RARE DISEASE
Congenital factor XIII deficiency
Congenital factor XIII deficiency
Congenital factor XIII deficiency
Synonyms: Fibrin-stabilizing factor deficiency
Synonyms: Fibrin-stabilizing factor deficiency
Synonyms: Fibrin-stabilizing factor deficiency
Drug discovery
5
drugs
With orphan designations
Overview
Congenital Factor XIII Deficiency is a rare autosomal recessive bleeding disorder caused by mutations in F13A1 (A-subunit) or F13B (B-subunit) genes. It presents with life-threatening umbilical cord bleeding at birth, delayed post-traumatic hemorrhage, intracranial hemorrhage (25-30% of cases), recurrent spontaneous abortions, and impaired wound healing. Routine coagulation tests (PT/aPTT) are normal; diagnosis requires FXIII activity assays. Prophylactic FXIII replacement (plasma-derived or recombinant) is essential to prevent fatal bleeding [1][4][6].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
213 drug discovery papers about Congenital factor XIII deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
213 drug discovery papers about Congenital factor XIII deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-11-01 | Postsurgical Hemorrhage in Senile Entropion Due to Factor XIII Deficiency
Background: When diagnosing postsurgical bleeding with normal coagulation tests, factor XIII (F XIII) deficiency must be ruled out. This circulates in plasma, mainly bound to fibrinogen, and has a half-life of 7 to 14 days. F XIII acts as a fibrin stabilizer and is involved in tissue repair and healing. In F XIII deficiency, coagulation tests are normal because it does not participate in thrombus formation but rather in its stabilization, both in congenital and acquired deficiency. Patients with FXIII levels below 1 U/dL are at high risk of early onset bleeding (with umbilical cord hemorrhage). With factor levels between 1 and 4 U/dL, the hemorrhagic phenotype is severe or moderate. With values above 5 U/dL, hemorrhagic symptoms are occasional. However, cases of mild deficiency (factor XIII activity levels of 30–60%) have been reported in which abnormal posttraumatic bleeding may occur. Treatment ranges from specific F XIII concentrate or fresh frozen plasma to antifibrinolytic drugs in mild cases. Methods: A 78-year-old patient, no toxic habits, with a history of high blood pressure, dyslipidaemia, type II diabetes mellitus, and ischemic heart disease. Two episodes of hospitalization for anemia of digestive origin. He had undergone transurethral resection of the prostate, infrarenal aortic aneurysm repair with endoprosthesis, and cataract surgery in both eyes without hemorrhagic complications. He was being treated with rosuvastatin, valsartan, bisoprolol, furosemide, and linagliptin. He required surgery for senile entropion of the lower eyelid of the right eye under local anesthesia. Preoperative tests, including a complete blood count, biochemistry, and coagulation, showed normal values. A lateral tarsal strip was performed to anchor the outer edge of the eyelid to the orbit to tighten it. Forty-eight hours after the operation, the patient presented with continuous bleeding from the surgical wound, hyposphagma, and a large hematoma on the lower eyelid. The surgical wound was examined on three occasions and, despite local compression and hemostatic measures, recurrent bleeding continued in the surgical bed for 2 weeks, requiring urgent attention on several occasions. Results: Subsequently, the study was expanded to include plasma factor determination, finding only a Factor XIII value of 42%. After ruling out other causes of hemorrhagic diathesis, Factor XIII deficiency was considered to be the cause of the condition. Treatment with tranexamic acid at a dose of 1 g every 8 hours orally helped to resolve the condition. Conclusion: Outpatient entropion surgery resulted in moderate hemorrhagic complications that complicated the postoperative period. The mild Factor XIII deficiency caused recurrent bleeding that required interventional and pharmacological treatment with antifibrinolytics. Publication History Article published online: 31 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-02-28 | Factor XI and XII inhibitors-Dawn of a new era.
The history of coagulation cascade dates back to 17th century. The extrinsic and intrinsic pathways were proposed in 1998. Extrinsic pathway includes the tissue factor and stable factor which activates factor X and with help of factor V, this converts prothrombin to thrombin which is stabilised by factor XIII. This helps to seal the bleeding vessel and is a physiological process as there is only "limited" production of thrombin which doe not expand beyond the damaged site due to absence of tissue factor. On the other hand intrinsic pathway is activated by polyanions, neutrophilic extracellular traps which are present during infection and inflammation. These activate factor XI which activates factor X with the help of factor IX and VIII and then the common pathway ensues. But newer discoveries have shown that this is a very simplified way of explaining the coagulation system. The researches propose that haemostasis is divided into initiation, amplification and propagation phase. Also, the factor VII-tissue factor complex formed activates factor IX and leads to sustained thrombin production as the amount of thrombin produced by extrinsic pathway alone is not sufficient to form a haemostatic plug. Thrombin also activates factor XI and lead to self perpetuation of intrinsic pathway. All the anticoagulants have an inherent property of bleeding. So the newer factor XI and XII inhibitors focus to inhibit the excessive thrombin production without hampering the physiological haemostasis process. This is supported by the fact that congenital factor XI and XII deficiency does not cause excessive bleeding but increased levels did make patients more vulnerable to thromboembolism. This review shall focus on the various factor XI and XII inhibitors which are in the pipeline.
2024-04-10 | Management of anticoagulation and factor XIII replacement in a patient with severe factor XIII deficiency and recurrent venous thromboembolic disease: case report and review of literature.
Thrombotic events in congenital factor (F)XIII deficiency are extremely rare. To our knowledge, we describe the first case of severe congenital FXIII deficiency associated with recurrent venous thrombotic events. How to deal with anticoagulation treatment in patients with severe FXIII deficiency? The patient was treated with rivaroxaban and plasma-derived FXIII substitution therapy as prophylaxis without bleeding complications. We aimed at FXIII trough levels of 50% during the loading doses of rivaroxaban, then 30% during the maintenance dose of rivaroxaban, and finally 20% during the long-term use of prophylactic dose of rivaroxaban. Treatment of thrombotic events with rivaroxaban in patients with severe bleeding disorders seems to be safe, requiring an adaptation of the intensity of the replacement therapy.
2023-02-23 | The Role of Different Matrixin Gene Expressions on Cerebral Bleeding among Patients with Deficiency of Coagulation Factor XIII.
Enzymes of the matrixin family could be seen as a critical determinant in the breakdown of the extracellular matrix, cell membrane, and tissue regeneration and are interned in the process of brain bleeding. On the other hand, coagulation factor XIII deficiency is a sporadic hemorrhagic disease with an estimated prevalence of 1 in 1-2 million people. Cerebral hemorrhage is the leading cause of death in these patients. This study investigated the relationship between the expression of matrix metalloproteinase 9 and 2 genes with cerebral hemorrhage in these patients. For this purpose, in this case-control study, by examining the clinical and general findings of the studied patients, the Q-Real-time RT-PCR method was used to quantitatively examine the mRNA levels of matrix metalloproteinase 9 and 2 in 42 patients with hereditary deficiency of coagulation factor XIII, including two groups with and without a history of cerebral hemorrhage (case and control groups, respectively). A comparative method (2-ΔΔCT) was used to check the expression level of the target genes. The GAPDH gene expression levels were used to standardize the expression of the measured matrix metalloproteinase genes. The results showed that bleeding from the umbilical cord was the most common clinical symptom among all patients. High levels of MMP-9 gene expression were observed in 13 patients of the case group (69.99%) and three patients of the control group (11.9%). which showed a significant difference (CI: 2.77-95.3, P=0.001) Patients with coagulation factor XIII deficiency show a wide range of clinical symptoms crucial in screening and diagnosing this group of patients. Based on the results of this study, it seems that the increased expression of the MMP-9 gene is due to polymorphism or inflammation related to the pathogenesis of cerebral hemorrhage in this category of patients. It may be conceivable to diminish this impact by utilizing MMP-9 inhibitors and offering assistance to diminishes these patients' hospitalization and passing rates.
2022-11-15 | Elimination of fibrin polymer formation or crosslinking, but not fibrinogen deficiency, is protective against diet-induced obesity and associated pathologies.
Obesity predisposes individuals to metabolic syndrome, which increases the risk of cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes. A pathological manifestation of obesity is the activation of the coagulation system. In turn, extravascular fibrin(ogen) deposits accumulate in adipose tissues and liver. These deposits promote adiposity and downstream sequelae by driving pro-inflammatory macrophage function through binding the leukocyte integrin receptor αM β2 . An unresolved question is whether conversion of soluble fibrinogen to a crosslinked fibrin matrix is required to exacerbate obesity-driven diseases. Here, fibrinogen-deficient/depleted mice (Fib- or treated with siRNA against fibrinogen [siFga]), mice expressing fibrinogen that cannot polymerize to fibrin (FibAEK ), and mice deficient in the fibrin crosslinking transglutaminase factor XIII (FXIII-) were challenged with a high-fat diet (HFD) and compared to mice expressing a mutant form of fibrinogen lacking the αM β2 -binding domain (Fib𝛾390-396A ). Consistent with prior studies, Fib𝛾390-396A mice were significantly protected from increased adiposity, NAFLD, hypercholesterolemia, and diabetes while Fib- and siFga-treated mice gained as much weight and developed obesity-associated pathologies identical to wildtype mice. FibAEK and FXIII- mice displayed an intermediate phenotype with partial protection from some obesity-associated pathologies. Results here indicate that fibrin(ogen) lacking αM β2 binding function offers substantial protection from obesity and associated disease that is partially recapitulated by preventing fibrin polymer formation or crosslinking of the wildtype molecule, but not by reduction or complete elimination of fibrinogen. Finally, these findings support the concept that fibrin polymerization and crosslinking are required for the full implementation of fibrin-driven inflammation in obesity.
antibodies
2026-04-07 | Factor XII in Thrombosis and Thromboinflammation: From Molecular Biology to Clinical Translation
Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein-kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies.
2025-03-23 | Congenital Factor XIII Deficiency in Taiwan: A Novel F13A1 p.Lys113* Variant Identified in a Patient With an Inhibitor and Our Experience to Induce Immune Tolerance
The authors declare no conflicts of interest. The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2024-09-25 | Development and Epitope Mapping of Seven Mouse Anti-Human Coagulation Factor XIII-B Subunit Monoclonal Antibodies.
Coagulation factor XIII (FXIII) is an enzyme that strengthens hemostatic clots, and its deficiency can cause life-threatening bleeding. We immunized mice with human plasma-derived FXIII to generate monoclonal antibodies (mAbs) against the B subunit (FXIII-B), which stabilizes the A subunit (FXIII-A) of FXIII, and analyzed their properties. The epitopes of the seven mouse antihuman FXIII-B mAbs obtained were found to be the 3rd, 5th, 6th, 9th, and 10th Sushi domains. One of these mAbs, mAb 5-6C, recognized the 10th Sushi domain and inhibited the fibrin cross-linking reaction without affecting the amine incorporation activity of FXIII. We previously reported that the 10th Sushi domain is the site where FXIII-B binds to fibrin and functions to bring FXIII-A closer to the substrate fibrin. Except for mAb 5-6C, mouse mAbs with high yields were used to measure the amount of FXIII-B antigen by an immunochromatography test (ICT), which showed a high correlation with enzyme-linked immunosorbent assay-obtained results. In addition, we developed a prototype ICT to detect anti-FXIII-B autoantibodies using mAb 1-3C, which showed good results in measuring the amount of FXIII-B antigen. Thus, mouse mAbs may be useful for clinical applications. mAb 5-6C targeting the 10th Sushi domain may also be useful for inhibiting thrombosis progression when humanized as antibody medicines.
2023-08-29 | Antibodies against Noncatalytic B Subunit of Factor XIII Inhibit Activation of Factor XIII and Fibrin Crosslinking.
Coagulation factor XIII (FXIII) is a proenzyme of plasma transglutaminase. It comprises two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). We previously reported that alloantibodies against FXIII-B could promote FXIII clearance in a patient with congenital FXIII-B deficiency who had received infusions of plasma-derived human FXIII (A2B2 heterotetramer). We aimed to investigate whether anti-FXIII-B antibodies affect the catalytic function of FXIII. FXIII activation and fibrin crosslinking were examined in the presence of patient plasma, isolated patient IgG, or rat anti-FXIII-B monoclonal antibodies. Alloantibody levels were increased by repeated infusions of plasma-derived A2B2 heterotetramer, which enhanced binding to the functionally important FXIII-B sushi domains. The patient plasma strongly inhibited cleavage of the FXIII-A activation peptide, amine incorporation, and fibrin crosslinking in normal plasma. Furthermore, anti-FXIII-B alloantibodies blocked the formation of the complex of FXIII-B with FXIII-A, and fibrinogen. Rat monoclonal antibodies against the 10th sushi domain of FXIII-B inhibited the incorporation of FXIII-B to fibrin, FXIII activation (i.e., cleavage of FXIII-A activation peptide), and ultimately fibrin crosslinking in normal plasma, independent of their effect on heterotetramer assembly with FXIII-A. Alloantibody binding to the A2B2 heterotetramer blocked the access of thrombin to the FXIII-A cleavage site, as indicated by the reaction of the alloantibodies to the A2B2 heterotetramer and FXIII-B, but not to FXIII-A. Anti-FXIII-B antibodies binding to the A2B2 heterotetramer and FXIII-B inhibited FXIII activation and its crosslinking function despite being directed against its noncatalytic subunit (FXIII-B).
2015-02-18 | Factor XIII activity mediates red blood cell retention in venous thrombi.
Venous thrombi, fibrin- and rbc-rich clots triggered by inflammation and blood stasis, underlie devastating, and sometimes fatal, occlusive events. During intravascular fibrin deposition, rbc are thought to become passively trapped in thrombi and therefore have not been considered a modifiable thrombus component. In the present study, we determined that activity of the transglutaminase factor XIII (FXIII) is critical for rbc retention within clots and directly affects thrombus size. Compared with WT mice, mice carrying a homozygous mutation in the fibrinogen γ chain (Fibγ390-396A) had a striking 50% reduction in thrombus weight due to reduced rbc content. Fibrinogen from mice harboring the Fibγ390-396A mutation exhibited reduced binding to FXIII, and plasma from these mice exhibited delayed FXIII activation and fibrin crosslinking, indicating these residues mediate FXIII binding and activation. FXIII-deficient mice phenocopied mice carrying Fibγ390-396A and produced smaller thrombi with fewer rbc than WT mice. Importantly, FXIII-deficient human clots also exhibited reduced rbc retention. The addition of FXIII to FXIII-deficient clots increased rbc retention, while inhibition of FXIII activity in normal blood reduced rbc retention and produced smaller clots. These findings establish the FXIII-fibrinogen axis as a central determinant in venous thrombogenesis and identify FXIII as a potential therapeutic target for limiting venous thrombosis.
proteins
2026-06-24 | Comparative Biochemical and Functional Characterization of a Novel Human Fibrinogen Concentrate (BT524) and Established Plasma-Derived Fibrinogen Concentrates
Abstract Human fibrinogen concentrate is used as replacement therapy for congenital and acquired fibrinogen deficiencies. Despite similar manufacturing principles, compositional differences among products may affect clot quality and hemostatic efficacy. BT524 (Biotest) is a newly developed human fibrinogen concentrate with proven clinical safety and efficacy. The objective of this study was to compare the biochemical composition and in vitro functional characteristics of BT524 with those of two commercially available plasma-derived fibrinogen concentrates (Products I and II). Three independent batches of each human fibrinogen concentrate were analyzed for the total and clottable protein, fibrinogen antigen, fibrinogen activity by Clauss, clotting factors, degradation markers (fibrinopeptide A and D-dimer), sub-visible particles, and aggregates. Maximum clot firmness and dynamics were assessed using rotational thromboelastometry (fibrin-based thromboelastometry). Fibrinogen deficient plasma with low factor XIII content was spiked each fibrinogen concentrate and increasing concentrations of factor XIII (0–0.8 U/mL). BT524 showed consistent fibrinogen content but contained no active factor VIII, factor XIII, or von Willebrand factor, indicating a precisely defined composition. Levels of degradation markers, aggregates, and sub-visible particles were markedly lower than in comparator products, reflecting the superior biochemical purity of BT524. BT524 achieved significantly higher maximum clot firmness than Product I (p<0.0001) and demonstrated comparable performance with Product II. Spiking of factor XIII resulted in an additional increase in maximum clot firmness in BT524 and Product II, but not in Product I, proving functional factor XIII susceptibility of BT524. BT524 demonstrates high biochemical purity and robust functional clot formation. These findings highlight that fibrinogen concentrates differ in composition, functionality and molecular integrity, which determines clot quality and hemostatic performance.
2026-05-06 | Essential Renal Bleeding Presenting as Persistent Unilateral Hematuria Successfully Treated With Factor XIII Replacement Therapy: A Case Report.
Essential renal bleeding is rare and lacks standardized treatment; organ-preserving options are critical in older patients with impaired renal function. A woman in her early 80s with atrial fibrillation treated with edoxaban, chronic heart failure, and advanced chronic kidney disease presented with gross hematuria and bladder tamponade. Bleeding was localized to the right renal pelvis and ureter, with no tumor, urolithiasis, vascular malformation, or glomerular disease; essential renal bleeding was diagnosed. Hematuria persisted despite edoxaban discontinuation, red blood cell and plasma transfusions, and carbazochrome sodium sulfonate administration. Isolated factor XIII activity was 22%. Intravenous plasma-derived factor XIII concentrate achieved sustained hemostasis, renal function remained stable, and reduced-dose edoxaban was safely resumed. Hematuria did not recur within 24 months. In this population, factor XIII deficiency may contribute to persistent unilateral hematuria despite normal conventional coagulation tests.
2026-01-26 | Factor XIII Deficiency: A Review of Biology, Testing, and Treatment.
Factor XIII (FXIII) deficiency is a rare bleeding disorder characterized by unstable hemostatic clots due to defective fibrin cross‑linking. Congenital FXIII deficiency arises from variants in the F13A1 (FXIII-A subunit) or F13B (FXIII-B subunit) genes, and classically presents with delayed umbilical stump hemorrhage, soft‑tissue and intracranial bleeding, impaired wound healing, and recurrent pregnancy loss. Acquired deficiency stems from inhibitory autoantibodies or from reduced synthesis or consumption in critical illness and surgery. Routine coagulation screening tests are normal and diagnosis relies on quantitative FXIII activity assays with or without antigenic phenotyping and, when indicated, inhibitor testing and molecular confirmation. Plasma‑derived FXIII concentrate reduces spontaneous and intracranial bleeding; recombinant FXIII‑A2 is appropriate for F13A1 defects but not patients with F13B variants. Perioperative and obstetric care target activity thresholds suited to procedural risk and individual pharmacokinetics. This review synthesizes the molecular biology, epidemiology, clinical features, diagnostic methods, and evidence‑based management of FXIII deficiency, with practical guidance for assay selection, validation, and result interpretation.
2025-12-31 | <b>ASSOCIATION OF COAGULATION FACTOR XIII DEFICIENCY WITH MENORRHAGIA AND NUTRITIONAL STATUS: A COMPREHENSIVE REVIEW OF CURRENT EVIDENCE</b>
The final enzyme of the coagulation cascade is Coagulation Factor XIII (FXIII) that has a direct role in cross-linking fibrin and stabilizing clot. FXIII deficiency, found either congenital or acquired, leads to development of mechanically unstable clots and a bleeding phenotype with a delay or repeat bleeding despite usual routine screening levels of coagulation. Womenorrhagia or heavy menstrual bleeding is also a common although poorly appreciated clinical presentation in females and it usually takes several years before diagnosis. Chronic menstrual blood loss has important nutritional consequences, especially iron homeostasis, and is a major cause of iron deficiency and iron deficiency anemia in the adolescent group and in women of child bearing age. On the other hand, an acquired form of FXIII deficiency can occur as a disease complication often linked with malnutrition such as chronic liver disease and inflammatory disease as well as protein-losing fistulas, thus indicating a two-way interaction between FXIII activity and nutritional wellbeing. The given review summarizes the existing body of evidence regarding the relationship between FXIII deficiency and menorrhagia and nutritional condition with a special focus on pathophysiology, clinical manifestation, diagnostic issues, and treatment planning. Impact of the late value of recognition, mediating impacts of iron deficiency as morbidities, and need of combined hematologic, gynecologic, and nutritional care are emphasized.
2024-11-05 | Rare Coagulation Disorders: A Comprehensive Study from the Largest Hospital in Latin America
Introduction: Rare inherited bleeding disorders (RIBD) represent approximately 5% of hereditary coagulopathies and include deficiencies of coagulation factors other than VII, IX, and von Willebrand factor. The global prevalence of RIBD varies by region and type of deficiency, with rates as low as 1 in 2,000,000 individuals. In low- and middle-income countries, such as Brazil, there is a paucity of data pertaining to the clinical presentation and the challenges in diagnosing these diseases, particularly within the public health system and its constrained resources. The objective of this study is to describe the clinical phenotype, as well as the patient journey to diagnosis and treatment, with the ultimate goal of raising awareness of RIBD in these regions. Materials and Methods: This is a case series study including all patients with RIBD followed in the largest hospital complex in Latin America, located in São Paulo, Brazil. Data collected included demographics, bleeding episodes, and severity according to the ISTH classification. This study was approved by the local ethics committee. Results: A total of 82 patients with RIBD were included in the study. The cohort comprised 48 females (58.5%) and 34 males (41.5%), with a median age of 40 years (SD ± 21.0). The average age at diagnosis was 27 years (SD ± 22.2). The median time from diagnostic suspicion to confirmation among the studied cohort was 165 days (IQR 25-75% 33-1348 days). Regarding the types of coagulopathies, the distribution was as follows: factor VII deficiency was the most common, accounting for 43.9% of cases. This was followed by factor XI deficiency at 19.5%, heritable fibrinogen disorders at 13.4%, factor V deficiency at 7.3%, factor XIII deficiency at 4.9%, combined factor V and factor VIII deficiency at 4.9%, factor X deficiency at 3.7%, combined vitamin K-dependent clotting factors deficiency at 1.2% and factor XII deficiency at 1.2%. In terms of bleeding severity according to ISTH classification, major bleeding occurred in 23% of cases, clinically significant minor bleeding in 12% of cases and minor bleeding in 26%. Parental consanguinity was reported in 13.8% of patients. Patients with fibrinogen disorders, factor XIII deficiency, combined factor V and factor VIII deficiency, and vitamin K-dependent clotting factors deficiency exhibited the highest incidence of bleeding. Regarding major bleedings, the RIBD with the highest rate of bleedings was vitamin K deficiency (100%), followed by factor XIII deficiency (75%), factor X deficiency (66%), and fibrinogen disorders (66%). Conclusion: Rare inherited bleeding disorders are diseases with highly diverse clinical manifestations and laboratory abnormalities, which present a significant challenge to diagnosis. The study highlights significant diagnostic delays experienced by patients with these diseases in a resource-limited country. Enhanced awareness and resource allocation are essential for improving the diagnosis and management of these disorders in developing countries.
cell therapies
2025-07-25 | Retroperitoneal fibrosis in presence of autoimmune coagulation factor XIII deficiency result in recurrent critical post-operative hemorrhage: a case report and molecular research with new insights.
Idiopathic retroperitoneal fibrosis is an IgG4-related disease where pathological role and clinical significance of IgG4 antibodies remain largely unknown. This report shows a rare case of retroperitoneal fibrosis in presence of Autoimmune coagulation factor XIII deficiency, in which an acute life-threatening hemorrhage was successfully managed with effective treatment strategies. Following this, we investigated the molecular mechanisms underlying the patient's pathology using experimental translational approach. The patient was a 60-year-old Asian man with a retroperitoneal mass. A laparoscopic biopsy confirmed that the lesion was retroperitoneal fibrosis with IgG4-expressing plasma cell infiltration. Though biopsy was completed without complications, the patient experienced repeated life-threatening intraperitoneal bleeding starting the next day. Despite performing one emergency laparotomy and three series of emergency transcatheter arterial embolization along with massive transfusions, achieving hemostasis was difficult. Suspecting a humoral autoimmune hemorrhagic disorder, we performed plasma exchange, which achieved complete hemostasis. Later, an abnormal decrease in the activity of coagulation Factor XIII was observed, leading to the diagnosis of Autoimmune coagulation Factor XIII deficiency. Subsequent treatment with steroids and coagulation Factor XIII concentrates prevented further bleeding. We investigated the potential involvement of IgG4-related disease and the effects of IgG4 on coagulation Factor XIII using an in vitro system, and it was demonstrated that both IgG1 and IgG4 recognized the A subunit of coagulation Factor XIII. The purified IgG antibody samples containing IgG1 and IgG4 were shown to significantly reduce the function of coagulation Factor XIII derived from healthy individuals. The patient experienced recurrent life-threatening bleeding due to Autoimmune coagulation Factor XIII deficiency, which was successfully controlled through plasma exchange therapy. This is the first reported case of concurrent retroperitoneal fibrosis and Autoimmune coagulation Factor XIII deficiency. Based on the results of our research, it is suggested IgG4 may play a role in the pathology of both disorders. It was hypothesized that this hematological disorder could be a part of the spectrum of IgG4 autoimmune diseases.
2023-06-01 | Perioperative therapeutic plasma exchange in a patient with rare Factor XIII inhibitor
Factor 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).To 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.The 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.TPE is useful in removing XIII inhibitory factor, but the effects are only short term.
other
2022-06-03 | The most common disease-causing mutation of factor XIII deficiency is corrected by CRISPR/CAS9 gene editing system.
Factor XIII (FXIII) deficiency is one of the most severe congenital bleeding disorders, with an estimated incidence of one person per one million. Patients with severe FXIII deficiency present a wide range of clinical manifestations, including umbilical cord bleeding, intracranial haemorrhage and recurrent miscarriages. Due to the high rate of life-threatening bleeding, primary prophylaxis is mandatory from the time of diagnosis. Although replacement therapy is the most common therapeutic choice, gene therapy remains the only curative option. In the present study, we assessed the efficacy of the clustered regularly interspaced short palindromic repeats - CRISPR-associated protein 9 (CRISPR/Cas9) system in the correction of the most common FXIII disease-causing mutation (c.562 T > C). A dermal fibroblast was harvested from the human skin biopsy of a young patient with FXIII deficiency. Sanger sequencing was used to confirm the presence of c.562 T>C mutation in the patient and in the harvested fibroblasts. PX459 vector was digested with BbsI restriction enzyme, and after annealing and ligation of two 20-bp guide-RNAs (g-RNAs) close to the PAM (NGG) sequence, the constructed vectors were amplified in Escherichia coli Top 10. Transfection was performed by a nucleofector device, and DNA extraction was performed after puromycin selection and serial dilution from potentially transfected colonies. A 50-bp template oligonucleotide was used to aid homologous repair for correction of the underlying mutation and synonymous mutation as an internal control. The synonymous mutation (AAT to ACT) near the mutation site was used as internal control. Sanger sequencing was done in order to check the gene correction. The c.562 T > C mutation was detected in homozygote state in the primary fibroblasts of the patient and wild-type alleles were confirmed in the normal individual. Colony PCR and sequencing revealed successful cloning of the designed gRNAs. The detected mutation was corrected from a homozygote mutant state (c.562 T > C) to a homozygote wild type in transfected dermal fibroblasts of the patient. The control mutation, as an internal control, was also corrected in the same fibroblasts in the heterozygote manner. The result of the study shows that the CRISPR/CAS9 gene editing system is an effective tool for correction of point mutations in transfected fibroblasts of patients with congenital FXIII deficiency and represents a new, potentially curative, option.
small molecules
2025-11-01 | Postsurgical Hemorrhage in Senile Entropion Due to Factor XIII Deficiency
Background: When diagnosing postsurgical bleeding with normal coagulation tests, factor XIII (F XIII) deficiency must be ruled out. This circulates in plasma, mainly bound to fibrinogen, and has a half-life of 7 to 14 days. F XIII acts as a fibrin stabilizer and is involved in tissue repair and healing. In F XIII deficiency, coagulation tests are normal because it does not participate in thrombus formation but rather in its stabilization, both in congenital and acquired deficiency. Patients with FXIII levels below 1 U/dL are at high risk of early onset bleeding (with umbilical cord hemorrhage). With factor levels between 1 and 4 U/dL, the hemorrhagic phenotype is severe or moderate. With values above 5 U/dL, hemorrhagic symptoms are occasional. However, cases of mild deficiency (factor XIII activity levels of 30–60%) have been reported in which abnormal posttraumatic bleeding may occur. Treatment ranges from specific F XIII concentrate or fresh frozen plasma to antifibrinolytic drugs in mild cases. Methods: A 78-year-old patient, no toxic habits, with a history of high blood pressure, dyslipidaemia, type II diabetes mellitus, and ischemic heart disease. Two episodes of hospitalization for anemia of digestive origin. He had undergone transurethral resection of the prostate, infrarenal aortic aneurysm repair with endoprosthesis, and cataract surgery in both eyes without hemorrhagic complications. He was being treated with rosuvastatin, valsartan, bisoprolol, furosemide, and linagliptin. He required surgery for senile entropion of the lower eyelid of the right eye under local anesthesia. Preoperative tests, including a complete blood count, biochemistry, and coagulation, showed normal values. A lateral tarsal strip was performed to anchor the outer edge of the eyelid to the orbit to tighten it. Forty-eight hours after the operation, the patient presented with continuous bleeding from the surgical wound, hyposphagma, and a large hematoma on the lower eyelid. The surgical wound was examined on three occasions and, despite local compression and hemostatic measures, recurrent bleeding continued in the surgical bed for 2 weeks, requiring urgent attention on several occasions. Results: Subsequently, the study was expanded to include plasma factor determination, finding only a Factor XIII value of 42%. After ruling out other causes of hemorrhagic diathesis, Factor XIII deficiency was considered to be the cause of the condition. Treatment with tranexamic acid at a dose of 1 g every 8 hours orally helped to resolve the condition. Conclusion: Outpatient entropion surgery resulted in moderate hemorrhagic complications that complicated the postoperative period. The mild Factor XIII deficiency caused recurrent bleeding that required interventional and pharmacological treatment with antifibrinolytics. Publication History Article published online: 31 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-02-28 | Factor XI and XII inhibitors-Dawn of a new era.
The history of coagulation cascade dates back to 17th century. The extrinsic and intrinsic pathways were proposed in 1998. Extrinsic pathway includes the tissue factor and stable factor which activates factor X and with help of factor V, this converts prothrombin to thrombin which is stabilised by factor XIII. This helps to seal the bleeding vessel and is a physiological process as there is only "limited" production of thrombin which doe not expand beyond the damaged site due to absence of tissue factor. On the other hand intrinsic pathway is activated by polyanions, neutrophilic extracellular traps which are present during infection and inflammation. These activate factor XI which activates factor X with the help of factor IX and VIII and then the common pathway ensues. But newer discoveries have shown that this is a very simplified way of explaining the coagulation system. The researches propose that haemostasis is divided into initiation, amplification and propagation phase. Also, the factor VII-tissue factor complex formed activates factor IX and leads to sustained thrombin production as the amount of thrombin produced by extrinsic pathway alone is not sufficient to form a haemostatic plug. Thrombin also activates factor XI and lead to self perpetuation of intrinsic pathway. All the anticoagulants have an inherent property of bleeding. So the newer factor XI and XII inhibitors focus to inhibit the excessive thrombin production without hampering the physiological haemostasis process. This is supported by the fact that congenital factor XI and XII deficiency does not cause excessive bleeding but increased levels did make patients more vulnerable to thromboembolism. This review shall focus on the various factor XI and XII inhibitors which are in the pipeline.
2024-04-10 | Management of anticoagulation and factor XIII replacement in a patient with severe factor XIII deficiency and recurrent venous thromboembolic disease: case report and review of literature.
Thrombotic events in congenital factor (F)XIII deficiency are extremely rare. To our knowledge, we describe the first case of severe congenital FXIII deficiency associated with recurrent venous thrombotic events. How to deal with anticoagulation treatment in patients with severe FXIII deficiency? The patient was treated with rivaroxaban and plasma-derived FXIII substitution therapy as prophylaxis without bleeding complications. We aimed at FXIII trough levels of 50% during the loading doses of rivaroxaban, then 30% during the maintenance dose of rivaroxaban, and finally 20% during the long-term use of prophylactic dose of rivaroxaban. Treatment of thrombotic events with rivaroxaban in patients with severe bleeding disorders seems to be safe, requiring an adaptation of the intensity of the replacement therapy.
2023-02-23 | The Role of Different Matrixin Gene Expressions on Cerebral Bleeding among Patients with Deficiency of Coagulation Factor XIII.
Enzymes of the matrixin family could be seen as a critical determinant in the breakdown of the extracellular matrix, cell membrane, and tissue regeneration and are interned in the process of brain bleeding. On the other hand, coagulation factor XIII deficiency is a sporadic hemorrhagic disease with an estimated prevalence of 1 in 1-2 million people. Cerebral hemorrhage is the leading cause of death in these patients. This study investigated the relationship between the expression of matrix metalloproteinase 9 and 2 genes with cerebral hemorrhage in these patients. For this purpose, in this case-control study, by examining the clinical and general findings of the studied patients, the Q-Real-time RT-PCR method was used to quantitatively examine the mRNA levels of matrix metalloproteinase 9 and 2 in 42 patients with hereditary deficiency of coagulation factor XIII, including two groups with and without a history of cerebral hemorrhage (case and control groups, respectively). A comparative method (2-ΔΔCT) was used to check the expression level of the target genes. The GAPDH gene expression levels were used to standardize the expression of the measured matrix metalloproteinase genes. The results showed that bleeding from the umbilical cord was the most common clinical symptom among all patients. High levels of MMP-9 gene expression were observed in 13 patients of the case group (69.99%) and three patients of the control group (11.9%). which showed a significant difference (CI: 2.77-95.3, P=0.001) Patients with coagulation factor XIII deficiency show a wide range of clinical symptoms crucial in screening and diagnosing this group of patients. Based on the results of this study, it seems that the increased expression of the MMP-9 gene is due to polymorphism or inflammation related to the pathogenesis of cerebral hemorrhage in this category of patients. It may be conceivable to diminish this impact by utilizing MMP-9 inhibitors and offering assistance to diminishes these patients' hospitalization and passing rates.
2022-11-15 | Elimination of fibrin polymer formation or crosslinking, but not fibrinogen deficiency, is protective against diet-induced obesity and associated pathologies.
Obesity predisposes individuals to metabolic syndrome, which increases the risk of cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes. A pathological manifestation of obesity is the activation of the coagulation system. In turn, extravascular fibrin(ogen) deposits accumulate in adipose tissues and liver. These deposits promote adiposity and downstream sequelae by driving pro-inflammatory macrophage function through binding the leukocyte integrin receptor αM β2 . An unresolved question is whether conversion of soluble fibrinogen to a crosslinked fibrin matrix is required to exacerbate obesity-driven diseases. Here, fibrinogen-deficient/depleted mice (Fib- or treated with siRNA against fibrinogen [siFga]), mice expressing fibrinogen that cannot polymerize to fibrin (FibAEK ), and mice deficient in the fibrin crosslinking transglutaminase factor XIII (FXIII-) were challenged with a high-fat diet (HFD) and compared to mice expressing a mutant form of fibrinogen lacking the αM β2 -binding domain (Fib𝛾390-396A ). Consistent with prior studies, Fib𝛾390-396A mice were significantly protected from increased adiposity, NAFLD, hypercholesterolemia, and diabetes while Fib- and siFga-treated mice gained as much weight and developed obesity-associated pathologies identical to wildtype mice. FibAEK and FXIII- mice displayed an intermediate phenotype with partial protection from some obesity-associated pathologies. Results here indicate that fibrin(ogen) lacking αM β2 binding function offers substantial protection from obesity and associated disease that is partially recapitulated by preventing fibrin polymer formation or crosslinking of the wildtype molecule, but not by reduction or complete elimination of fibrinogen. Finally, these findings support the concept that fibrin polymerization and crosslinking are required for the full implementation of fibrin-driven inflammation in obesity.
antibodies
2026-04-07 | Factor XII in Thrombosis and Thromboinflammation: From Molecular Biology to Clinical Translation
Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein-kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies.
2025-03-23 | Congenital Factor XIII Deficiency in Taiwan: A Novel F13A1 p.Lys113* Variant Identified in a Patient With an Inhibitor and Our Experience to Induce Immune Tolerance
The authors declare no conflicts of interest. The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2024-09-25 | Development and Epitope Mapping of Seven Mouse Anti-Human Coagulation Factor XIII-B Subunit Monoclonal Antibodies.
Coagulation factor XIII (FXIII) is an enzyme that strengthens hemostatic clots, and its deficiency can cause life-threatening bleeding. We immunized mice with human plasma-derived FXIII to generate monoclonal antibodies (mAbs) against the B subunit (FXIII-B), which stabilizes the A subunit (FXIII-A) of FXIII, and analyzed their properties. The epitopes of the seven mouse antihuman FXIII-B mAbs obtained were found to be the 3rd, 5th, 6th, 9th, and 10th Sushi domains. One of these mAbs, mAb 5-6C, recognized the 10th Sushi domain and inhibited the fibrin cross-linking reaction without affecting the amine incorporation activity of FXIII. We previously reported that the 10th Sushi domain is the site where FXIII-B binds to fibrin and functions to bring FXIII-A closer to the substrate fibrin. Except for mAb 5-6C, mouse mAbs with high yields were used to measure the amount of FXIII-B antigen by an immunochromatography test (ICT), which showed a high correlation with enzyme-linked immunosorbent assay-obtained results. In addition, we developed a prototype ICT to detect anti-FXIII-B autoantibodies using mAb 1-3C, which showed good results in measuring the amount of FXIII-B antigen. Thus, mouse mAbs may be useful for clinical applications. mAb 5-6C targeting the 10th Sushi domain may also be useful for inhibiting thrombosis progression when humanized as antibody medicines.
2023-08-29 | Antibodies against Noncatalytic B Subunit of Factor XIII Inhibit Activation of Factor XIII and Fibrin Crosslinking.
Coagulation factor XIII (FXIII) is a proenzyme of plasma transglutaminase. It comprises two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). We previously reported that alloantibodies against FXIII-B could promote FXIII clearance in a patient with congenital FXIII-B deficiency who had received infusions of plasma-derived human FXIII (A2B2 heterotetramer). We aimed to investigate whether anti-FXIII-B antibodies affect the catalytic function of FXIII. FXIII activation and fibrin crosslinking were examined in the presence of patient plasma, isolated patient IgG, or rat anti-FXIII-B monoclonal antibodies. Alloantibody levels were increased by repeated infusions of plasma-derived A2B2 heterotetramer, which enhanced binding to the functionally important FXIII-B sushi domains. The patient plasma strongly inhibited cleavage of the FXIII-A activation peptide, amine incorporation, and fibrin crosslinking in normal plasma. Furthermore, anti-FXIII-B alloantibodies blocked the formation of the complex of FXIII-B with FXIII-A, and fibrinogen. Rat monoclonal antibodies against the 10th sushi domain of FXIII-B inhibited the incorporation of FXIII-B to fibrin, FXIII activation (i.e., cleavage of FXIII-A activation peptide), and ultimately fibrin crosslinking in normal plasma, independent of their effect on heterotetramer assembly with FXIII-A. Alloantibody binding to the A2B2 heterotetramer blocked the access of thrombin to the FXIII-A cleavage site, as indicated by the reaction of the alloantibodies to the A2B2 heterotetramer and FXIII-B, but not to FXIII-A. Anti-FXIII-B antibodies binding to the A2B2 heterotetramer and FXIII-B inhibited FXIII activation and its crosslinking function despite being directed against its noncatalytic subunit (FXIII-B).
2015-02-18 | Factor XIII activity mediates red blood cell retention in venous thrombi.
Venous thrombi, fibrin- and rbc-rich clots triggered by inflammation and blood stasis, underlie devastating, and sometimes fatal, occlusive events. During intravascular fibrin deposition, rbc are thought to become passively trapped in thrombi and therefore have not been considered a modifiable thrombus component. In the present study, we determined that activity of the transglutaminase factor XIII (FXIII) is critical for rbc retention within clots and directly affects thrombus size. Compared with WT mice, mice carrying a homozygous mutation in the fibrinogen γ chain (Fibγ390-396A) had a striking 50% reduction in thrombus weight due to reduced rbc content. Fibrinogen from mice harboring the Fibγ390-396A mutation exhibited reduced binding to FXIII, and plasma from these mice exhibited delayed FXIII activation and fibrin crosslinking, indicating these residues mediate FXIII binding and activation. FXIII-deficient mice phenocopied mice carrying Fibγ390-396A and produced smaller thrombi with fewer rbc than WT mice. Importantly, FXIII-deficient human clots also exhibited reduced rbc retention. The addition of FXIII to FXIII-deficient clots increased rbc retention, while inhibition of FXIII activity in normal blood reduced rbc retention and produced smaller clots. These findings establish the FXIII-fibrinogen axis as a central determinant in venous thrombogenesis and identify FXIII as a potential therapeutic target for limiting venous thrombosis.
proteins
2026-06-24 | Comparative Biochemical and Functional Characterization of a Novel Human Fibrinogen Concentrate (BT524) and Established Plasma-Derived Fibrinogen Concentrates
Abstract Human fibrinogen concentrate is used as replacement therapy for congenital and acquired fibrinogen deficiencies. Despite similar manufacturing principles, compositional differences among products may affect clot quality and hemostatic efficacy. BT524 (Biotest) is a newly developed human fibrinogen concentrate with proven clinical safety and efficacy. The objective of this study was to compare the biochemical composition and in vitro functional characteristics of BT524 with those of two commercially available plasma-derived fibrinogen concentrates (Products I and II). Three independent batches of each human fibrinogen concentrate were analyzed for the total and clottable protein, fibrinogen antigen, fibrinogen activity by Clauss, clotting factors, degradation markers (fibrinopeptide A and D-dimer), sub-visible particles, and aggregates. Maximum clot firmness and dynamics were assessed using rotational thromboelastometry (fibrin-based thromboelastometry). Fibrinogen deficient plasma with low factor XIII content was spiked each fibrinogen concentrate and increasing concentrations of factor XIII (0–0.8 U/mL). BT524 showed consistent fibrinogen content but contained no active factor VIII, factor XIII, or von Willebrand factor, indicating a precisely defined composition. Levels of degradation markers, aggregates, and sub-visible particles were markedly lower than in comparator products, reflecting the superior biochemical purity of BT524. BT524 achieved significantly higher maximum clot firmness than Product I (p<0.0001) and demonstrated comparable performance with Product II. Spiking of factor XIII resulted in an additional increase in maximum clot firmness in BT524 and Product II, but not in Product I, proving functional factor XIII susceptibility of BT524. BT524 demonstrates high biochemical purity and robust functional clot formation. These findings highlight that fibrinogen concentrates differ in composition, functionality and molecular integrity, which determines clot quality and hemostatic performance.
2026-05-06 | Essential Renal Bleeding Presenting as Persistent Unilateral Hematuria Successfully Treated With Factor XIII Replacement Therapy: A Case Report.
Essential renal bleeding is rare and lacks standardized treatment; organ-preserving options are critical in older patients with impaired renal function. A woman in her early 80s with atrial fibrillation treated with edoxaban, chronic heart failure, and advanced chronic kidney disease presented with gross hematuria and bladder tamponade. Bleeding was localized to the right renal pelvis and ureter, with no tumor, urolithiasis, vascular malformation, or glomerular disease; essential renal bleeding was diagnosed. Hematuria persisted despite edoxaban discontinuation, red blood cell and plasma transfusions, and carbazochrome sodium sulfonate administration. Isolated factor XIII activity was 22%. Intravenous plasma-derived factor XIII concentrate achieved sustained hemostasis, renal function remained stable, and reduced-dose edoxaban was safely resumed. Hematuria did not recur within 24 months. In this population, factor XIII deficiency may contribute to persistent unilateral hematuria despite normal conventional coagulation tests.
2026-01-26 | Factor XIII Deficiency: A Review of Biology, Testing, and Treatment.
Factor XIII (FXIII) deficiency is a rare bleeding disorder characterized by unstable hemostatic clots due to defective fibrin cross‑linking. Congenital FXIII deficiency arises from variants in the F13A1 (FXIII-A subunit) or F13B (FXIII-B subunit) genes, and classically presents with delayed umbilical stump hemorrhage, soft‑tissue and intracranial bleeding, impaired wound healing, and recurrent pregnancy loss. Acquired deficiency stems from inhibitory autoantibodies or from reduced synthesis or consumption in critical illness and surgery. Routine coagulation screening tests are normal and diagnosis relies on quantitative FXIII activity assays with or without antigenic phenotyping and, when indicated, inhibitor testing and molecular confirmation. Plasma‑derived FXIII concentrate reduces spontaneous and intracranial bleeding; recombinant FXIII‑A2 is appropriate for F13A1 defects but not patients with F13B variants. Perioperative and obstetric care target activity thresholds suited to procedural risk and individual pharmacokinetics. This review synthesizes the molecular biology, epidemiology, clinical features, diagnostic methods, and evidence‑based management of FXIII deficiency, with practical guidance for assay selection, validation, and result interpretation.
2025-12-31 | <b>ASSOCIATION OF COAGULATION FACTOR XIII DEFICIENCY WITH MENORRHAGIA AND NUTRITIONAL STATUS: A COMPREHENSIVE REVIEW OF CURRENT EVIDENCE</b>
The final enzyme of the coagulation cascade is Coagulation Factor XIII (FXIII) that has a direct role in cross-linking fibrin and stabilizing clot. FXIII deficiency, found either congenital or acquired, leads to development of mechanically unstable clots and a bleeding phenotype with a delay or repeat bleeding despite usual routine screening levels of coagulation. Womenorrhagia or heavy menstrual bleeding is also a common although poorly appreciated clinical presentation in females and it usually takes several years before diagnosis. Chronic menstrual blood loss has important nutritional consequences, especially iron homeostasis, and is a major cause of iron deficiency and iron deficiency anemia in the adolescent group and in women of child bearing age. On the other hand, an acquired form of FXIII deficiency can occur as a disease complication often linked with malnutrition such as chronic liver disease and inflammatory disease as well as protein-losing fistulas, thus indicating a two-way interaction between FXIII activity and nutritional wellbeing. The given review summarizes the existing body of evidence regarding the relationship between FXIII deficiency and menorrhagia and nutritional condition with a special focus on pathophysiology, clinical manifestation, diagnostic issues, and treatment planning. Impact of the late value of recognition, mediating impacts of iron deficiency as morbidities, and need of combined hematologic, gynecologic, and nutritional care are emphasized.
2024-11-05 | Rare Coagulation Disorders: A Comprehensive Study from the Largest Hospital in Latin America
Introduction: Rare inherited bleeding disorders (RIBD) represent approximately 5% of hereditary coagulopathies and include deficiencies of coagulation factors other than VII, IX, and von Willebrand factor. The global prevalence of RIBD varies by region and type of deficiency, with rates as low as 1 in 2,000,000 individuals. In low- and middle-income countries, such as Brazil, there is a paucity of data pertaining to the clinical presentation and the challenges in diagnosing these diseases, particularly within the public health system and its constrained resources. The objective of this study is to describe the clinical phenotype, as well as the patient journey to diagnosis and treatment, with the ultimate goal of raising awareness of RIBD in these regions. Materials and Methods: This is a case series study including all patients with RIBD followed in the largest hospital complex in Latin America, located in São Paulo, Brazil. Data collected included demographics, bleeding episodes, and severity according to the ISTH classification. This study was approved by the local ethics committee. Results: A total of 82 patients with RIBD were included in the study. The cohort comprised 48 females (58.5%) and 34 males (41.5%), with a median age of 40 years (SD ± 21.0). The average age at diagnosis was 27 years (SD ± 22.2). The median time from diagnostic suspicion to confirmation among the studied cohort was 165 days (IQR 25-75% 33-1348 days). Regarding the types of coagulopathies, the distribution was as follows: factor VII deficiency was the most common, accounting for 43.9% of cases. This was followed by factor XI deficiency at 19.5%, heritable fibrinogen disorders at 13.4%, factor V deficiency at 7.3%, factor XIII deficiency at 4.9%, combined factor V and factor VIII deficiency at 4.9%, factor X deficiency at 3.7%, combined vitamin K-dependent clotting factors deficiency at 1.2% and factor XII deficiency at 1.2%. In terms of bleeding severity according to ISTH classification, major bleeding occurred in 23% of cases, clinically significant minor bleeding in 12% of cases and minor bleeding in 26%. Parental consanguinity was reported in 13.8% of patients. Patients with fibrinogen disorders, factor XIII deficiency, combined factor V and factor VIII deficiency, and vitamin K-dependent clotting factors deficiency exhibited the highest incidence of bleeding. Regarding major bleedings, the RIBD with the highest rate of bleedings was vitamin K deficiency (100%), followed by factor XIII deficiency (75%), factor X deficiency (66%), and fibrinogen disorders (66%). Conclusion: Rare inherited bleeding disorders are diseases with highly diverse clinical manifestations and laboratory abnormalities, which present a significant challenge to diagnosis. The study highlights significant diagnostic delays experienced by patients with these diseases in a resource-limited country. Enhanced awareness and resource allocation are essential for improving the diagnosis and management of these disorders in developing countries.
cell therapies
2025-07-25 | Retroperitoneal fibrosis in presence of autoimmune coagulation factor XIII deficiency result in recurrent critical post-operative hemorrhage: a case report and molecular research with new insights.
Idiopathic retroperitoneal fibrosis is an IgG4-related disease where pathological role and clinical significance of IgG4 antibodies remain largely unknown. This report shows a rare case of retroperitoneal fibrosis in presence of Autoimmune coagulation factor XIII deficiency, in which an acute life-threatening hemorrhage was successfully managed with effective treatment strategies. Following this, we investigated the molecular mechanisms underlying the patient's pathology using experimental translational approach. The patient was a 60-year-old Asian man with a retroperitoneal mass. A laparoscopic biopsy confirmed that the lesion was retroperitoneal fibrosis with IgG4-expressing plasma cell infiltration. Though biopsy was completed without complications, the patient experienced repeated life-threatening intraperitoneal bleeding starting the next day. Despite performing one emergency laparotomy and three series of emergency transcatheter arterial embolization along with massive transfusions, achieving hemostasis was difficult. Suspecting a humoral autoimmune hemorrhagic disorder, we performed plasma exchange, which achieved complete hemostasis. Later, an abnormal decrease in the activity of coagulation Factor XIII was observed, leading to the diagnosis of Autoimmune coagulation Factor XIII deficiency. Subsequent treatment with steroids and coagulation Factor XIII concentrates prevented further bleeding. We investigated the potential involvement of IgG4-related disease and the effects of IgG4 on coagulation Factor XIII using an in vitro system, and it was demonstrated that both IgG1 and IgG4 recognized the A subunit of coagulation Factor XIII. The purified IgG antibody samples containing IgG1 and IgG4 were shown to significantly reduce the function of coagulation Factor XIII derived from healthy individuals. The patient experienced recurrent life-threatening bleeding due to Autoimmune coagulation Factor XIII deficiency, which was successfully controlled through plasma exchange therapy. This is the first reported case of concurrent retroperitoneal fibrosis and Autoimmune coagulation Factor XIII deficiency. Based on the results of our research, it is suggested IgG4 may play a role in the pathology of both disorders. It was hypothesized that this hematological disorder could be a part of the spectrum of IgG4 autoimmune diseases.
2023-06-01 | Perioperative therapeutic plasma exchange in a patient with rare Factor XIII inhibitor
Factor 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).To 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.The 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.TPE is useful in removing XIII inhibitory factor, but the effects are only short term.
other
2022-06-03 | The most common disease-causing mutation of factor XIII deficiency is corrected by CRISPR/CAS9 gene editing system.
Factor XIII (FXIII) deficiency is one of the most severe congenital bleeding disorders, with an estimated incidence of one person per one million. Patients with severe FXIII deficiency present a wide range of clinical manifestations, including umbilical cord bleeding, intracranial haemorrhage and recurrent miscarriages. Due to the high rate of life-threatening bleeding, primary prophylaxis is mandatory from the time of diagnosis. Although replacement therapy is the most common therapeutic choice, gene therapy remains the only curative option. In the present study, we assessed the efficacy of the clustered regularly interspaced short palindromic repeats - CRISPR-associated protein 9 (CRISPR/Cas9) system in the correction of the most common FXIII disease-causing mutation (c.562 T > C). A dermal fibroblast was harvested from the human skin biopsy of a young patient with FXIII deficiency. Sanger sequencing was used to confirm the presence of c.562 T>C mutation in the patient and in the harvested fibroblasts. PX459 vector was digested with BbsI restriction enzyme, and after annealing and ligation of two 20-bp guide-RNAs (g-RNAs) close to the PAM (NGG) sequence, the constructed vectors were amplified in Escherichia coli Top 10. Transfection was performed by a nucleofector device, and DNA extraction was performed after puromycin selection and serial dilution from potentially transfected colonies. A 50-bp template oligonucleotide was used to aid homologous repair for correction of the underlying mutation and synonymous mutation as an internal control. The synonymous mutation (AAT to ACT) near the mutation site was used as internal control. Sanger sequencing was done in order to check the gene correction. The c.562 T > C mutation was detected in homozygote state in the primary fibroblasts of the patient and wild-type alleles were confirmed in the normal individual. Colony PCR and sequencing revealed successful cloning of the designed gRNAs. The detected mutation was corrected from a homozygote mutant state (c.562 T > C) to a homozygote wild type in transfected dermal fibroblasts of the patient. The control mutation, as an internal control, was also corrected in the same fibroblasts in the heterozygote manner. The result of the study shows that the CRISPR/CAS9 gene editing system is an effective tool for correction of point mutations in transfected fibroblasts of patients with congenital FXIII deficiency and represents a new, potentially curative, option.
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Drug Discovery Landscape
5 orphan drug designations for Congenital factor XIII deficiency, including 2 approved therapies.
5 orphan drug designations for Congenital factor XIII deficiency, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Catridecacog [NovoThirteen & Trifeda] | proteins | EMA | 2003-12-12 | — | Novo Nordisk A/S |
coagulation factor XIII A-subunit (recombinant) [TRETTEN] | proteins | FDA | 2003-11-06 | 2013-12-23 | Novo Nordisk, Inc. |
Factor XIII [A2] homodimer, recombinant DNA origin | proteins | FDA | 2003-05-21 | — | Novo Nordisk Pharmaceuticals, INc. |
Factor XIII, recombinant | proteins | FDA | 1993-04-22 | — | Zymogenetics, Inc. |
factor XIII concentrate (human) [Corifact] | proteins | FDA | 1985-01-16 | 2011-02-17 | CSL Behring LLC |
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