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.

Do Family History Questions Improve the Predictive Value of a Standardized Pediatric Bleeding Assessment Tool?

Bleeding assessment tools to standardize and interpret bleeding history have variable reported sensitivity and specificity to identify patients with mild bleeding disorders (MBD), particularly in subspecialty referral cohorts or younger patients with fewer hemostatic challenges. Here we review the predictive value of the International Society of Thrombosis and Haemostasis (ISTH) bleeding assessment tool, BAT, with or without the addition of 2 family history questions (FHQ), the BAT+, in our clinical cohort. Our hypothesis was that the addition of FHQ would improve the predictive value of the BAT for presence of a MBD in newly referred pediatric hematology clinic patients, particularly those < 8 yr. After 4 quality improvement cycles, a BAT flowsheet in the electronic medical record has been administered to new clinic patients referred to rule out MBD. The exploratory FHQ are added (BAT+), asking about the presence of a first degree relative with a bleeding disorder (yes = 1 point) or first- or second-degree relatives with any of a list of bleeding symptoms (yes = 1 point for each symptom). After IRB approval, electronic records from new clinic visits for "possible MBD" from 1/29/19 to 2/28/20 were retrospectively reviewed for clinical and demographic data, including scoring of the BAT/BAT+. Data are reported descriptively. Positive predictive values (PPV) and negative predictive values (NPV) were compared to assess the predictive power of dichotomized scores. The predictive power of continuous scores were assessed by comparing area under the curves (AUC) of receiver operating characteristics (ROC) curves for each questionnaire. To assess whether higher scores were predictive of multiple diagnoses, we estimated nested hurdle and Poisson regressions with robust standard errors, with the count of bleeding diagnoses as dependent variable and BAT/BAT+ scores as predictors. Over 13 months, in 313 new visits in patients ages 0-21 yr., 309 (98.7%) had BAT+ assessment and were evaluable. Common referral indications were abnormal lab results (48%), epistaxis (20%) and easy bruising (15%). Clinician-initiated documentation of screening for joint hypermobility by examination or history-taking occurred in 85 visits (28%), with 15 (5%) assigned a hypermobility diagnosis. At least 1 MBD was identified in 86 (28%) and 171 ( 55%) had MBD ruled out by the clinician. The average scores for BAT/BAT+ were 1.7/2.6 respectively for those judged by clinician not to have MBD, vs. 2.5/3.9 for 1 MBD diagnosis and 4/6.2 for 2 or more MBD. Using a threshold score of 3 for BAT as predictor of MBD in pediatrics, a threshold of 6 for the BAT+ was selected because its NPV for the whole group was close to that of the BAT for threshold of 3. For all patients and children <8 yr. the PPV of the BAT+ was higher than for the BAT, indicating better ability to predict MBD, for a comparable NPV. This was statistically significant (p=0.033) in the full sample and marginally so (p=0.064) among <8 yr. (Table 2). The AUC for the entire group were 0.597 (0.523-0.670) for the BAT, improving to 0.627 (0.555- 0.6) for the BAT+; however, for < 8 yr. the BAT AUC of 0.528 (0.396-0.660) vs. 0.559 (0.426-0.692) for BAT+ did not significantly differ. By Poisson regression analyses, higher scores on either the BAT or BAT+ predicted more diagnoses, with FHQ improving the goodness of fit (p=0.012) for the whole group (and similar but not statistically significant for < 8 yr.). Scores trended higher for platelet disorders and hypermobility than for low von Willebrand factor/disease or other factor deficiencies. We conclude that the BAT is helpful for standardizing bleeding history among clinicians and trainees and, with flowsheet format, can streamline documentation and sustain high utilization rates. While estimates suggest that FHQ improve predictive power of the BAT, a larger sample size is needed for confirmation. Threshold scores cutoffs based upon pubertal status and gender in < 21 year-olds may need to be lower than for older adults with additional hemostatic challenges. In the entire group and for <8 yr., the BAT under-performed compared to highest published estimates for PPV, NPV and AUC, as has been reported in recent, more rigorous literature, highlighting the complexity of evaluating young specialty referral populations for MBD. Figure 1 Figure 1. Disclosures Tarango: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Anticoagulant therapy in patients with congenital FXI deficiency

The bleeding phenotype of FXI deficiency is unpredictable. Bleeding is usually mild, and mostly occurs after injury. Although FXI deficiency renders antithrombotic protection, some patients might eventually develop thrombosis or atrial fibrillation, requiring anticoagulant therapy. There is almost no evidence on the bleeding risk in this scenario. Our retrospective study of 269 Caucasian FXI-deficient subjects (1995-2021) identified 15 cases requiring anticoagulation. They harbored eight different F11 variants, mainly in heterozygosis (one case was homozygote) and had mild-moderate deficiency (FXI:C:20-70%). Two subjects (13.3%) had bleeding history before anticoagulation. Atrial fibrillation was the main indication (12/15,80%). Fourteen patients started therapy with vitamin K antagonists (VKA), but four were on direct oral anticoagulants (DOACs) at the end of follow-up. Over more than 1000 months of anticoagulation, two mild bleeding episodes in two patients (13.3%,95%CI:3.7-37.9%) were recorded. No major/fatal events were reported. "Pre-post" bleeding localization and severity did not change despite treatment. On VKA, drug dosing and management were also standard, unaltered by FXI deficiency. We provide the largest description of anticoagulant use in FXI deficiency, and the first cases receiving DOACs. While further studies are needed, our observations suggest that moderate FXI deficiency does not interfere with anticoagulant management nor bleeding risk.

Case Series: The Coexistence of Thrombocytopenia and Thromboembolism in COVID-19 Patients on ECMO: A Case Series and Literature Review

Thrombocytopenia and thromboembolism are common complications in coronavirus disease 2019 (COVID-19) patients. The fact that COVID-19 patients develop both thrombocytopenia and thromboembolism has been observed, and multiple studies have investigated the underlying pathophysiology. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID-19 patients who develop respiratory failure and not respond to conventional mechanical ventilation. ECMO induces thromboembolism and raises the incidence of developing thromboembolic events in COVID-19 patients. Here, we report the hospital courses and outcomes of three COVID-19 patients who were treated with ECMO, then developed both thrombocytopenia and thromboembolism. The coexistence of thrombocytopenia and thromboembolism challenges the clinical treatment strategy, including the decision of initiating anticoagulation. Based on current data, anticoagulation is recommended to all hospitalized COVID-19 patients unless there is active bleeding, previous bleeding history within 3 days, or platelet count is lower than 30,000 cells/μl. Further investigation into the mechanisms and implications of thrombocytopenia and thromboembolism in patients with COVID-19 pneumonia will lead to significantly improved outcomes and prognosis for the patients.

Bleeding after surgery and application bleeding assessment tool to surgical patients in Hanoi Medicine University Hospital

Objectives: Describe bleeding characteristics and evaluate the correlation between surgical-related bleeding and bleeding risk according by ISTH – BATs. Methods: Research was conducted on 340 surgical patients at Hanoi Medical University Hospital. Results: The percentage of patients with bleeding during and after surgery is 13.5%. The proportion of patients at risk of bleeding according to BATs is 1.8%. There was a correlation between bleeding risk according to ISTH - BAT with bleeding status during and after surgery with p = 0.004. The positive predictive value of ISTH - BATs is 66.7%, negative predictive value is 87.4%, the sensitivity is 8.7%, the specificity is 99.3%. Conclusions: Surgery has a high risk of abnormal bleeding. Bleeding history has important implications in assessing bleeding risk during and after surgery. The ISTH - BATs is a bleeding history assessment tool that can be used to assess the risk of bleeding before surgery.

Study on Menorrhagia: Correlation with Fibroids

Background: Excessive menstrual bleeding called menorrhagia is a common presentation of females seeking medical attention. Normally there is considerable variation in menstrual cycle length, duration and flow. Objective: To find out the assocation of fibroids in patients presenting with menorrhagia. Materials and Methods: This cross-sectional prospective study was done from January to June 2013 among the female patients admitted in the department of Gynaecology & Obstetrics in Dhaka Medical College & Hospital. Patients presented with the complaints of menorrhagia and treated by surgical management were included. Results: Total 96 patients were included. The age range was 28–49 years with mean age 41.08 ± 5.174 years. In 92 (46.5%) patients excessive per vaginal bleeding was noted. Pain during menstruation was another major complaint (45, 46.5%). Lower abdominal heaviness was reported in 32 patients (16.2%). In about half of the patients (49%) uterine fibroid was diagnosed. In 29 patients (30.2%) adenomyosis was the finding. Out of 47 fibroid cases 39 (83%) had per vaginal bleeding history. Only 10 patients without fibroid experienced pervaginal bleeding. Chi-squared test was done to see whether there was any association between these two variables and the result was highly significant (p<0.001). Conclusion: As medical treatment is disappointing and surgery is the mainstay of treatment of menorrhagia caused by fibroids, diagnosis should be confirmed by different imaging techniques. Advancement in the field of imaging like saline infusion sonohysterography and hysteroscopy helps greatly to diagnose submucous fibroids and save patients from undue prolongation of medical treatment. J Enam Med Col 2020; 10(2): 99-103

Two-year outcomes of more than 30 000 elderly patients with atrial fibrillation: results from the All Nippon AF In the Elderly (ANAFIE) Registry

Aims To clarify the real-world clinical status and prognosis of elderly and very elderly non-valvular atrial fibrillation (NVAF) patients, more than 30 000 elderly patients with NVAF aged ≥75 years were enrolled in the ANAFIE Registry. Methods and Results This multicentre, prospective, observational study followed elderly NVAF patients in Japan for ∼2 years. Among 32 275 patients (mean age 81.5 years; men, 57.3%; mean CHA2DS2-VASc score 4.5), 2445 (7.6%) were not receiving oral anticoagulants (OACs) and 29 830 (92.4%) were given OACs. Of these, 21 585 (66.9%) were receiving direct OACs (DOACs) and 8233 (25.5%), warfarin (mean time in therapeutic range: ∼75%). In total, the 2-year incidence rate was 3.01% for stroke/systemic embolic events (SEE); 2.00%, major bleeding; and 6.95%, all-cause death. As compared with the warfarin group, the DOAC group had a lower hazard ratio (HR) for stroke/SEE, major bleeding, and all-cause death after adjusting for confounders. The group without OACs had a higher HR for stroke/SEE and all-cause death, with a lower HR for major bleeding. History of falls within 1 year at enrolment and of catheter ablation were positive and negative independent risk factors, respectively, for stroke/SEE, major bleeding and all-cause death. Conclusion In Japan, a large proportion of elderly and very elderly NVAF patients were receiving DOACs, which was significantly associated with lower rate of stroke/SEE, major bleeding, and all-cause death vs well-controlled warfarin. History of falls and of catheter ablation were independently associated with stroke/SEE, major bleeding, and all-cause death.

Determinants for under- and overdosing of direct oral anticoagulants and physicians' implementation of clinical pharmacists' recommendations

Aim: To analyze the appropriateness of DOAC dosing and determinants for under-and overdosing as well as acceptance and implementation rates of interventions by clinical pharmacists. Methods: Cross-sectional study from January 2019-December 2019 in a tertiary hospital in hospitalized patients with atrial fibrillation on DOACs (n=1688). Primary outcome was the proportion of patients with inappropriate DOAC prescribing with identification of determinants for under-and overdosing. Secondary outcomes included acceptance and implementation rates of pharmacists’ advices and determination of reasons for non-acceptance/non-implementation. Results: In 16.9% of patients, inappropriate prescribing was observed. For all DOACs considered together, body weight<60 kg(OR 0.46 [0.27-0.77]), edoxaban use(OR 0.42 [0.24-0.74]), undergoing surgery(OR 0.57 [0.37-0.87]) and being DOAC naïve(OR 0.45 [0.29-0.71]) were associated with a significantly lower odds of underdosing. Bleeding history(OR 1.86 [1.24-2.80]) and narcotic use(OR 1.67 [1.13-2.46]) were associated with a significantly higher odds for underdosing. Determinants with a significantly higher odds of overdosing were renal impairment(OR 11.29 [6.23-20.45]) and body weight<60 kg(OR 2.34 [1.42-3.85]), whereas the use of dabigatran(OR 0.24 [0.08-0.71]) and apixaban(OR 0.18 [0.10-0.32]) were associated with a significantly lower odds of overdosing compared to rivaroxaban. Physicians accepted the pharmacists’ advice in 179 cases (79.2%) consisting of 92 (51.4%) advices for underdosing, 82 (45.8%) for overdosing and 5 (2.8%) for contraindications. The advices were effectively implemented for 75 (81.5%) underdosed, 69 (84.1%) overdosed and 4 (80.0%) contraindicated cases. Conclusion: Inappropriate DOAC prescribing remains common. Clinical services led by pharmacists helps physicians to reduce the number of inadequate prescriptions for high risk medications such as DOACs.

Incorporation of Evidence Based Guidelines on Bleeding Risk Assessment Prior to Surgery into Practice: Real Time Experience

Background: Despite guidelines recommending no-need for coagulation testing prior to surgeries when challenging history of bleeding is negative, yet surgeons still overuse it in this part of the world. We aim to measure unbiased estimate of hemostatic outcomes in ENT surgeries and assess the surgeons’ behavior of pre-operative coagulation testing. Methods: All patients who underwent ENT surgeries during the period from July 2017 to January 2018 were enrolled. The primary outcome was post-operative bleeding. Surgeons were asked about their decision on history alone or doing coagulation testing and their reason. 2 Results: 730 patients were recruited; 372 were interviewed for a challenging bleeding history alone; group1 and 358 had pre-operative coagulation testing; group2. Coagulation testing was repeated twice or more in 55% of patients and more than half of them had coagulation factor and VWF assays. Most surgeons were doing the coagulation testing because of habitual practice. Conclusion: Almost half of local surgeons consider coagulation testing as standard practice to evaluate bleeding risk prior to surgical procedures. This has resulted in unnecessary delays in surgeries, parents/patients anxiety and additional total cost. We recommend awareness campaigns for surgeons and involvement of surgical societies to adhere to guidelines of detailed hemostatic history.

Retrospective Chart Review of Gastrointestinal Bleeding in Patients with Von Willebrand Disease

Background: Recurrent overt or occult gastrointestinal (GI) bleeding is a serious complication of von Willebrand Disease (VWD) and is the most common cause of hospitalization for patients with VWD. Data from the VWD Prophylaxis Network (VPN) emphasized the importance of prophylaxis in minimizing bleeding episodes in VWD; however, the management of GI bleeding in these patients remains challenging. Despite the availability of von Willebrand factor (VWF) replacement therapy, GI bleeding may be refractory and require the use of multiple treatment approaches. Currently, there are limited published data and no consensus regarding the most effective treatment for GI bleeding in patients with VWD. Aims: To describe the natural history of treatment and management of GI bleeds in patients with VWD, stratified by those patients who have a history of GI bleeding that precedes this chart review versus patients who experienced their first GI bleed within the 5 years of this chart review. Outcomes following the use of VWF replacement products and adjuvant therapy, including recombinant VWF were collected. Methods: This ongoing retrospective, multicenter, observational chart review (abstraction initiated 2019) will include up to 20 patients from 6 US centers with confirmed congenital VWD with ≥1 GI bleed within the last 5 years. Demographics and clinical information, including potential etiology, treatment regimens, will be gathered from patient records on all recorded GI bleeds within the last 5 years. Clinical effectiveness will be defined by treatment response, change in duration of treatment, or time to bleed resolution across treatment cohorts (e.g., prophylaxis vs on-demand; recombinant VWF [rVWF] vs plasma-derived VWF [pdVWF]), at the time of a GI bleed and for any subsequent period of prophylactic treatment to prevent GI bleed recurrence. Data will be analyzed descriptively. Results: To date, data on 37 bleeds in 13 patients with Type 1 (23%), Type 2 (46%) or Type 3 (31%) VWD have been abstracted; 54% were female, mean (±SD) age was 53.9 (22.0) years, 85% had ≥1 recorded GI-specific morbidity, 6 patients (46%) had no history of prior GI bleeding. Three patients (23%) were on regular prophylaxis using pdVWF-factor VIII (FVIII) concentrates at initial GI bleed presentation. All were receiving Humate-P; dose was not recorded for 2 patients and 1 patient received 50 IU/kg. Out of 37 bleeding episodes, 9 (24%) occurred in patients during VWF prophylaxis, of which 7 occurred in 1 patient. Among the 7 patients with a previous history of GI bleeding, 1 was on a prophylactic regimen prior to the initial GI bleeding episode. None of the patients without a history of GI bleeding were on a prophylactic regimen at the initiation of the chart review; 1 patient was receiving prophylaxis at the time the fourth bleed was documented. On-demand treatment for GI bleeding included aminocaproic acid, tranexamic acid, pdVWF-FVIII concentrates, rFVIII, rVWF, corticosteroids, polypectomy, and thalidomide. After resolution of the GI bleeding episode, in 17/37 bleeding events, prophylactic treatment continued (either as part of the final treatment regimen to resolve the bleed and sustained prophylaxis, or after the final treatment regimen purely as prophylaxis). At the conclusion of data collection for the current patients, 4 out of 6 without a GI bleeding history, and 1 out of 7 with a GI bleeding history, were receiving prophylaxis. Conclusions: Data from this retrospective chart review are the first to describe prophylactic regimens prior to and after GI bleeding, in VWD patients with and without a GI bleeding history. More patients with congenital VWD and a history of GI bleeding were treated with prophylaxis following GI bleeds, compared to patients without a history of GI bleeds. These data describe the role of prophylaxis in management of GI bleeding and add to existing data from the VPN describing a modest reduction of GI bleeding in some patients on prophylaxis. These data underscore the continuing unmet need of the successful management of GI bleeding in VWD. Further data will be collected, and additional analyses performed to determine if this trend persists in a larger sample of patients with VWD. Disclosures Roberts: uniQure:Consultancy;Takeda:Consultancy, Research Funding, Speakers Bureau;Pfizer:Consultancy;Novo Nordisk:Consultancy, Speakers Bureau;Sanofi:Consultancy, Speakers Bureau;Octapharma:Consultancy, Speakers Bureau.Escobar:National Hemophilia Foundation:Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi:Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech, Inc.:Consultancy, Membership on an entity's Board of Directors or advisory committees;Novo Nordisk:Consultancy, Membership on an entity's Board of Directors or advisory committees.Acharya:Novonordisk, BPL:Membership on an entity's Board of Directors or advisory committees.Hwang:Takeda:Honoraria;Shire:Honoraria.Wang:Bioverativ Inc:Honoraria;CSL Behring:Honoraria;Biomarin:Honoraria;Genentech:Honoraria;Takeda:Honoraria;Bayer:Honoraria.Hale:Takeda Pharmaceutical Company Limited:Current Employment.Oladapo:Takeda:Current Employment, Current equity holder in publicly-traded company.Asghar:HCD Economics:Current Employment.