Successful perinatal management of a woman with congenital factor XIII deficiency using recombinant factor XIII: A case report and literature review.

Factor XIII deficiency is an extremely rare autosomal recessive genetic disorder, occurring in 1 of 3-5 million people, and is associated with perinatal complications, such as habitual abortion and prolonged bleeding. Although plasma-derived factor XIII (Fibrogamin®) carries a risk of infection and contains very low concentrated forms of factor XIII (FXIII) used for a pregnant woman with congenital coagulation factor XIII deficiency, recombinant factor XIII (rFXIII, Novo Thirteen®; Tretten®, Novo Nordisk, Bagsvaerd, Denmark), which has no risk of infection and is highly concentrated, has emerged as a novel formulation. Herein, we report the first case of a Japanese pregnant woman with congenital coagulation factor XIII deficiency successfully managed by rFXIII. She had a good perinatal course without pregnancy-related complications and transfusion through the perinatal period.

Reduced plasma coagulation factor XIII in patients with acute leukemia in remission during consolidation chemotherapy cycles.

Acute leukemia (AL) is a malignancy from hematologic stem cells (HSC). Consolidation with intensive chemotherapy is required after induced remission and repeatedly causes treatment-related bleeding that is usually attributed to chemotherapy-induced thrombocytopenia (CIT). However, our previous study demonstrated that severe deficiency of plasma coagulation factor XIII (pFXIII) also participated in the bleeding of CIT in AL. However, the relationship between pFXIII deficiency and consolidation chemotherapy was unknown. Here, we observed the concentration of pFXIII in patients with AL before and after consolidation chemotherapy and reevaluated the correlation to bleeding in myelosuppression. Thus, we found that the concentration of pFXIII before chemotherapy in all patients was markedly lower than in the control data and was further decreased by chemotherapy, related to bleeding in myelosuppression. These findings indicated that chemotherapy-induced pFXIII deficiency should be of concern and explored in depth.

Management of autoimmune factor XIII deficiency in a frail, elderly patient.

Autoimmune factor XIII/13 deficiency (aFXIII deficiency) is a rare hemorrhagic disorder, for which typical guideline-directed treatment is aggressive immunosuppressive therapy. Approximately 20% of patients are over 80 years old; however, and optimum management of such patients has not reached consensus. Our elderly patient had massive intramuscular hematoma, and aFXIII deficiency was diagnosed. The patient opted against aggressive immunosuppressive therapy, so he was managed with conservative treatment only. Thorough survey of other correctable causes of bleeding and anemia is also required in similar cases. Our patient's serotonin-norepinephrine reuptake inhibitor use and multivitamin deficiency (vitamin C, B 12 and folic acid) were revealed to be aggravating factors. Fall prevention and muscular stress prevention are also important in elderly patients. Our patient had two relapses of bleeding within 6 months, which were improved spontaneously by bed rest without factor XIII replacement therapy or blood transfusion. Conservative management may be preferred for frail and elderly patients with aFXIII deficiency when they opt against standard therapy.

A multicenter, real-world experience with recombinant FXIII for the treatment of patients with FXIII deficiency: from pharmacokinetics to clinical practice. The Italian FXIII Study.

BACKGROUND: Congenital factor XIII (FXIII) deficiency is a rare coagulation disorder characterized by muscular or mucocutaneous bleeding with life-threatening intracranial hemorrhages (ICHs), especially in cases with severe disease. The best treatment is the use of prophylactic plasma-derived or recombinant FXIII (rFXIII). Few data on the use of rFXIII in the real-world scenario are available. The main goal of this study was to assess the efficacy and safety of catridecacog (NovoThirteen®) in a population of patients with FXIII deficiency. Other objectives were to compare the different pharmacokinetic (PK) profiles of each patient and to use them to create a tailored prophylaxis regimen. MATERIALS AND METHODS: We collected and analyzed all pharmacokinetic and clinical data in our registry of the patients with congenital FXIII deficiency treated with rFXIII at eleven Italian hemophilia centers. Data were collected from January 2019 to December 2020. RESULTS: Overall, data on 20 patients with FXIII deficiency were collected, 16 of whom presented with severe disease. Pharmacokinetics was assessed in 18 cases before starting prophylaxis. Prophylaxis was subsequently started in these patients using a wide range of dosages (25.0-80.0 IU/kg; mean 33.8 IU/kg) and infusion intervals (3.0-8.0 weeks). During a mean follow up of 47 months, two minor bleeds and one ICH in a severe patient who had remained under on-demand treatment were reported. DISCUSSION: Efficacy and safety of rFXIII were proven in all patients. The dosage and infusion timing for the treated patients sometimes differed to those reported in the MENTOR pivotal studies, thus underlying the importance of tailored management in a real-world scenario.

The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing.

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.

Real-Life Population Pharmacokinetics of Recombinant Factor XIII and Dosing Considerations for Preventing the Risk of Bleeding in Patients with FXIII Congenital Deficiency.

BACKGROUND AND OBJECTIVE: Recombinant factor XIII (rFXIII) at the recommended dosage of 35 IU/kg every 4 weeks is currently used for prophylaxis of bleeding in patients affected by FXIII deficiency. The aim of this study was to describe the population pharmacokinetics of rFXIII in patients with FXIII deficiency being treated with rFXIII in real-life and to assess, using Monte Carlo simulations, the attainment of defined FXIII concentration thresholds associated with prevention of the risk of bleeding over time. METHODS: A nonlinear mixed-effects model approach was used for population analysis. Monte Carlo simulations were used to generate 10,000 FXIII concentration-time profiles associated with incremental doses of 25, 30, 35, 40, 45 and 50 IU/kg of rFXIII. The probability of target attainment (PTA) of FXIII concentrations at thresholds of > 0.05, > 0.10 and > 0.15 IU/mL were calculated weekly, from days 7 to 49. RESULTS: A total of 18 patients provided 99 FXIII concentrations; most patients (77.8%, 14/18) had severe FXIII deficiency. A two-compartment pharmacokinetic model with linear elimination from the central compartment best described rFXIII data. No covariates were associated with rFXIII disposition. Pharmacokinetic parameter estimates were 0.16 mL/h/kg for clearance, 57.35 mL/kg for volume of distribution at steady-state, and 11.72 days for elimination half-life. The standard 35 IU/kg dose resulted in PTAs of the pharmacodynamic thresholds of FXIII concentrations of > 0.05, > 0.10 and > 0.15 IU/mL at day 28 that were equal to 89.9%, 68.9% and 47.8%, respectively. CONCLUSIONS: Intensive FXIII monitoring from day 14, and/or shortening the dosing interval between rFXIII administrations, should be considered to minimise the risk of bleeding.

Patient-centered approach to managing factor XIII deficiency.

Factor XIII (FXIII) is a thrombin-activated protransglutaminase that plays a key role in blood clot formation. Congenital FXIII A-subunit deficiency represents a rare bleeding disorder that affects one in 2-3 million individuals worldwide and is treated with recombinant FXIII (rFXIII). However, due to the rarity of the disease, clinicians are often left to weigh individual variation in FXIII activity and/or symptoms to optimally guide dosing. Cases often become further complicated when patients experience refractory bleeding, which can be difficult to treat. This report describes an approach to rFXIII dosing in two patients who required deviation from standard protocols to maintain therapeutic FXIII troughs. We highlight limitations in our understanding of FXIII deficiency management, while also providing an example of the application of pharmacokinetic data to individualise therapy for improved outcomes. Finally, the case reminds us of the importance of patient-centered, cost-conscious care and multidisplinary teamwork in complex cases.

Acquired FXIII inhibitor: Patient characteristics and treatment outcome, a case series in Taiwan.

INTRODUCTION: Acquired factor XIII (FXIII) inhibitor is a rare but possibly underdiagnosed bleeding disorder. To date, less than one hundred cases have been reported, but the number has increased rapidly in recent years, especially in Japan. Because of the rarity of this disorder, no treatment guidelines are available. In some reports, physicians treated the bleeding with cryoprecipitate or factor XIII concentrate and eradicated the inhibitor with various immune suppressants. METHODS: From January 2015 to December 2018, we collected consecutive patients diagnosed as having acquired FXIII inhibitor. FXIII activity and inhibitor were measured by a fluorescent factor XIII assay using isopeptidase reaction catalyzed by activated factor XIII and the Bethesda method, respectively. Factor XIII antigen was measured by latex-enhanced immunoassay. RESULTS: We found five adult patients with detectable FXIII inhibitor. Four of them were older than 70. Two had systemic lupus erythematosus. All the patients presented with ecchymosis and intramuscular hematoma. No life-threatening bleeding was observed. Delayed diagnosis was common with varied time periods needed to achieve a correct diagnosis. All bleedings were treated and improved by cryoprecipitate. Steroids were given to all patients and cyclophosphamide, rituximab, and other immune suppressants were also used. FXIII inhibitor was totally resolved in three, partially resolved in one, and persisted in one patient. CONCLUSION: We documented five patients with acquired FXIII inhibitor, found over 4 years. The most common presentations were ecchymosis and intramuscular hematomas. Cryoprecipitate was effective in controlling most bleeds. Steroid, cyclophosphamide and rituximab were effective in eradicating inhibitor in some patients.

Autoimmune factor XIII deficiency with unusual laboratory and clinical phenotype.

Hemorrhagic diathesis due to anti-factor XIII (FXIII) autoantibody is a rare but severe disorder. Challenges of the diagnosis and treatment is demonstrated by the case of a 67-year-old female without previous bleeding history, who suffered a huge muscular hematoma. Without blank subtraction 18% plasma FXIII activity was measured; however, after correction for blank the activity was below the limit of detection and the lack of fibrin cross-linking in the patient's plasma confirmed the latter result. FXIII-A2 antigen was not detectable by enzyme-linked immunosorbent assay (ELISA); however, it was well detected by western blotting. The autoantibody showed high affinity toward FXIII-A2 . Its considerable inhibitory activity was demonstrated by high titer in Bethesda units and the low immunoglobulin G concentration required for inhibition. The main biochemical effect was the inhibition of Ca2+ -induced activation. Eradication therapy was only partially successful. Four months after the last hemorrhagic event the patient suffered deep vein thrombosis complicated by pulmonary embolism.

Acquired Factor Xiii Deficiency: An Uncommon But Easily Missed Cause Of Severe Bleeding

Factor XIII (FXIII) is a plasma clotting protein involved in clot stabilization. Severe FXIII deficiency may present with severe, even fatal bleeding. Critically however, routine coagulation assays may be normal and only specific FXIII assays will detect the abnormality. Herein we discuss a case report of a patient with acquired FXIII deficiency in order to highlight the clinical challenges associated with establishing the diagnosis and discuss the treatment approach. A 70-year-old man presented with a gluteal haematoma despite no preceding personal history of bleeding. Extensive initial haemostatic investigations were normal until a specific FXIII assay showed a marked reduction in FXIII levels. With directed treatment, bleeding episodes ceased and remission was achieved. Clinical awareness of FXIII deficiency is important, so appropriate testing can be implemented in patients with unexplained bleeding diatheses, particularly those in whom bleeding responds poorly to standard replacement therapy.

Recombinant factor XIII A-subunit in a patient with factor XIII deficiency and recurrent pregnancy loss.

Essentials Inherited factor XIII deficiency is a very rare bleeding disorder. We used recombinant factor XIII-A in a pregnant patient with factor XIII-A subunit deficiency. The patient had a successful pregnancy outcome with no pregnancy related complications. The dose of recombinant factor XIII-A was minimized by using frequent trough level monitoring. SUMMARY: Inherited factor XIII deficiency is a very rare bleeding disorder, and is one of the causes of recurrent pregnancy loss. The use of plasma-derived FXIII to improve pregnancy outcomes has been reported. We report a 26-year-old woman with FXIII A-subunit (FXIII-A) deficiency who was treated with recombinant FXIII-A and had a successful pregnancy outcome with no pregnancy-related complications. Our case illustrates that the dose of recombinant FXIII-A can be minimized and adjusted on the basis of frequent trough level monitoring.

Lobar Hemorrhage Induced by Acquired Factor XIII Deficiency in a Patient with Cerebral Amyloid Angiopathy.

A 68-year-old man presented with intracranial hemorrhage in the right frontal lobe, which rapidly increased the day after admission. We performed hematoma removal with a biopsy of the cortex around the hematoma. The day after the operation, a subcutaneous hematoma over the craniotomy appeared, and the computed tomography showed a recurrent hemorrhage with an acute subdural hematoma. We were aware of a bleeding tendency, and a detailed hematologic examination by hematologists revealed autoimmune acquired factor XIII deficiency due to an antifactor XIII antibody. Specimens taken around the hematomas were pathologically diagnosed as cerebral amyloid angiopathy (CAA) on immunohistochemical examination. We considered that acquired factor XIII deficiency had induced lobar hemorrhage in the frontal lobe affected with CAA, and the coagulation disorder induced postoperative rebleeding. The patient died from repeated lobar hemorrhage 3 years after the surgery. There is no routine screening coagulation test including the active partial thromboplastin time and the prothrombin time for factor XIII deficiency. It is important for neurologists and neurosurgeons to be aware of this rare disease in patients with a bleeding tendency.

Minimal factor XIII activity level to prevent major spontaneous bleeds.

Essentials A strong association between bleeding severity and FXIII activity level (FXIII:C) was shown. The range 5-30 IU dL-1 of FXIII:C was associated with a high variability of bleeding severity. The PROspective study confirmed the association between FXIII:C activity and bleeding severity. A FXIII: C of 15 IU dL-1 is a proposed target to start prophylaxis for prevention of major bleeding. SUMMARY: Background Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder associated with significant bleeding manifestations. The European Network of Rare Bleeding Disorders (EN-RBD) study, performed from 2007 to 2010, showed a strong association between bleeding severity and FXIII activity in plasma of patients with FXIII deficiency. Among these patients, variable levels of FXIII activity, from undetectable to 30%, were associated with a wide range of bleeding severity. Objectives and patients The present cross-sectional study, in the frame of the PRO-RBDD project, a prospective cohort study, analyzed data of 64 patients with FXIII deficiency and different types of clinical and laboratory severity. Results The results of this analysis confirmed that FXIII coagulant activity in plasma is well associated with clinical severity of patients. In addition, 15 IU dL-1 of FXIII activity was identified to be the level under which the probability of spontaneous major bleeding sharply increases (from 50% for levels of 15 IU dL-1 to more than 90% for levels of 5 IU dL-1 or lower). Conclusion The PRO-RBDD study suggests a FXIII coagulant activity level of 15 IU dL-1 as a target to start prophylaxis in order to prevent major bleedings, such as central nervous system or gastrointestinal tract hemorrhages.

Recombinant factor XIII prophylaxis is safe and effective in young children with congenital factor XIII-A deficiency: international phase 3b trial results.

Essentials Prophylaxis is the standard of care for congenital factor XIII-A (FXIII-A) deficiency. Six children with FXIII-A deficiency received once-monthly prophylaxis with recombinant FXIII-A. Prophylaxis was well tolerated and no anti-FXIII antibodies were detected. Prophylaxis was effective with an annualized bleeding rate of zero. SUMMARY: Background Factor XIII deficiency is a rare, severe congenital bleeding disorder. Monthly prophylaxis with recombinant FXIII A-Subunit (rFXIII) has demonstrated favorable safety and efficacy in patients aged ≥ 6 years, and may similarly benefit younger children. Objective To evaluate the long-term safety and efficacy of rFXIII in children aged < 6 years with congenital FXIII A-subunit deficiency. Patients/methods Six children, who had previously completed a single-dose pharmacokinetic trial of rFXIII, received 35 IU kg-1 rFXIII every 28 days (± 2 days) for a minimum of 52 weeks, and were evaluated for bleeding and adverse events. The Berichrom FXIII activity assay was used to monitor FXIII activity. Results The children, three girls and three boys, had an average age of 3.0 years (range: 1-4 years) at enrollment. The total treatment duration was 1.8-3.5 years, giving a total of 16.6 patient-years. No antibody development, thromboembolic events or allergic reactions occurred. There were 93 mild and seven moderate adverse events. Two adverse events (lymphopenia and gastroenteritis) were reported as probably or possibly related to rFXIII in two children. Two serious adverse events, unrelated to rFXIII, were reported in a single child, each related to head injury, and neither resulting in intracranial hemorrhage. The geometric mean FXIII activity trough was 0.19 IU mL-1 . No bleeding episodes requiring treatment with an FXIII-containing hemostatic agent occurred during the trial; thus, the annualized bleeding rate was 0. Conclusions Consistent with data from older age groups, prophylaxis with rFXIII appears to be safe and effective in young children with congenital FXIII A-subunit deficiency.

Comparison of F13A1 gene mutations in 73 patients treated with recombinant FXIII-A2.

INTRODUCTION: Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder usually caused by mutations in the F13A1 gene that produce a severe quantitative (type I) deficiency of the FXIII-A subunit. AIM: To determine the genotypes of patients with severe FXIII-A deficiency treated with recombinant FXIII-A subunit (rFXIII-A2 ) participating in three international efficacy and safety trials. METHODS: We determined the genotypes of 73 patients in total; 32 had already undergone genotype analysis and were known to carry F13A1 mutations that have been previously reported in the literature. Mutation screening was performed in 41 patients with unknown genetic status using direct sequencing. RESULTS: In total, 51 distinct mutations in 73 patients were identified. Two patients showed a phenotype of severe FXIII-A deficiency, despite having heterozygous missense mutations. Two siblings carried a missense mutation in the F13A1 gene (p.Ser296Arg) in combination with a novel, probably polymorphic variant of the F13B gene (p.Ser654Phe). Molecular modelling of five F13A1 novel missense mutations (p.Leu171Phe, p.Glu204Lys, p.Leu276Phe, p.Asp405His and p.Gly411Cys) predicted a damaging effect of these mutations on protein structure. Although five patients treated with rFXIII-A2 had transient, low-titre, non-neutralizing anti-rFXIII antibodies, no patients developed FXIII-neutralizing antibodies (inhibitors). CONCLUSION: The identified mutations are causally implicated in severe FXIII deficiency; however, they do not appear to increase the risk of neutralizing antibody development against rFXIII-A2 .

Treatment with Recombinant Factor XIII (Tretten) in a Pregnant Woman with Factor XIII Deficiency.

BACKGROUND Factor XIII deficiency is associated with recurrent miscarriages in women. CASE REPORT In this report, we present a patient with factor XIII deficiency and some comorbidities who had had previous miscarriages. She began treatment with factor XIII subunit A (XIII-A) replacement treatment Recombinant factor XIII (Tretten) at a dose of 2500 units monthly and was able, for the first time, to carry a pregnancy almost to term. Although she experienced some obstetrical complications, she delivered a healthy baby. To the best of our knowledge, this is the first report of the use of Tretten during pregnancy. CONCLUSIONS Tretten, which is not indicated in pregnancy, offered a safe, effective treatment for miscarriages secondary to factor XIII-A deficiency in our patient. Further research is required to confirm this finding.

Long-term prophylaxis in patients with severe congenital factor XIII deficiency is not complicated by inhibitor formation.

: Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder accompanied by a variety of bleeding events. Severely deficient patients require regular replacement therapy. With development of FXIII concentrate, the risk of viral infections transmitted by fresh frozen plasma and cryoprecipitate is diminished, but the possibility of inhibitor development remains a challenging issue in the management of these patients. The aim of this study was to assess FXIII inhibitor development in Iranian patients with FXIII deficiency (FXIIID). This study enrolled 50 (30 women and 20 men) patients with severe congenital FXIIID from southeast Iran who underwent long-term (more than 4 years or more than 50 injections) prophylaxis with FXIII concentrate (Fibrogammin P, Dade Behring, Marburg, Germany). We evaluated plasma FXIII activity and FXIII inhibitor on day 28 after the last prophylaxis administration. The method for investigation of FXIII inhibitor was based on Bethesda assay. The mean age of the study population was 13.8 ±â€Š8.3 years. The minimum and maximum FXIII activity levels were less than 1-4.5% (mean ±â€ŠSD, 2.6 ±â€Š0.7%). Our investigations showed that all patients with severe form of FXIIID were treated without inciting inhibitor development. Despite long-term prophylaxis in the studied patients, none was found to have developed FXIII inhibitors.