Acquired Factor XIII Deficiency in a Patient with Metastatic Lung Cancer

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

Important roles of the human leukocyte antigen class I and II molecules and their associated genes in the autoimmune coagulation factor XIII deficiency via whole-exome sequencing analysis

Autoimmune coagulation factor XIII deficiency is a bleeding disorder caused by the formation of autoantibodies against the coagulation factor XIII (FXIII); however, the molecular mechanism underlying this process is unknown. Therefore, in the present study, we aimed to elucidate this mechanism by performing whole-exome sequencing analysis of 20 cases of autoimmune FXIII deficiency. We identified approximately 21,788–23,916 variants in each case. In addition to their ability to activate T cells, present antigens, and immune tolerance, the candidate alleles were further narrowed down according to their allelic frequencies and the magnitude of damage caused by the substitution of amino acids. After selecting 44 candidate alleles, we investigated whether they were associated with the FXIII inhibitory titers and/or the anti-FXIII autoantibodies. We found that two polymorphisms whose variant allele frequencies were significantly lower in the patients tended to decrease FXIII inhibitory titers as the number of variant alleles increased. We also found that five polymorphisms whose variant allele frequencies were significantly higher in the patients tended to increase the levels of the anti-FXIII autoantibodies as the number of variant alleles increased. All of these polymorphisms were found in the human leukocyte antigen (HLA) class I and II molecules and their associated genes. In particular, the HLA class II molecule and its associated genes were found to be involved in the presentation of foreign antigens as well as the negative regulation of the proliferation of T-cells and the release of cytokines. Polymorphisms in the HLA class II molecules and the cytotoxic T lymphocyte antigen 4 have been reported to be associated with the development of autoantibodies in acquired hemophilia A. Therefore, we hypothesized that these polymorphisms may be associated with the development of autoantibodies in autoimmune FXIII deficiency.

Abstract P357: Induction Of Soluble P-selectin And CD40 Ligand And, FXIII Deficiency Promote Aberrant Coagulation And Thromboembolism In Severe COVID-19

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential underlying molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. In this series, 30 hospitalized COVID-19 patients presenting elevated D-dimer with (severe cases that required intensive care) or without pneumonia (moderate cases) were included in the study. Patients with anticoagulant/ antiplatelet therapy or with a history of cardiovascular diseases were excluded. Phenotypic and molecular characterizations were carried out employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The findings revealed slightly higher prothrombin and activated partial thromboplastin times (aPTT) with normal platelet counts. Elevated levels of plasma P-selectin and CD40 ligand (CD40L), markers of platelet activation, were observed in the moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, analysis of the coagulation pathways revealed comparable FIX, prothrombin, and anti-thrombin levels, and a significantly higher level of fibrinogen was observed in both the moderate and severe patients vs. control group. Interestingly, the levels of plasma tissue factor pathway inhibitor (TFPI) and FXIII, a regulator of stable thrombus formation, were significantly lower particularly in the severe COVID-19 cases. Moreover, a dysregulated fibrinolysis was indicated by elevated tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), and D-dimer levels in COVID-19 cases. In summary, SARS-CoV-2 infection-mediated endothelial cell lining damage potentially enhances soluble P-selectin and CD40L levels inducing platelet activation. Furthermore, in severe COVID-19, a decreased level of TFPI possibly contributes to additional thrombin generation through activation of the TF pathway and provides positive feedback to platelet activation and thrombus formation. FXIII deficiency plays a key role in thrombus instability which most likely promotes thromboembolism in the severe COVID-19.

Induction of soluble platelet activation markers and FXIII deficiency promote COVID-19 severity

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19 patients. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. A broader investigation was conducted including hospitalized COVID-19 patients with (severe cases that required intensive care) or without pneumonia (moderate cases). Phenotypic and molecular characterizations were performed employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The investigations revealed induction of plasma P-selectin and CD40 ligand (sCD40L) in moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, a profound reduction in plasma tissue factor pathway inhibitor (TFPI) and FXIII were identified particularly in the severe COVID-19. Further analysis revealed a profound induction of fibrinogen in both moderate and severe patients. Interestingly, an elevated plasminogen activator inhibitor-1 more prominently in moderate, and tissue plasminogen activator (tPA) particularly in severe COVID-19 cases were observed. Particularly, the levels of fibrinogen and tPA directly correlated with the severity of COVID-19. In summary, SARS-CoV-2 infection induces the levels of platelet activation markers soluble P-selectin and sCD40L in hospitalized COVID-19 patients. Furthermore, an attenuated level of TFPI indicates TF pathway activation and, acquired FXIII deficiency likely plays a key role in thrombus instability and promotes thromboembolism in severe cases. The progression of COVID-19 severity could be limited with anti-platelet in combination with recombinantTFPI treatment. Furthermore, thromboembolic events in severe COVID-19 patients could be minimized if treated with recombinantFXIII in combination with LMW heparin.

Factor XIII Deficiency and Intracranial Bleed: Surgical Management and Prophylaxis with Cryoprecipitate

Factor XIII (FXIII) deficiency is a rare bleeding disorder with affected patients having high propensity for intracranial hemorrhage. A 12-year-old girl presented with severe headache, limb weakness, and rapidly worsening sensorium over 4 days. Magnetic resonance imaging of the brain and computed tomography (CT) of the head showed intraparenchymal bleed. Patient had normal coagulation profile and abnormal FXIII level. The perioperative management included cryoprecipitate transfusion to bring the FXIII value to 74%. She underwent craniotomy and evacuation of the hematoma. Postoperatively, she received prophylaxis against rebleed with cryoprecipitate. In the absence of FXIII concentrate, correction of FXIII deficiency is possible with cryoprecipitate in emergent situations.

Acquired FXIII deficiency is associated with high morbidity

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

Postpartum Hemorrhage in Heterozygote Factor XIII Deficient Women Compared With Healthy Women. A Cross-Sectional Experience From Iran

Postpartum hemorrhage (PPH) is a major cause of maternal mortality, which is a common clinical manifestation in women with rare bleeding disorders. In this study, we compare PPH and its complications in heterozygote factor XIII (FXIII) deficient women with healthy women. In this cross sectional case study, 50 women with heterozygote FXIII deficiency and 50 healthy women are evaluated. Data were initially collected by interviewing the women who were receiving FXIII replacement therapy after their childbirths. Data were analysed using SPSS (Version 22) and a P-value of less than .05 was considered statistically significant. The mean age in the patient and control groups were 31.2 and 32.5 years respectively. The occurring rate of PPH in the patient group was significantly higher than the control group (34% vs 2%) ( P-value <.0001). None of the confounding variables such as maternal age, gestational age, numbers, and types of delivery in women with PPH showed any significant differences between the control and patient groups. According to the results of this study, the risk of PPH (early and late), miscarriage, and menorrhagia in women who are heterozygous for FXIII deficiency is significantly higher than healthy women. However, the effect of other factors such as maternal age, gestational age, number, and type of delivery require further studies to delineate any confounding factors.

Mild Acquired Factor XIII Deficiency and Clinical Relevance at the ICU—A Retrospective Analysis

Acquired FXIII deficiency is a relevant complication in the perioperative setting; however, we still have little evidence about the incidence and management of this rarely isolated coagulopathy. This study aims to help find the right value for the substitution of patients with an acquired mild FXIII deficiency. In this retrospective single-center cohort study, we enrolled critically ill patients with mild acquired FXIII deficiency (>5% and ≤70%) and compared clinical and laboratory parameters, as well as pro-coagulatory treatments. The results of the present analysis of 104 patients support the clinical relevance of FXIII activity out of the normal range. Patients with lower FXIII levels, beginning at <60%, had lower minimum and maximum hemoglobin values, corresponding to the finding that patients with a minimum FXIII activity of <50% needed significantly more packed red blood cells. FXIII activity correlated significantly with general coagulation markers such as prothrombin time, activated partial thromboplastin time, and fibrinogen. Nevertheless, comparing the groups with a cut-off of 50%, the amount of fresh frozen plasma, thrombocytes, PPSB, AT-III, and fibrinogen given did not differ. These results indicate that a mild FXIII deficiency occurring at any point of intensive care unit stay is also probably relevant for the total need of packed red blood cells, independent of pro-coagulatory management. In alignment with the ESAIC guidelines, the measurement of FXIII in critically ill patients with the risk of bleeding and early management, with the substitution of FXIII at levels <50%-60%, could be suggested.

Management of Neuraxial Analgesia in a Parturient with Factor XIII Deficiency: A Case Report and Proposed Management Algorithm

Factor XIII (FXIII) deficiency is a rare coagulation defect that can be associated with significant bleeding. A 28-year-old pregnant woman, with a history of hemorrhagic stroke secondary to severe congenital FXIII deficiency, presented in active labor requesting an epidural. Factor XIII levels had been monitored throughout her pregnancy and treated with intermittent factor XIII infusions to maintain factor levels above 30% of normal. After careful multidisciplinary peripartum evaluation and FXIII replacement, neuraxial analgesia was performed without complication. Neuraxial analgesia can be performed without complication in patients with FXIII deficiency if FXIII levels are carefully managed and no other coagulopathy exists.