). Low FXIII activity was significantly associated with long ICU stays and a high incidence of major bleeding. Acquired FXIII deficiency is associated with high morbidity. The hemostatic level of FXIII in the setting of acquired FXIII deficiency might be above 30%.

The Acquired Factor XIII Deficiency from the use of Valproic Acid (4130)

The Acquired Factor XIII Deficiency from the use of Valproic Acid (4130)