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.

Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit.

INTRODUCTION AND AIM: Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known. MATERIALS AND METHODS: Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB. RESULTS AND CONCLUSION: We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT.

[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.

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

INTRODUCTION: 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). PATIENT AND METHOD: 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. RESULTS: 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. CONCLUSIONS: TPE is useful in removing XIII inhibitory factor, but the effects are only short term.

The potential impact of coagulation factor XIII in trauma-induced coagulopathy - a retrospective case series analysis.

BACKGROUND: The role of factor XIII (FXIII) in trauma-induced coagulopathy (TIC) is not fully understood. METHODS: We evaluated FXIII supplementation in severely injured patients with persistent bleeding. This was a retrospective case series analysis. RESULTS: Twenty-four patients received FXIII concentrate within 24 h of admission for bleeding that continued after transfusion of > 6 U red blood cells (RBCs); control patients (n = 27) did not receive FXIII concentrate. Both study groups were similar regarding injury severity score and global coagulation tests, but FXIII activity levels were significantly higher and lactate levels significantly lower in the control group, respectively. The differences in FXIII activity between the groups could be attributed to a more severe trauma-induced coagulopathy in FXIII-deficient patients, as demonstrated by lower fibrinogen and higher lactate levels. The median dose of FXIII concentrate within 24 h of admission was 2500 IU (IQR: 1250-4375). Median 24-h transfusion of RBCs (primary study endpoint) was significantly higher in the FXIII group versus controls (10.0 U, IQR 5-14 U vs. 2, IQR 0-6 U; p < 0.01). Subsequently, while patients were in the intensive care unit, there was no statistically significant difference regarding RBC transfusion anymore and the overall clinical outcomes were similar in both patient groups. CONCLUSIONS: The substitution of FXIII in patients who were more seriously compromised due to higher lactate levels and who presented with initially more severe bleedings than patients in the control group, resulted in a comparable transfusion necessity after 24 h. Thus, we guess that the substitution of FXIII in severely injured patients with ongoing bleeding might have an impact on their clinical outcome.

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

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

Factor XIII levels, clot strength, and impact of fibrinogen concentrate in infants undergoing cardiopulmonary bypass: a mechanistic sub-study of the FIBCON trial.

BACKGROUND: Acquired factor XIII (FXIII) deficiency after major surgery can increase postoperative bleeding. We evaluated FXIII contribution to clot strength and the effect of fibrinogen concentrate administration on FXIII activity in infants undergoing cardiac surgery using cardiopulmonary bypass. METHODS: We conducted a prospectively planned, mechanistic sub-study, nested within the Fibrinogen Concentrate Supplementation in the Management of Bleeding During Paediatric Cardiopulmonary Bypass: A Phase 1B/2A, Open-Label Dose Escalation Study (FIBCON) trial, which investigated fibrinogen concentrate supplementation during cardiopulmonary bypass (ISRCTN: 50553029) in 111 infants (median age 6.4 months). The relationships between platelet number, fibrinogen concentration, and FXIII activity with rotational thromboelastometry clot strength (EXTEM-MCF) in blood taken immediately before cardiopulmonary bypass and after separation from bypass were estimated using multivariable linear regression. Changes in coagulation variables over time were quantified using a generalised linear model comparing three groups: fibrinogen concentrate-supplemented infants, placebo, and a third cohort with lower bleeding risk. RESULTS: Overall, 48% of the variability (multivariable R2) in EXTEM-MCF clot strength was explained by three factors: the largest contribution was from FXIII activity (partial R2=0.21), followed by platelet number (partial R2=0.14), and fibrinogen concentration (partial R2=0.095). During cardiopulmonary bypass, mean platelet count fell by a similar amount in the three groups (-36% to -41%; interaction P=0.98). Conversely, fibrinogen concentration increased in all three groups: 132% in the fibrinogen concentrate-supplemented group, 26% in the placebo group, and 51% in the low-risk group. A similar increase was observed for FXIII activity (61%, 23%, and 25%, respectively; interaction P<0.0001). CONCLUSIONS: FXIII contribution to clot strength is considerable in infants undergoing cardiac surgery. Fibrinogen concentrate supplementation also increased FXIII activity, and hence clot strength. CLINICAL TRIAL REGISTRATION: ISRCTN: 50553029.

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.

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.

The Efficacy of Fibrinogen Concentrates in Relation to Cryoprecipitate in Restoring Clot Integrity and Stability against Lysis.

Loss of fibrinogen is a feature of trauma-induced coagulopathy (TIC), and restoring this clotting factor is protective against hemorrhages. We compared the efficacy of cryoprecipitate, and of the fibrinogen concentrates RiaSTAP® and FibCLOT® in restoring the clot integrity in models of TIC. Cryoprecipitate and FibCLOT® produced clots with higher maximal absorbance and enhanced resistance to lysis relative to RiaSTAP®. The fibrin structure of clots, comprising cryoprecipitate and FibCLOT®, mirrored those of normal plasma, whereas those with RiaSTAP® showed stunted fibers and reduced porosity. The hemodilution of whole blood reduced the maximum clot firmness (MCF) as assessed by thromboelastography. MCF could be restored with the inclusion of 1 mg/mL of fibrinogen, but only FibCLOT® was effective at stabilizing against lysis. The overall clot strength, measured using the Quantra® hemostasis analyzer, was restored with both fibrinogen concentrates but not cryoprecipitate. α2antiplasmin and plasminogen activator inhibitor-1 (PAI-1) were constituents of cryoprecipitate but were negligible in RiaSTAP® and FibCLOT®. Interestingly, cryoprecipitate and FibCLOT® contained significantly higher factor XIII (FXIII) levels, approximately three-fold higher than RiaSTAP®. Our data show that 1 mg/mL fibrinogen, a clinically achievable concentration, can restore adequate clot integrity. However, FibCLOT®, which contained more FXIII, was superior in normalizing the clot structure and in stabilizing hemodiluted clots against mechanical and fibrinolytic degradation.

Factor XIII and surgical bleeding.

Factor XIII (FXIII) is the final factor in the coagulation cascade. It converts soluble fibrin monomers into a stable fibrin clot, prevents premature degradation of fibrin, participates in wound healing, and helps prevent the loss of the endothelial barrier function. FXIII deficiency is believed to be rare, and this may explain why clinicians do not routinely take it into consideration. Congenital FXIII deficiency is a rare disease with a reported prevalence of 1 per million. However, the prevalence of acquired FXIII deficiency is much higher. Acquired forms have been described in patients with decreased hepatic or bone marrow synthesis, overconsumption and increased degradation by autoantibodies. This review offers guidance on how to suspect and diagnose FXIII deficiency in both the preoperative consultation and different surgical settings. We also analyze current scientific evidence in order to clarify when and why this clinical situation should be suspected, and how it may be treated.

Predictive value of coagulation factor XIII on bleeding risk in ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: Intravenous thrombolysis (IVT) therapy with recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke (AIS) has a known risk of intracerebral hemorrhage (ICH). We aimed to identify the predictive value of coagulation factor XIII (FXIII) on post-thrombolytic ICH risk in AIS patients. METHODS: The study cohort included 69 diagnosed AIS patients undergoing IVT treatment within 24 hours of symptom onset. Blood samples taken on admission were analyzed for FXIII antigen levels with an automated latex enhanced immunoassay. Conventional coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-dimer (DD) were also tested. RESULTS: Of the 69 AIS patients, 23 (33.3%) developed post-thrombolytic ICH. Plasma FXIII levels showed a significant decrease, accompanied with elevated FIB and DD levels in AIS patients with post-thrombolytic ICH. Multivariable logistic regression (LR) revealed that FXIII and FIB were independently associated with post-thrombolytic ICH progression. Area under receiver operating characteristic curve of FXIII selected by the further forward logistic regression was 0.823 [95% confidence interval (CI): 0.712-0.904], and the cutoff value of 76.6% yielded good sensitivity at 91.3% and good negative predictive value (NPV) at 93.9%. CONCLUSIONS: Our findings indicated that plasma FXIII level may be an independent determinant for predicting post-thrombolytic bleeding risk in AIS patients.

In-vitro assessment of the effects of fibrinogen, recombinant factor VIIa and factor XIII on trauma-induced coagulopathy.

: Trauma-induced coagulopathy (TIC) occurs commonly as a second event following severe injury. We evaluated the effects of fibrinogen, recombinant factor VIIa and factor XIII on blood clotting and fibrinolysis in an in-vitro TIC model. The TIC model included hemodilution, hyperfibrinolysis, acidosis and hypothermia. The extent of clot formation and fibrinolysis was evaluated using rotational thromboelastometry. Clot strength was increased following spiking the TIC blood with either 1.0 mg/ml fibrinogen, 3.0 µg/ml recombinant factor VIIa or 2.0 IU/ml factor XIII. Maximal effect was achieved by all agents in combination approximating the extent of clot formation to those in normal blood. Fibrinolysis was inhibited by factor XIII, while the reduction was stronger using all agents together. When each of the agents used in two times lower concentrations, clot strength was near to threshold. Fibrinogen and factor XIII but not factor VIIa exerted stimulation of clot strength, whereas synergistic effect of fibrinogen and factor XIII was observed. Maximal effect was achieved combining all agents. The antifibrinolytic effect was observed only by co-administration of fibrinogen, factor XIII and factor VIIa. On the basis of our study, we suggest that stimulation of clot formation and inhibition of fibrinolysis may be achieved by combination of FG, rFVIIa an FXIII using each of them at minimal effective concentration. Taken into consideration, multifactorial TIC pathogenesis, this approach may be preferable for improving coagulopathy than separate blood spiking with the essayed factors at high concentrations.

Complete hemostasis achieved by factor XIII concentrate administration in a patient with bleeding after teeth extraction as a complication of aplastic anemia and chronic disseminated intravascular coagulation.

: Hemostatic treatment of disseminated intravascular coagulation (DIC) due to aortic aneurysm involves numerous difficulties. An 89-year-old man with aplastic anemia and chronic DIC developed periodontitis and loose teeth requiring extraction, after which hemostasis was difficult. Platelet concentrates and fresh-frozen plasma transfusions were ineffective, and there was a risk of hemorrhage; therefore, administration of anticoagulant agents for DIC was inappropriate. A decrease in factor XIII (FXIII) was discovered, and FXIII concentrate was administered, resulting in hemostasis together with wound healing. No complications were seen, but the following coagulation markers were found to decrease: fibrin degradation products, D-dimer, thrombin-antithrombin complex, and plasmin-α2 plasmin inhibitor complex. By 1 month after FXIII administration, FXIII had returned to the preadministration level, thus, the FXIII decrease was deduced to be have been due to DIC. These findings suggest that FXIII concentrate is useful for treating hemorrhage associated with DIC due to aortic aneurysm.

Repeated Intracranial Hemorrhage After Delivery Induced by Coagulopathy Associated with Multiple Venous Malformations.

BACKGROUND: Venous malformations are classified as slow-flow vascular malformations. Coagulation abnormalities are known to be frequent among patients with venous malformations. We report a case of repeated intracranial hemorrhage after delivery, induced by coagulopathy associated with multiple venous malformations. CASE DESCRIPTION: A 28-year-old woman presented with left chronic subdural hematoma 1 month after successfully giving birth. She had a history of multiple venous malformations around the pubic region and hips. The hematoma was evacuated by burr hole surgery. Three hours later, her level of consciousness rapidly deteriorated and computed tomography showed acute epidural hematoma. The hematoma was removed immediately by craniotomy under general anesthesia. No bleeding points were apparent in the operative field. Continuous bleeding around the dura mater and subdural space were encountered, and hemostasis was not achieved by electrocoagulation. After using fresh frozen plasma, hemostasis was achieved. Level of consciousness and neurologic symptoms improved postoperatively. Magnetic resonance imaging revealed multiple venous malformations in bilateral lower extremities and the pelvis. Disseminated intravascular coagulopathy was diagnosed, and thrombomodulin and blood coagulation factor XIII were administered. She was discharged home without any neurologic deficits. CONCLUSIONS: The delivery activated localized intravascular coagulopathy in the venous malformations and induced chronic subdural hematoma. Surgical interventions then resulted in progression of the coagulopathy to disseminated intravascular coagulopathy, inducing acute epidural hematoma.