Factor XI deficiency and delayed hemorrhages after resection of choroid plexus papilloma: illustrative case

BACKGROUND Factor XI deficiency, also known as hemophilia C, is a rare inherited bleeding disorder that may leave routine coagulation parameters within normal range. Depending on the mutation subtype, prolonged activated partial thromboplastin time may occasionally be found. The disease has an autosomal transmission, with an estimated prevalence in the general population of approximately 1 in 1 million. Heterozygosis accounts for partial deficits, but the tendency to bleed is unrelated to the measured activity of factor XI. Diagnosis usually follows unexpected hemorrhages occurring spontaneously or after trauma or surgical procedures. OBSERVATIONS Few cases have been reported in the neurosurgical literature, all occurring spontaneously or after head trauma. Owing to its subtle features, the true incidence of the disease is probably underestimated. The authors report a case of a patient with previously undiagnosed factor XI deficiency who underwent uncomplicated resection of a fourth-ventricle papilloma and experienced delayed, severe hemorrhagic complications. LESSONS The known association between choroid plexus tumors and intracranial bleeding raised differential diagnosis issues. This report may serve to help to investigate delayed hemorrhages after cranial surgery.

741 A complex clinical mosaic of severe autoimmune calcific constrictive pericarditis with striking haemodynamic response to immunosuppressive therapy

Autoimmune constrictive pericarditis constitutes a conundrum to modern cardiology with much uncertainty surrounding both pathophysiology and optimal treatment strategies. We hereby describe the case of a 35-year-old woman of Nigerian origin with severe right heart failure secondary to calcific constrictive pericarditis. Her past medical history included coagulation factor XI deficiency, leukopenia, 2nd trimester miscarriage and premature labour due to placenta previa with fibrin deposition. Further investigations revealed atrial fibrillation, severe biatrial enlargement, moderate tricuspid and mitral regurgitation, pericardial thickening, post-capillary pulmonary hypertension and right ventricular dip-and-plateau pattern, compatible with severe constrictive pericarditis. Extensive screening for infectious and autoimmune causes only revealed borderline positive ANA (1:80). Thereafter, the patient underwent complete surgical pericardiectomy with pericardial biopsies revealing fibrous thickening, diffuse calcification and lymphocyte/macrophage infiltrates, in the absence of giant multinucleated cells or granulomas. The patient was later discharged but soon experienced relapse of exertional dyspnoea presenting with right-sided haemo-pneumothorax (requiring pleural drainage), diffuse alveolar haemorrhage, large right-sided basal and infrascissural pleural effusion, and ascites. She was treated with high dose iv furosemide, oral ibuprofen and colchicine, suspension of rate control medications, achieving initial reduction in pulmonary oedema and ascites, relapsing however after attempts to switch to oral diuretic therapy. Due to the finding of persistent lymphopenia, further immunological tests were conducted, revealing raised IgG1 levels as well as altered peripheral lymphocyte populations (raised CD4+/CD8+ ratio and CD8+ central memory, reduced CD8 effector memory). This finding in conjunction with the history of factor XI deficiency, 2nd trimester miscarriage and placental fibrin deposition as well as the observation of painful cutaneous nodules at sites of venepuncture, suggestive of Koebner’s phenomenon, veered the diagnostic focus to a potential autoimmune aetiology and in particular to systemic lupus erythematosus (>10 ACR-EULAR score points with case reports describing all the above as potential disease manifestations). Furthermore, revision of thoracic CT scans, demonstrated bilateral migratory peribronchovascular nodules with ground-glass halo. CT- guided biopsies thereof were performed revealing focal alveolar damage with capillaritis and alveolar haemorrhage, further corroborating the clinical suspicion of autoimmune disease and justifying the introduction of high-dose oral corticosteroid therapy. In liaison with our tertiary rheumatology centre, the patient was later switched to mycophenolate with gradual weaning from corticosteroid. Concurrent cardiological follow-up revealed persistence of good haemodynamic status (NYHA class II, absence of pulmonary oedema and ascites) with oral diuretic therapy, regression of cutaneous symptoms and echocardiography demonstrating consistent reduction in both mitral and tricuspid regurgitation. This constitutes to our knowledge the first report of autoimmune calcific constrictive pericarditis with significant haemodynamic response to immunosuppressive therapy. Despite the relative rarity of this disease entity, early recognition and instatement of immunosuppressive treatment may prove fundamental to halt and potentially reverse the haemodynamic progression of this highly morbid condition.

Obstetrical and Peri-Operative Management of Patients with Factor XI Deficiency - a Retrospective Observational Study

Introduction Factor XI deficiency (FXI) is an autosomally inherited injury-related bleeding disorder. Although relatively rare worldwide, it is common amongst Ashkenazi and Iraqi Jewish ancestry with a heterozygosity rate as high as 8 to 9%. FXI deficiency does not provoke spontaneous bleeding; however, it predisposes to a potential risk of life-threatening bleeding at childbirth or surgery. Unfortunately, data regarding obstetrical and perioperative management of this condition is scarce, with less than 500 cases reviewed in the last 20 years. Therefore, this study aimed to expand this database and identify factors associated with increased bleeding risk. Methods We performed a retrospective chart review of patients (pts) with FXI deficiency who underwent childbirth or other surgical procedures between August 2011 to April 2021 within the Mount Sinai Health System in New York City. Data on age, sex, ethnicity, genotype, family or personal history of bleeding, type of anesthesia, estimated blood loss, peri-procedural bleeding complication, and type and timing of blood product or hemostatic agent administered in the peri-operative period were collected. Prior history of bleeding was defined as 1 or more of the following: easy bruisability, epistaxis, heavy menstrual bleeding, bleeding related to dental, surgical or obstetrical procedure. The paired t-test was used to compare the initial and subsequent FXI levels measured during pregnancy. We performed logistic regression to test the association between historical, laboratory, and procedural variables with the bleeding endpoint (defined as acute postpartum or postoperative hemorrhage or any bleeding warranting non-prophylactic administration of packed red blood cells, fresh frozen plasma [FFP], or tranexamic acid). Receiver operative characteristic (ROC) curve was plotted for FXI levels to identify the cutoff for optimal sensitivity and specificity. Analyses were performed using SPSS software. Results We identified 198 pts who underwent 252 procedures in total- including 143 vaginal deliveries, 64 C-sections and 45 other surgical procedures. Mean age was 36 years with 94% females, and ~70% were Ashkenazi Jews. c.403G>T p.E135X (42%) and c.901T>C p.F301L (44.8%) were the most common genotypes identified. 38 out of 252 procedures resulted in bleeding complications. In multivariable logistic regression, both prior history of bleeding (odds ratio (OR) 8.97, p=0.02) and lower FXI levels ( OR 1.03 per U/dL increase, p=0.05) were independently associated with the bleeding endpoint. Family history of bleeding, ethnicity, genotype, pre-procedural PTT and platelet levels were not associated with bleeding risk. There were no cases of epidural or spinal hematomas associated with neuraxial anesthesia in our cohort. Mean FXI level for pts receiving neuraxial anesthesia was 50 U/dl (3-118 U/dl). Five pts who had a negative bleeding history despite surgical challenges received neuraxial anesthesia at FXI level <10 U/dl without any complications (only 1/5 received prophylactic FFP). Mean FXI level for pts receiving prophylactic FFP was 25.6 U/dl (range 1-71 U/dl). 8 out of 21 (38%) pts suffered a bleeding complication despite prophylactic FFP use. ROC analyzing FXI levels as a risk factor for the bleeding endpoint resulted in an AUC of 0.605 with specificity of 96%, 94%, 91%, 83%, 49% and sensitivity of 11%, 12%, 19%, 35%, 65% respectively for cut-off values of 10, 20, 30, 40 and 50 U/dl. Of note, there was no significant variation in FXI levels during pregnancy [mean first measurement was 49.7 U/dl vs final measurement of 48.3 U/dl, p=0.3]. Conclusions Personal history of bleeding is the strongest predictor of perioperative or obstetrical bleeding in pts with FXI deficiency. Higher FXI levels correlate with a slightly lower but statistically significant odds of surgical bleeding. Although a FXI level cut-off of 40 U/dl may predict bleeding risk with reasonable specificity (83%), it lacks sensitivity and must be interpreted in the context of personal bleeding history. FXI levels remain stable during pregnancy and repeat measurements may not be necessary. Neuraxial anesthesia appears to be safe to use in this cohort. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The Association between Factor XI Deficiency and the Risk of Bleeding, Cardiovascular, and Venous Thromboembolic Events

The objective of this study was to assess the relationship between factor XI (FXI) deficiency and the risks of bleeding and cardiovascular (CV) events. We conducted a retrospective cohort study using data from Maccabi Healthcare Services (MHS). We identified adults with FXI deficiency (severe: <15%, partial: 15 to <50%, any deficiency: <50%) that had been tested for FXI between 2007 and 2018 and matched to patients from the general MHS population. We estimated 10-year risks of outcomes using the Kaplan–Meier approach. Using Cox proportional hazards regression, we compared outcomes among patients with versus without FXI deficiency. Less than 10% of patients tested for FXI activity had activity levels <50% (mean age: 39 years; 72.2% females). Compared with the general population, patients with any FXI deficiency were at higher risk of severe bleeding (adjusted hazard ratio [aHR]: 2.56, 95% confidence interval [CI]: 1.13–5.81; 10-year risk: 1.90%, 95% CI: 0.50–3.20% vs. 0.90%, 95% CI: 0.50–1.30%) and clinically relevant nonsevere bleeding (CRNSB) (aHR: 1.45, 95% CI: 1.08–1.97; 10-year risk: 11.60%, 95% CI: 8.30–14.80% vs. 9.20%, 95% CI: 8.00–10.40%). Severe FXI deficiency was associated with a greater risk of CRNSB. While few CV events (N = 2) and venous thromboembolisms (VTE) (N = 1) were observed in the FXI overall deficient group, there was a nonsignificant negative association between any FXI deficiency and CV events (aHR: 0.55; 95% CI: 0.13–2.36) and VTEs (aHR: 0.45; 95% CI: 0.06–3.47). Overall FXI deficiency was associated with an increased risk of severe bleeding and CRNSB. Further research is warranted to explore the lower risk of CV and VTE among patients with FXI deficiency compared with the general population.