Acquired factor XIII deficiency and its unprecedented association with multiple myeloma: case report and literature review.

This case involves a 58-year-old patient, with no personal or family history of bleeding, diagnosed with stage III-A IgG Kappa multiple myeloma in 2016 and underwent autografting in 2017. In March 2022, he suffered a myeloma relapse. In October 2022, the patient presented with a large spontaneous compressive hematoma in the left shoulder and hemithorax, requiring two surgical procedures. The platelet count and hemostasis parameters were within normal range. Further diagnostic testing revealed acquired factor XIII deficiency and acquired thrombopathy. Diagnostic challenges arose from the absence of specific assays for the B subunit of Factor XIII. Treatment involved transfusions and corticosteroids, but efficacity was limited. The patient's response to chemotherapy raised questions about the involvement of the monoclonal component. Subsequent follow-ups showed factor XIII levels fluctuating, even without symptoms. The patient was deemed ineligible for autograft due to a significant risk of hemorrhage.

Limited value of testing for factor XIII and α2-antiplasmin deficiency in patients with a bleeding disorder of unknown cause.

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

Traumatic intracranial hemorrhage in pediatrics: Implications of factor XIII deficiency and consumptive coagulopathy in abusive head trauma evaluation.

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

Abnormal bleeding after lumbar vertebrae surgery because of acquired factor XIII deficiency: A case report and literature review.

RATIONALE: Abnormal bleeding due to low fibrinogen (Fib) and coagulation factor XIII (FXIII) levels after lumbar vertebral surgery is exceedingly rare. Excessive bleeding is also associated with secondary hyperfibrinolysis. This report presents a case of abnormal incision bleeding caused by coagulation factor XIII deficiency (FXIIID) and secondary hyperfibrinolysis in a state of low fibrinogen after lumbar vertebral surgery. PATIENT CONCERNS: A middle-aged woman experienced prolonged incision and excessive bleeding after lumbar vertebral surgery. DIAGNOSIS: Combined with coagulation factors, coagulation function tests, and thromboelastography, the patient clinical presentation supported the diagnosis of FXIIID and secondary hyperfibrinolysis in a hypofibrinogenemic state. INTERVENTIONS: Cryoprecipitat, Fresh Frozen Plasma, Fibrinogen Concentrate, Leukocyte-depleted Red Blood Cells, Hemostatic (Carbazochrome Sodium Sulfonate; Hemocoagulase Bothrops Atrox for Injection; Tranexamic Acid). OUTCOMES: After approximately a month of replacement therapy and symptom treatment, the patient coagulation function significantly improved, and the incision healed without any hemorrhage during follow-up. LESSONS: Abnormal postoperative bleeding may indicate coagulation and fibrinolysis disorders that require a full set of coagulation tests, particularly coagulation factors. Given the current lack of a comprehensive approach to detect coagulation and fibrinolysis functions, a more comprehensive understanding of hematology is imperative. The current treatment for FXIIID involves replacement therapy, which requires supplementation with both Fib and FXIII to achieve effective hemostasis.

Novel Insights into Heterozygous Factor XIII Deficiency.

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

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.

A case of anti-NPX-2 antibody-positive dermatomyositis resulting in massive haemothorax with acquired factor XIII deficiency.

Autoimmune diseases, including dermatomyositis, can be complicated by an acquired autoimmune coagulation factor XIII deficiency, which sometimes results in fatal bleeding. Here, we report the case of a young woman with anti-NPX-2 antibody-positive dermatomyositis who developed massive haemothorax with acquired factor XIII deficiency during treatment, including plasma exchange therapy. Emergency transcatheter arterial embolisation was performed and coagulation factor XIII concentrates (Fibrogammin P® 240 U/day for 5 days) were supplemented. Subsequently, the patient was discharged and managed with oral prednisolone and tacrolimus. Coagulation system test results were followed up regularly and remained within normal limits and the patient progressed without recurrence of bleeding symptoms. Coagulation factor XIII deficiency cannot be assessed without measuring coagulation factor XIII activity because common coagulation-fibrinolytic system test results are not abnormal. The measurement of factor XIII activity should be performed when autoimmune diseases are complicated by unexplained bleeding.

[A Case of Autoimmune Acquired Factor XIII Deficiency Diagnosed from Recurrent Postoperative Bleeding].

The patient was a 79-year-old man with ureteroileal anastomotic stricture after a Bricker ileal conduit. Endourological treatment of stenosis was performed via percutaneous nephrostomy and ileal conduit. The patient experienced lower abdominal pain on the following day, and computed tomographic (CT) scan showed hematoma retention around the kidney and active bleeding from the renal artery branches. Transarterial embolisation (TAE) was performed and the bleeding was controlled. Two days later, there was a sudden progression of anemia and CT showed an increase in hematoma around the kidney. We subsequently performed nephrectomy for hemostasis. Five days later, the anemia progressed further. There was hematoma retention in the retroperitoneal cavity, and emergency laparotomy hemostasis was performed. Routine coagulation test results were normal. Heavy bleeding was observed several days after TAE and the possibility of coagulation factor XIII deficiency was considered. Factor XIII deficiency was confirmed by a low factor XIII activity level. The patient was given plasma-derived factor XIII. After receiving factor XIII replacement, factor XIII activity remained unchanged and the patient continued to bleed. Thereafter, a cross-mixing test was performed and the patient was diagnosed with autoimmune acquired factor XIII deficiency. Cortical steroids were administered to remove the factor XIII inhibitor. Steroid administration showed a rapid increase in factor XIII activity, and bleeding symptoms were no longer observed. In cases of serious bleeding of unknown cause with a normal coagulation profile, acquired factor XIII deficiency should be suspected and factor XIII activity measured.

[Factor XIII deficiency - not only a congenital bleeding disorder]. / Koagulationsfaktor XIII ­ inte bara ett kongenitalt blödningsproblem.

Factor XIII (FXIII) cross-links fibrin monomers to strengthen clots. The congenital severe autosomal type of FXIII deficiency with <5 percent of normal FXIII activity is an extremely rare bleeding disorder with <10 cases in Sweden. It often debuts at birth with prolonged umbilical cord bleedings and an increased risk for bleeding throughout life. Patients with severe congenital FXIII deficit have an established FXIII concentrate treatment, both for prophylaxis and at bleeding episodes. Acquired autoantibodies against FXIII are also rare, with high bleeding risks. Quantitative FXIII analyses are only available in few laboratories in Sweden. Sometimes more complex antigen/antibody/gene mutation tests are needed for diagnosis, but these are not available in Sweden. Other acquired FXIII deficiencies can occur in patients with several diseases and during surgery/trauma. Their treatment and diagnostic logistics are less defined. Recent European guidelines on perioperative bleeding have suggested FXIII concentrate treatment.

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.

Déficit adquirido de Factor XIII como causa de hemorragia masiva con compromiso de vía aérea superior en cirugía oncológica de cavidad oral / Acquired Factor XIII deficiency as a cause of massive hemorrhage with upper airway compromise in oncological surgery of the oral cavity

El diagnóstico etiológico de una hemorragia postoperatoria persistente en pacientes adultos sin antecedentes médicos de interés supone un reto a día de hoy. Dentro de las distintas causas encontramos el déficit adquirido del Factor XIII (F. XIII) de la coagulación. El déficit de este factor suele pasar desapercibido al no ser valorado en el estudio preoperatorio rutinario. Presentamos el caso de un varón de 70 años con déficit de F. XIII adquirido, no diagnosticado previamente, que tras ser intervenido por un carcinoma epidermoide de suelo de boca sufrió un sangrado de cavidad oral y cervical bilateral con compromiso de la vía aérea. (AU)

The etiological diagnosis of persistent postoperative bleeding in adult patients with no relevant medical history is currently a challenge. Among the different causes, we find the acquired deficiency of Factor XIII (F. XIII) of coagulation. The deficit of this factor usually goes unnoticed as it is not tested in the routine preoperative studies. We present the case of a 70-year-old man with previously undiagnosed acquired F. XIII deficiency who, after undergoing surgery for squamous cell carcinoma of the floor of the mouth, suffered oral and bilateral cervical bleeding causing airway compromise. (AU)

Acquired Factor XIII Deficiency in Patients with Multiple Trauma.

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

[Autoimmune acquired coagulation factor XIII/13 deficiency caused by type Ab anti-FXIII-A autoantibody].

An 88-year-old man became unconscious and was admitted to our hospital due to severe anemia. Extensive subcutaneous hemorrhage around the chest and back and pectoralis major muscle hematoma were observed. Coagulation screening tests showed moderately reduced factor XIII/13 (FXIII) activity. During hospitalization, the patient had repeated bleeding events in the gastrointestinal tract and muscles, leading to hemorrhagic shock. We suspected the presence of FXIII inhibitors from FXIII infusion test results. The cross-mixing test for cross-linking of fibrin revealed inhibition of polymerization of α-chain and α2-plasmin inhibitor incorporation into fibrin. In addition, by detecting IgG autoantibody to thrombin-activated FXIII, we confirmed the presence of type Ab anti-FXIII-A subunit autoantibody, which represses the catalytic subunit activity of activated FXIII. Autoimmune FXIII deficiency should be considered when a patient presents with severe hemorrhagic diathesis with no other cause than moderately reduced of FXIII activity, as reported in this case.

Delayed and prolonged umbilical stump bleeding in a Caucasian newborn as a presenting feature of factor XIII deficiency.

A term Caucasian neonate with an uncomplicated birth history presented with persistent umbilical stump bleeding unresponsive to extensive topical haemostatic measures initially. He subsequently developed hypovolaemic shock. Routine full blood count and basic coagulation screen were unremarkable. He received packed red cell and cryoprecipitate transfusions. Further specialist coagulation studies performed revealed factor XIII deficiency. Genetic investigations demonstrated a compound heterozygosity for the disorder. He was later started on monthly prophylactic treatment of plasma-derived factor XIII. Clinicians should have a high index of suspicion for factor XIII deficiency for newborns with abnormal umbilical stump bleeding in the presence of no bleeding risk factors and normal routine blood investigations.

Transient Platelet Dysfunction in Congenital Factor XIII Deficiency with Enhanced Thrombin Generation Potential.

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

Hyperfibrinolysis secondary to acquired factor XIII deficiency A case report.

INTRODUCTION: Hyperfibrinolysis induced by factor XIII deficiency (FXIIID) is extremely rare, and patients with no manifestations of active bleeding can easily and frequently be neglected in clinical practice, leading to a missed diagnosis. Herein, we report a rare case of idiopathic FXIIID with secondary hyperfibrinolysis. PATIENT CONCERNS: A 69-year-old man presented with ecchymosis of the right arm and chest wall. DIAGNOSIS: Considering the clinical picture, coagulation function test results, and FXIII activity, the patient was finally diagnosed with hyperfibrinolysis secondary to acquired factor XIII deficiency. INTERVENTIONS: The patient was treated with fresh frozen plasma, aminomethylbenzoic acid, a prothrombin complex, etamsylate, dexamethasone, and cryoprecipitate. OUTCOMES: The patient improved and was discharged after factor replacement therapy, and no further bleeding was reported 1 month after discharge. CONCLUSION: This case report illustrates that the complications of Factor XIII deficiency may include hyperfibrinolysis. Since timely diagnosis of FXIIID is challenging, detailed coagulation factor examinations are needed for definitive diagnosis. It has been suggested that gene testing and antibody testing can help in diagnosis. If ideal treatment is not available, alternative treatment should be provided to reduce bleeding.

Acquired Factor XIII Deficiency in a 19-year-Old Male Following Ballistic Injury.

Factor XIII deficiency is a rare cause of post-operative bleeding. It poses a diagnostic challenge as standard coagulation tests including prothrombin time, international normalized ratio, and activated partial thromboplastin time are usually normal in factor XIII deficiency. We present the case of our patient, a 19-year-old male with acquired factor XIII deficiency diagnosed after ballistic injury with a post-operative course complicated by hemorrhage. This case demonstrates an uncommon cause of coagulopathy, acquired factor XIII deficiency, and the challenges it poses to post-operative management. The diagnosis of acquired factor XIII deficiency may be challenging, but a high clinical suspicion is imperative to avoid a missed diagnosis and delayed treatment.

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.