Acquired Factor XIII 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

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.

Perioperative therapeutic plasma exchange in a patient with rare Factor XIII inhibitor

IntroductionFactor XIII deficiency is a rare bleeding disorder which could be severe if inherited or less severe if acquired. We report a case of acquired Factor XIII inhibitor in a 75-year-old male with a suspicious left renal mass treated perioperatively with therapeutic plasma exchange (TPE). Patient and methodTo perform kidney biopsy and ablation of the renal mass, six daily TPE treatments were performed before and after biopsy to minimize bleeding risk because the patient did not respond to drug therapy. Both thromboelastography (TEG) and laboratory-based coagulation tests were performed to assess coagulation status prior to and after TPE. ResultsThe biopsy indicated oncocytoma which was removed by surgical procedure. Factor XIII activity remained below 15 % throughout TPE treatments, but Factor XIII inhibitor titer reduced from initial positive value of 1:40 to negative following the third TPE and remained negative through the sixth TPE. Unfortunately, the inhibitor titer was positive at 1:20 in the fifth month and 1:5 in the sixth month during follow-up. ConclusionsTPE is useful in removing XIII inhibitory factor, but the effects are only short term.

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

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.

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

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

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

Pathological coagulation parameters in as many as 54 patients with autoimmune acquired factor XIII deficiency due to anti-factor XIII autoantibodies.

Autoimmune factor XIII (FXIII) deficiency (AiF13D) due to anti-FXIII autoantibodies is an extremely rare, life-threatening bleeding disorder that mostly occurs in the elderly. The number of patients diagnosed with AiF13D has been increasing in Japan, probably because of the nationwide survey on AiF13D supported by the Japanese Ministry of Health, Labour and Welfare. To explore the pathologic characteristics of coagulation parameters in AiF13D. AiF13D-suspected cases were consulted, and underwent unified/integrated coagulation screening and were definitively diagnosed as AiF13D separately. AiF13D patients had lower FXIII antigen levels than non-AiF13D patients, but their values overlapped. Among a series of 22-item screening tests and their resulting parameters, the 'FXIII inhibitory potential' yielded by a 1:1 mixing test of the patient's and healthy control's plasma and its 'residual FXIII activity' in 54 AiF13D cases were most distinguishable from 139 non-AiF13D cases, followed by FXIII activity per se and FXIII-specific activity. While the cross-linked α2 -plasmin inhibitor level reduced, the levels of D-dimer, fibrin/fibrinogen degradation products and plasmin-plasmin inhibitor complex increased, probably because the patients' haematoma nonspecifically induced secondary fibrinolysis in both AiF13D and non-AiF13D patients. AiF13D appears to induce a hypocoagulopathy combined with a hyper-fibrinolytic state secondary to severe FXIII deficiency caused by anti-FXIII autoantibodies, and the consequent bleeding further modifies its pathological conditions. In addition, the 1:1 mixing test of FXIII activity was confirmed to be a reliable screening method for AiF13D, especially when its derivative parameter, such as the 'FXIII inhibitory potential' or 'FXIII inhibitory potential ratio', is employed.

Патогенетические механизмы развития гипофибриногенемии при COVID-19

Введение. Коагулопатия у пациентов с новой коронавирусной инфекцией COVID-19 имеет важное значение в течении и прогнозе заболевания. Типичными проявлениями коагулопатии в острой фазе болезни является склонность к гиперкоагуляции, гиперфибриногенемии и повышенному тромбообразованию. Гипофибриногенемия при COVID‑19 широко не представлена в литературе, и частота, а также причины её развития неизвестны. Одной из возможных причин возникновения гипофибриногенемии является применение генно-инженерных биологических препаратов (ГИБП), однако механизмы развития данного состояния не ясны. Цель исследования: определить роль терапии антагонистами рецепторов интерлейкина-6 при развитии гипофибриногенемии у пациентов с COVID-19-пневмонией, клиническую значимость гипофибриногенемии и механизм её возникновения. Материалы и методы. В ретроспективное исследование путём случайной выборки включено 239 пациентов в возрасте от 18 до 96 лет с подтверждённой методом полимеразной цепной реакции SARS-CoV-2 инфекцией, КТ-признаками (при поступлении в стационар) вирусной пневмонии 2–4 степени и длительностью госпитализации более 2 сут. Всем пациентам проводили лабораторный мониторинг, включавший определение значений гемоглобина, тромбоцитов, С-реактивного белка (СРБ), печёночных ферментов и фибриногена по Клаусу. Всем пациентам проводилась стартовая терапия гидроксихлорохином и азитромицином. Тоцилизумаб на момент исследования был единственным ГИБП, применяемым в стационаре. Терапия тоцилизумабом была проведена 164 (68,6%) пациентам. В исследовании учитывали максимальные и минимальные значения гемоглобина, тромбоцитов, фибриногена и СРБ в течение всей госпитализации. Результаты. Гипофибриногенемия различной степени выраженности наблюдалась у 39 пациентов, получивших тоцилизумаб, что значимо выше частоты гипофибриногенемии у 2 пациентов, не получавших терапию тоцилизумабом (ОР = 8,9; 95% ДИ = 2,2–25,9). Заключение. Применение тоцилизумаба у пациентов с COVID‑19 достоверно повышает риск развития гипофибриногенемии. Background. Coagulopathy in patients with new coronavirus infection COVID-19 is important for the course and prognosis of the disease. Hypercoagulation, hyperfibrinogenemia and thrombosis are typical manifestations of coagulopathy in the acute phase of the disease. Hypofibrinogenemia in COVID‑19 is not widely reported in the literature, and the frequency and reasons of its development are unknown. The use of genetically engineered biological drugs (GEBD) may be one of the possible causes of hypofibrinogenemia but the mechanisms of its development are not clear. Objectives: to determine the role of therapy with interleukin-6 receptor antagonists in the development of hypofibrinogenemia in patients with COVID-19-pneumonia, the clinical significance of hypofibrinogenemia and the mechanism of its occurrence. Patients/Methods. A randomized retrospective study included 239 patients aged 18 to 96 years with confirmed by polymerase chain reaction SARS-CoV-2 infection, computed tomography signs (upon admission to the hospital) of viral pneumonia (grade 2–4) and a duration of hospitalization of more than 2 days. All patients underwent laboratory monitoring, including the determination of hemoglobin, platelets, C-reactive protein (CRP), liver enzymes and fibrinogen according to Claus. All patients received initial therapy with hydroxychloroquine and azithromycin. At the time of the study, tocilizumab was the only GEBD drug used in the hospital. Therapy with tocilizumab was performed in 164 (68.6%) patients. The study took into account the maximum and minimum values of hemoglobin, platelet, fibrinogen and CRP levels during the hospitalization. Results. Hypofibrinogenemia of varying severity was observed in 39 patients treated with tocilizumab, that was significantly higher than hypofibrinogenemia frequency in 2 patients who did not receive tocilizumab (RR = 8.9; 95% CI = 2.2–25.9). Conclusions. Tocilizumab usage in patients with COVID-19 significantly increases the risk of hypofibrinogenemia.

Autoimmune Acquired Factor XIII Deficiency: A Case Report

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.

Massive Delayed Bleeding after Breast Reconstruction Caused by Acquired Factor XIII Deficiency

Massive Delayed Bleeding after Breast Reconstruction Caused by Acquired Factor XIII Deficiency