Life-threatening Bleeding Episodes Research Articles

Large, ulcerated infantile hemangioma of the chest wall complicated by life-threatening hemorrhage: Case report and literature review.

While ulceration is one of the most common infantile hemangioma (IH) complications, severe bleeding is a rare consequence, with a paucity of patients reported. We report a 5-month-old girl with a very large, mixed, partial segmental IH of the upper chest wall who, despite medical intervention, developed severe ulceration and multiple episodes of life-threatening bleeding that ultimately led to hemorrhagic shock. Experience in our patient and a review of six previous reports shows that severe bleeding is a risk when ulceration extends directly into an arterial feeding vessel that is often visible clinically. Other potential predictors for severe bleeding include large to very large IH size with extension of the tumor into underlying structures, segmental or partial segmental patterning, mixed and bulky morphology, and white discoloration as a sign of impending or worsening ulceration.

Plasma-derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency.

Hereditary factor X (FX) deficiency (HFXD) is an autosomal recessive rare bleeding disorder that leads to defects in the FX protein. Depending on the degree of deficiency, patients may be at risk of life-threatening bleeding episodes. Historical treatments for FX deficiency include prothrombin complex concentrates, which can increase the risk of thrombosis, and fresh frozen plasma, which can cause volume overload and transfusion reactions. Plasma-derived FX (pdFX), a single-factor, high-purity, high-potency human FX treatment, was approved in 2015 in the United States and in 2016 in Europe for on-demand treatment and prophylaxis of bleeding episodes and perioperative management of patients with HFXD. Five studies that examined the use of pdFX in patients with mild (plasma FX activity [FX:C] ≥5IU/dL), moderate (FX:C ≥1 and<5IU/dL), or severe (FX:C<1IU/dL) HFXD were reviewed: TEN01, TEN02 and TEN03 were prospective, open-label, multicentre, nonrandomised studies, and TEN05 and TEN06 were multicentre retrospective studies. When used as an on-demand treatment, pdFX was judged by investigators to be successful in treating 41/42 (97.6%), 2/3 (66.6%) and 79/79 (100%) bleeds in TEN01, TEN02 and TEN05, respectively. When used prophylactically, pdFX was judged 'excellent' for the prevention of bleeds in nine (100%) and eight (100%) patients in TEN02 and TEN05, respectively. Perioperative treatment and pharmacokinetics were also assessed. pdFX was safe and well tolerated. Together, these studies support the use of pdFX for on-demand treatment of bleeding, routine prophylaxis, and perioperative management of bleeding in patients with HFXD.

Pharmacogenetic substantiation of personalized prescription of oral anticoagulants in clinical practice

Thromboembolic diseases are of great clinical concern because of their high prevalence and consequences, which are often fatal. Despite significant progress in the prevention and treatment of thrombotic events, patients remain at risk of life-threatening bleeding episodes and other side effects arising from anticoagulant therapy, so the issue of personalizing prescriptions taking into account the genetic characteristics of patients has become urgent. The purpose of the study is to substantiate the need for patient genotype analysis in order to increase the effectiveness and safety of individual pharmacotherapy. The article has a conceptual nature, therefore the following research methods were chosen: systematization and generalization; analysis and specification; abstract and logical. For the search, we used PubMed, PubMedCentral, Google Scholar, dbSNP, Elsevier, Springer from September 2000 to November 2022. The review included studies written in English and Ukrainian. There were analyzed literature data on two main subclasses of oral antithrombotic agents, including oral anticoagulants and antiplatelet agents, namely warfarin, apixaban, rivaroxaban, and clopidogrel. Prognostically significant for evaluating the effectiveness and safety of anticoagulant use, as well as the most studied in this aspect, are CYP2C9 (rs1799853, rs1057910), CYP2C19 (rs4244285, rs4986893, rs12248560), VKORC1 (rs9923231, rs7294, rs9934438), MDR1 (rs4148738, rs2032582, rs1045642), FGB (rs1800787), PAI-1 (rs1799889) genes. The results of CYP2B6, CYP3A4/5 (rs776746), CYP4F2 (rs2108622) genes analysis indicate a certain influence on the anticoagulants metabolism and require further detailed study. Factors such as age, race, sex, smoking, diet, and other medications are known to influence the effectiveness of antithrombotic therapy, but the most influential factor is genetics, which accounts a significant percentage of interindividual variability. Future research should focus on the study of known and novel genetic variants that influence drug metabolism, as well as the molecular mechanisms that contribute to changes in plasma anticoagulant levels. The article provides a brief overview of action mechanisms, pharmacogenetics, and interactions between drugs and the genes responsible for their metabolism. The results indicate the need for studies of gene variants considered in this review before starting anticoagulant therapy, and attention should also be paid to the possibility of inhibitors and inductors influence on components of the metabolic pathway of anticoagulants and gene expression products that participate in their metabolism. The totality of these measures will ensure an increase in the efficiency and safety of individual pharmacotherapy and allow optimizing the choice and dosage of anticoagulants.

Recognizing life-threatening bleeding in pediatric trauma: A standard for when to activate massive transfusion protocol.

Traumatic hemorrhage is the most common cause of preventable death in civilian and military trauma. Early identification of pediatric life-threatening hemorrhage is challenging. There is no accepted clinical critical administration threshold (CAT) in children for activating massive transfusion protocols. Children 0 to 17 years old who received any transfusion in the first 24 hours after injury between 2010 and 2019 were included. The type, volume, and time of administration for each product were recorded. The greatest volume of weight-adjusted products transfused within 1 hour was calculated. The cut point for the number of products that maximized sensitivity and specificity to predict in-hospital mortality, need for urgent surgery, and second life-threatening bleeding episode was determined using Youden's index. A binary variable (CAT+) was generated using this threshold for inclusion in a multivariable logistic regression model. In total, 287 patients were included. The median (interquartile range) age was 6 (2-14) years, 60% were males, 83% sustained blunt trauma, and the median (interquartile range) Injury Severity Score was 26 (17-35). The optimal cutoff to define CAT+ was >20 mL/kg of product; this optimized test characteristics for mortality (sensitivity, 70%; specificity, 77%), need for urgent hemorrhage control procedure (sensitivity, 65%; specificity, 74%). and second bleeding episode (sensitivity, 77%; specificity, 74%). There were 93 children (32%) who were CAT+. On multivariate regression, being CAT+ was associated with 3.4 increased odds of mortality (95% confidence interval, 1.67-6.89; p = 0.001) after controlling for age, hypotension, Injury Severity Score, and Glasgow Coma Scale. For every unit of product administered, there was a 10% increased risk of mortality (odds ratio, 1.1; p < 0.001). Transfusion of more than 20 mL/kg of any blood product within an hour should be used as a threshold for activating massive transfusion protocols in children. Children who meet this CAT are at high risk of mortality and need for interventions; this population may benefit from targeted, timely, and aggressive hemostatic resuscitation. Therapeutic/Care Management; Level III.

Emergent Reversal of Antithrombotics and Treatment of Life-Threatening Bleeding from Coagulopathies: A Clinical Review

BackgroundReversal of antithrombotic agents and treatment of life-threatening bleeding episodes from coagulopathies can be a stressful scenario for clinicians, especially when the selection of treatment options should occur quickly. Understanding the options available for these agents requires emergency physicians to be familiar with the current data surrounding new therapies and dosing strategies for the treatment of bleeding from reversible and nonreversible antithrombotics and coagulopathic conditions. ObjectiveTo provide quick resource guides for the reversal of major or life-threatening bleeding caused by antithrombotic agents or in the setting of coagulopathies. MethodsA literature search for articles published through September 2021 related to antithrombotic reversal and treatment of acute bleeding from coagulopathies was conducted using the PubMed clinical database. Selected articles were used to generate 5 guidance tables in this clinical review. DiscussionFour guidance tables for how to treat major or life-threatening bleeding from antithrombotic agents and 1 table for how to manage life-threatening bleeding for coagulopathies are presented as a quick reference tool for the emergency physician. Additional information on upcoming reversal agents and possible treatment options are provided herein. ConclusionsIn this clinical review, a series of 5 tables were created to provide quick and comprehensive guidance for the emergency physician when treating major or life-threatening bleeding caused by antithrombotic agents or coagulopathies. © 2022 Elsevier Inc.

A Machine Learning Framework Predicts the Clinical Severity of Hemophilia B Caused by Point-Mutations

Blood coagulation is a vital physiological mechanism to stop blood loss following an injury to a blood vessel. This process starts immediately upon damage to the endothelium lining a blood vessel, and results in the formation of a platelet plug that closes the site of injury. In this repair operation, an essential component is the coagulation factor IX (FIX), a serine protease encoded by the F9 gene and whose deficiency causes hemophilia B. If not treated by prophylaxis or gene therapy, patients with this condition are at risk of life-threatening bleeding episodes. In this sense, a deep understanding of the FIX protein and its activated form (FIXa) is essential to develop efficient therapeutics. In this study, we used well-studied structural analysis techniques to create a residue interaction network of the FIXa protein. Here, the nodes are the amino acids of FIXa, and two nodes are connected by an edge if the two residues are in close proximity in the FIXa 3D structure. This representation accurately captured fundamental properties of each amino acid of the FIXa structure, as we found by validating our findings against hundreds of clinical reports about the severity of HB. Finally, we established a machine learning framework named HemB-Class to predict the effect of mutations of all FIXa residues to all other amino acids and used it to disambiguate several conflicting medical reports. Together, these methods provide a comprehensive map of the FIXa protein architecture and establish a robust platform for the rational design of FIX therapeutics.

A thrombopoietin receptor agonist to rescue an unusual platelet transfusion-induced reaction in a p.V1316M-associated von Willebrand disease type 2B patient.

This report describes the first case of splenic injury in a patient with p.V1316M-associated von Willebrand disease type 2B (VWD2B) with chronic thrombocytopenia, successfully treated with nonoperative management including von Willebrand factor (VWF) replacement therapy, and platelet transfusions relayed by a thrombopoietin receptor agonist (TPO-RA, Eltrombopag). Eltrombopag was initially introduced to rescue an unusual post-platelet-transfusion reaction exacerbating the thrombocytopenia. In-depth analysis of the dramatic platelet count drop and VWF measurements timeline ruled out an allo-immune reaction and supported an alternative hypothesis of a sudden platelet clearance as a consequence of stress-induced release of abnormal VWF. One year later, a second life-threatening bleeding episode required urgent surgery successfully managed with VWF replacement therapy and platelet transfusions. Eltrombopag was further introduced in the post-surgery period to allow bleeding-free and platelet-transfusion-free successful recovery. Treatment decisions are particularly challenging in patients with VWD2B, and this case highlights how such decisions can benefit from understanding the molecular origin of platelet count fluctuations observed in these patients. Here, we successfully used a new therapeutic approach combining VWF-replacement therapy and initial platelet-transfusion relayed by TPO-RA to optimize patient management.Plain language summaryA combination of von Willebrand factor replacement and thrombopoietin receptor agonist in thrombocytopenic patients with von Willebrand disease type 2B: a new therapy approach to optimize patient management?Therapeutic management of patients with von Willebrand disease type 2B are particularly challenging in case of severe thrombocytopenia.Treatment includes von Willebrands factor replacement therapy and iterative platelet transfusions.We describe the first case of splenic injury in a patient with p.V1316M-associated von Willebrand disease type 2B successfully treated with nonoperative management including von Willebrand factor replacement therapy and platelet transfusions relayed by a thrombopoietin receptor agonist.We showed that the unusual post-platelet-transfusion reaction associated with a dramatic platelet count drop was a consequence of stress-induced release of abnormal von Willebrand factor.The combination of von Willebrand factor replacement therapy and thrombopoietin receptor agonist may offer a new therapeutic approach to optimize patient management.

Short dual antiplatelet strategy following left atrial appendage closure with Watchman and Watchman FLX: 1-year outcomes

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Left atrial appendage occlusion (LAAO) is an effective stroke prevention strategy in patients with non-valvular atrial fibrillation and high bleeding risk. Oral anticoagulation or dual antiplatelet (DAPT) therapy is recommended for the period of device endothelisation but confers an increased bleeding risk. Purpose This study sought to examine the one-year outcomes of a short DAPT strategy following LAA occlusion in a large UK tertiary centre. Methods This retrospective study included all patients discharged on a short DAPT strategy (6-8 weeks) following a LAAO device implantation from January 2010 and December 2020 in our institution. Medical notes, procedural, and imaging reports were reviewed and adverse event rates were calculated at one year. Yearly bleeding risk was extrapolated from the Swedish National Cohort study according to CHA2DS2-VASc and HASBLED score. Results A total of 140 patients (106 Watchman and 36 Watchman-FLX) were discharged on a planned short DAPT strategy (age 74 ± 9 years, 70% male, 71% had previous bleeding on OAC, 95% previous major or life-threatening bleeding episodes, 52% previous ischaemic stroke, CHA2DS2-VASc score 4.5 ± 1.2, HASBLED score 3.2 ± 0.7). The median time to switching to either single antiplatelet (APT) or no ATP was 62 days. After first follow-up, 90% were either on SAPT (46.3% aspirin and 39.3% clopidogrel) or no ATP (6.4%). Seven (5%) patients had device-related thrombus on transoesophageal echocardiography and were started on anticoagulation and 4 (3.5%) patients remained on DAPT. At one year, of the 129 patients on a short DAPT strategy the composite of death, ischaemic stroke and non-procedural bleeding occurred in 11 patients (KM 8.9%; 95% CI, 3.7% -13.8%). Four patients (3.1/100 patient-years) suffered a major bleed and 3 (2.3/100 patient-years) had an ischaemic stroke on SAPT (mean time of 315 days). Compared to estimated annual stroke and bleeding risk adjusted for CHA2DS2-VASc and HASBLED score, this represents a 65% and 38% relative risk reduction in ischaemic stroke and major bleeding, respectively. Conclusion In our cohort, a short DAPT strategy following LAAO device appears safe with reduction of both thromboembolic and major bleeding events at 1-year. Abstract Figure 1

Periprocedural safety and efficacy after left atrial appendage closure in a large UK tertiary centre: 10-year experience

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Left atrial appendage (LAA) thrombus is responsible for up 90% of atrial fibrillation (AF) related ischaemic strokes. Mechanical closure of the LAA is an alternative stroke prevention strategy in patients with non-valvular AF who are at a high risk of bleeding. LAA morphology is highly variable which may affect acute procedural success rates. Purpose This study sought to examine the periprocedural safety and efficacy, and short-term outcomes in patients undergoing left atrial appendage occlusion (LAAO) device implantation in a large UK tertiary centre. Methods This retrospective study included all patients listed for a LAAO device in our institution from January 2010 to December 2020. Medical notes, procedural and imaging reports were reviewed and adverse event rates were calculated at discharge, 30 and 90 days. A Cox regression model was used for multivariable analysis with pre-specified covariates to assess outcomes at 90 days. Results Of 237 patients listed for a LAAO device, 8 (3.4%) had a LAA thrombus and the procedure was abandoned (4 had a successful implant at a later date). In 225 (94.9%) patients a LAAO device was implanted and 4 (1.7%) had unsuitable anatomy precluding device deployment. Seventy-two percent were male, age 74 ± 8 years, BMI 27 ± 6 kg/m2, CHA2DS2-VASc score 4.4 ± 1.2, HASBLED score 3.2 ± 0.8 and at high risk of stroke (98 ischaemic strokes and 129 haemorrhagic strokes) and bleeding (151 major or life-threatening bleeding episodes). The mean procedural and fluoroscopy time were 52.5 ± 30.5 and 8.0 ± 5.9 minutes, respectively. Three different LAAO devices were used (136 Watchman, 54 Watchman FLX and 35 Amplatzer Cardiac Plug) with no significant difference in acute procedural success (97.8%, 98.2% and 94.4%, p = 0.41, respectively). Complete seal was achieved in 202 (92%) patients with only 1 (0.4%) moderate leak. Procedure-related mortality was 1.3% and non-fatal serious adverse events occurred in 5 (2.1%) patients. At 90 days, 28 patients experienced an adverse event (KM 12.5%; 95% CI, 8%-16.1%) and 16 patients suffered a serious adverse event (KM 7.1%; 95% CI, 3.7%-10.4%). In a covariate-adjusted Cox model, CHA2DS2-VASc score less than 4 had hazard ratio of 0.21 (95% CI, 0.06 -0.71, p = 0.01) for serious events at 90 days. Conclusion The acute procedural success rate was high (97%) with a low number of periprocedural complications. Serious adverse events at both 30 and 90-days were low in keeping with other published registries. Abstract Figure.

Long-term outcomes in patients with non-valvular atrial fibrillation and left atrial appendage closure in a large UK tertiary centre: 10-year experience

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Left atrial appendage occlusion (LAAO) is a well-established stroke prevention strategy in patients with non-valvular atrial fibrillation (AF) and high risk of bleeding or contra-indication to oral anticoagulation (OAC). Despite encouraging randomised control trial and international registry safety and efficacy data, long-term outcome data remains sparce. Purpose This study sought to evaluate the long-term outcomes in ‘real-world’ AF patients undergoing left atrial appendage occlusion in a large UK tertiary centre. Methods This retrospective study included all patients that had a LAAO device implanted in our institution from January 2010 to December 2020. Medical notes, electronic patient records, procedural and imaging reports were reviewed. Annual bleeding risk was extrapolated from the Swedish National Cohort study according to CHA2DS2-VASc and HASBLED score. Results During the study period a total of 225 patients underwent LAAO device implant. Seventy-two percent were male, age 74 ± 8 years, BMI 27 ± 6 kg/m2, CHA2DS2-VASc score 4.4 ± 1.2, HASBLED score 3.2 ± 0.8 and at high risk of stroke (98 ischaemic strokes and 129 haemorrhagic strokes) and bleeding (151 life-threatening bleeding episodes). Three different LAAO devices were used: 136 Watchman, 54 Watchman FLX and 35 Amplatzer Cardiac plugs. Three patients (1.3%) had fatal complications related to the procedure. At discharge, 10% were taking single antiplatelet (ATP), 79% dual-antiplatelet (DAPT), 1.4% OAC, 3.6% ATP and OAC, 3.1% DAPT and OAC, 1.3% were not taking any anti-thrombotic. Nine (4%) patients had device-related thrombus on follow-up transoesophageal echocardiography with no significant difference between devices (5.0%, 2.8% and 6.7% p = 0.8, respectively) and anticoagulation strategy (p = 0.7). Over a total follow-up of 889 patient-years (mean follow-up 3.9 ± 3.7 years), 24 (10.4%) patients died, 55 patients (6.2/100 patient-years) suffered an adverse event, 15 ischaemic strokes (1.7/100 patient-years) and 20 non-procedural major bleeding episodes (2.3/100 patient-years) occurred. Compared to estimated annual stroke and bleeding risk adjusted for CHA2DS2-VASc and HASBLED score, our cohort had a 79% and 65% relative risk reduction in ischaemic stroke and major bleeding, respectively. Conclusion In this cohort of "real-world" high-risk patients, major bleeding and thromboembolic rate remained low on long-term follow-up. Abstract Figure 1

Australian and New Zealand Registry of Anticoagulation in the Obese: Prescribing Patterns, Drug Levels and Patient Outcomes

Background: There is limited data to guide prescribing of all available anticoagulants in obese patients, in particular those weighing &amp;gt; 150kg or with a BMI &amp;gt; 40kg/m2. We aimed to examine anticoagulant prescribing patterns in obese patients in Australia and New Zealand including choice of agent and dosing, determine whether patients with obesity achieve appropriate direct oral anticoagulant (DOAC) levels and evaluate the efficacy and safety of anticoagulation in obese patients. Methods: Patients with a BMI &amp;gt; 35kg/m2 or weight &amp;gt; 120kg receiving anticoagulant therapy are prospectively identified at 7 sites in Australia and New Zealand. Demographic data, indication for anticoagulation and choice of anticoagulant are collected at baseline. At follow-up visits, drug specific levels, dose adjustments and clinical progress (symptoms, imaging, recurrent thrombosis and adverse events) are recorded. Results: 155 patients have been recruited across seven sites (recruitment ongoing). The median age of patients was 53 (range 22-85) and 49% of patients were male. 77 (50%) of patients were anticoagulated for pulmonary embolus (PE) while 40% were anticoagulated for deep vein thrombosis (DVT) without PE. Initial anticoagulant prescribed was apixaban in 37 patients, dabigatran in 4 patients, rivaroxaban in 57 patients, low molecular weight heparin (LMWH) in 29 patients and warfarin in 28 patients (Table 1). A subset of patients initially received LMWH for 5-14 days prior to transition to a DOAC (rivaroxaban in 7, dabigatran in 6). There was cross-over between agents during the study period. Table 2 demonstrates median peak and trough DOAC levels. All peak apixaban levels and 25 of 37 (68%) peak rivaroxaban levels were within the therapeutic ranges published by the International Council for Standardization in Haematology (Gosselin, Thromb Haemost. 2018). Assessment of appropriate trough levels was limited by the limit of detection at different laboratories. 27 patients receiving enoxaparin had at least one peak Anti-Xa level (target peak 0.5-1.2U/ml). The median enoxaparin dose to achieve therapeutic peak Anti-Xa was 0.9mg/kg (range 0.52-1.3). 15 patients weighing &amp;gt; 150kg had a recorded peak Anti-Xa, 10 of these patients were prescribed a capped dose of 150mg BD (weight range 155-290kg) and nine had a therapeutic Anti-Xa and one had a supratherapeutic Anti-Xa measurement. One patient had a PE on apixaban 5mg twice daily (in the setting of suspected non-compliance), one patient had a new confirmed PE after 4 days of non-compliance with rivaroxaban 20mg daily and another patient had a confirmed recurrence on therapeutic warfarin. 1 patient had a PE when warfarin was withheld for emergency surgery. An equivocal recurrence occurred on enoxaparin with a supratherapeutic Anti-Xa (1.76 U.ml) and 1 DVT occurred on dabigatran for a cardiac indication (no drug level available). One patient had recurrent superficial thrombophlebitis on rivaroxaban 20mg daily (peak 301ng/L and trough &amp;lt;30ng/L). There was one episode of life-threatening gastrointestinal bleeding on dabigatran. Conclusion: There is limited data to guide prescribing of all anticoagulants in obese patients, in particular in patients weighing &amp;gt; 150kg or BMI &amp;gt; 40kg/m2. There is increasing use of DOACs in Australia and New Zealand in patients with obesity given the ease of administration and lack of monitoring required. Despite the recommendation to perform DOAC levels in this group of patients, interpretation of levels is difficult due to a lack of well validated therapeutic ranges with clinical correlation. Further data regarding the clinical utility of DOAC levels, appropriate dosing strategy for enoxaparin, and clinical outcomes in this population is required. Our registry provides data regarding drug levels in this population, prescribing characteristics and clinical outcome data. Disclosures No relevant conflicts of interest to declare.

Idarucizumab for Urgent Dabigatran Reversal in Clinical Practice: A Case Series of First Use in Vietnam

The benefits of non-Vitamin K oral antagonists in prevention or treatment of thrombosis have been studied in many randomized control trials. However, episodes of life-threatening bleeding caused by using novel oral anticoagulants have occurred in clinical practice and necessitate the development of aims for reversal of the anticoagulant effects. We report here three cases in which the use of idarucizumab, a humanized monoclonal antibody fragment, has successfully reversed the anticoagulation effects of dabigatran and produced favorable outcomes.

Hereditary Haemorrhagic Telangiectasia (HHT) Marked by ACVRL1C1120T Variant Displays Hypopigmented Naevi and Frequent Bleeding Episodes if CYP2C9 Co-Mutated: Clinical Notes &amp; Rationale of Patient Registry

Hereditary haemorrhagic telangiectasia (HHT) exhibits considerable phenotypic heterogeneity. Therefore, precise mutation screening and evaluation of patient risk must be determined in every HHT family. We present an HHT-2 case with an initial life-threatening bleeding episode that led to identification of a relatively large HHT family. Exome sequencing of the family members determined HHT-associated ACVRL1C1120T variant resulting in Arg374Trp substitution at the Ser/Thr-kinase domain region. The affected members display typical epistaxis symptomatology from early childhood resulting in sideropoenia. In addition, the HHT patients also displayed dermatology findings such as facial teleangiectasias and trunk/limb white spots representing post-inflammatory hypopigmentation. Interestingly, co-segregating with modifying cytochrome P450 (CYP2C) variant in the HHT patients led to NSAID intolerance marked by increased frequency of bleeding episodes. No arterial-venous malformation of the visceral organs and brain or association with cancer were observed. The heterogeneity of clinical presentation and the role of other variants support the need of regular patient monitoring and development of a nation-wide patient registry.

Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study.

Vitamin K antagonists (VKAs), although commonly used to reduce thromboembolic risk in atrial fibrillation, have been incriminated as probable cause of accelerated vascular calcification (VC) in patients on hemodialysis. Functional vitamin K deficiency may further contribute to their susceptibility for VC. We investigated the effect of vitamin K status on VC progression in 132 patients on hemodialysis with atrial fibrillation treated with VKAs or qualifying for anticoagulation. Patients were randomized to VKAs with target INR 2-3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 µg thrice weekly during 18 months. Systemic dp-ucMGP levels were quantified to assess vascular vitamin K status. Cardiac and thoracic aorta calcium scores and pulse wave velocity were measured to evaluate VC progression. Baseline dp-ucMGP was severely elevated in all groups. Initiation or continuation of VKAs further increased dp-ucMGP, whereas levels decreased in the rivaroxaban group and to a larger extent in the rivaroxaban+vitamin K2 group, but remained nevertheless elevated. Changes in coronary artery, thoracic aorta, and cardiac valve calcium scores and pulse wave velocity were not significantly different among the treatment arms. All cause death, stroke, and cardiovascular event rates were similar between the groups. Bleeding outcomes were not significantly different, except for a lower number of life-threatening and major bleeding episodes in the rivaroxaban arms versus the VKA arm. Withdrawal of VKAs and high-dose vitamin K2 improve vitamin K status in patients on hemodialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs.

1544 Klippel-Trenaunay-Weber: Rare Congenital Syndrome Causing Persistent Rectal Bleeding

INTRODUCTION: Klippel-Trenaunay Weber syndrome (KTS) is a rare congenital disorder characterized by a triad of cutaneous capillary malformation (port-wine stain), venous malformations and limb hypertrophy. Diffuse vascular malformations of the gut in KTS can lead to gastrointestinal (GI) bleeding ranging from minor to life threatening hemorrhage necessitating surgical intervention. We describe a case of persistent rectal bleeding and iron dependent anemia in a patient with KTS. CASE DESCRIPTION/METHODS: A 32-year-old female with previous diagnosis of KTS was seen for recurrent hematochezia and iron deficiency anemia. A recent colonoscopy demonstrated non-bleeding arteriovenous malformations (Figure 1), presumed to be the source for the recurrent rectal bleeding episodes. On exam, she appeared pale, had a right hip deep purple telangiectasia, right posterior thigh palpable mass without visible varicosities and no limb hypertrophy. Her laboratory tests revealed: Hb: 9 g/dl, mean corpuscular volume: 75.0 fl, ferritin: 3 ng/ml and serum iron: 22 mcg/dl. CT abdomen/pelvis showed diffuse thickening of the rectum and sigmoid colon with scattered mural calcifications. A repeat colonoscopy demonstrated non-bleeding large circumferential vascular malformation extending from the dentate line to about 20 cm in the rectum (Figure 2) and multiple soft, pale lymphatic blebs in the colon and rectum (Figure 3). Her iron deficiency anemia from chronic blood loss was treated with oral and IV iron therapy. Despite conservative therapy, patient continues to bleed intermittently but has decided against surgical intervention at this time. DISCUSSION: GI hemorrhage occurring in association with KTS is an uncommon cause of rectal bleeding but is the most common symptom and potentially life-threatening emergency of KTS involving the gut. Investigation should begin with visualization of the entire GI tract for localization and extension of the disease. Angiography remains the gold standard and carries the advantage of allowing therapeutic interventions to control bleeding. The management of GI vascular malformations in KTS depends on the frequency and severity of blood loss requiring transfusions. Conservative management and iron supplements may be sufficient in the patient who presents with occasional non-debilitating bleeding. Transfusion dependency and life-threatening bleeding episodes necessitate definitive surgical therapy which involves resection of the diseased bowel.

Abstract 283: Healthcare Resource Utilization and Costs Associated with Oral Anticoagulant Reversal Therapy

Introduction: Oral anticoagulants (OAC) are essential for stroke prevention in atrial fibrillation (AF). Occasionally, reversal of anticoagulation is critical for treating life-threatening or uncontrolled bleeding episodes, as well as emergency surgery/urgent procedures. Prothrombin complex concentrates (PCC) or specific anticoagulant reversal agents such as idarucizumab (IDA) are initiated in patients who present with a significant bleed or who require urgent surgery. Currently, there is a scarcity of published data regarding healthcare resource utilization (HCRU) or costs incurred by these anticoagulant reversal agents in patients with AF or venous thromboembolism (VTE). Hence, we sought to describe the HCRU and total costs sustained among patients with AF or VTE receiving IDA or PCC in US-based healthcare systems. Methods: A retrospective observational study using the Premier Healthcare Database was undertaken. The study included adult patients aged ≥18 years treated with IDA or 3 or 4-factor PCC (Kcentra, Feiba, Profilnine, or unspecified) to reverse the effects of dabigatran or warfarin, respectively, between October 2015 and February 2018. Patients who received PCC were excluded if they had no evidence of warfarin use, or were administered a direct OAC within the 12-month period prior to first hospitalization admission with a record of IDA/PCC use (index hospitalization). Clinical characteristics, HCRU, and total costs during index hospitalization for patients treated with IDA or PCC were examined by use of unadjusted descriptive analysis. Results: The median ages for IDA (n=1,232) and PCC (n=4,939) patients were 78 [IQR: 70-85] and 74 [IQR: 65-83] years, respectively. Both treatment groups had a slightly higher representation of males (55.0% for IDA, 55.2% for PCC), and were predominantly of Caucasian race (86.6% in IDA, 79.7% in PCC). Among IDA patients, 59.3% had life-threatening bleeds and 30.4% underwent emergency/urgent surgery, with 56.7% and 30.8% for PCC patients, respectively. The median length of stay for the index hospitalization was 6 [IQR: 3-9] and 7 [IQR: 4-14] days for patients who received IDA or PCC, respectively. Intensive Care Unit admission rates were 61.3% for IDA patients and 68.7% for PCC patients. Median total costs per hospitalization were $19,357 for IDA patients and $26,920 for PCC patients, with the median cost of IDA and PCC therapy per hospitalization being $3,277 and $4,424, respectively. Conclusions: This observational, descriptive analysis revealed numerically lower HCRU and total hospital costs in patients administered IDA compared with PCC for reversal of OAC, though there were differences in population characteristics. Further studies are needed to determine the factors that potentially drive the disparate HCRU and associated costs between patients receiving IDA or PCC.

Incidence of Thromboembolic Disease in Hereditary Hemorrhagic Telangiectasia (Osler Weber Rendu Syndrome)

▪The Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia that affects 1-5000 individuals worldwide. Is characterized by fragile mucocutaneous telangiectasia and vascular malformations in organs such as brain, lungs, liver and the gastrointestinal tract. Nose and gastrointestinal bleeding are remarkable, leading to frequent iron deficiency anemia (IDA) or life threatening bleeding episodes. Venous thromboembolic events (VTE) in HHT are probably more frequent than general population due to high plasmatic levels of FVIII specially in clinical conditions like long time immobilization due to brain abscesses or severe anemia. Additionally, in those patients with pulmonary fistula, the thromboembolic events can produce paradoxal strokes. On the other hand, almost all HHT medical treatments usually used to treat HHT related bleeding could produce thromboembolic disease. Anticoagulation (ACO) in this bleeding condition is a challenge, nevertheless, almost 50% can tolerate it well.Objective: To report the incidence of VTE in the HHT population.Methods: Ambispective cohort of adult based on the Institutional Registry of HHT. VTE was defined as the first episode of pulmonary embolism (PE), deep venous thrombosis (VTE) or thrombosis in the fistula sac or the progression of a prior event after its first 48 hs despite anticoagulation.Result: Over 524 patients 394 adults with HHT confirmed by Curazao criteria or positive genetic test and complete data were included. There were 18 VTE events 4.6% (CI95% 2.7-6.8%), 9 DVT (2.3% IC95% 1.2-4.4%) and 3 PE (0.7% IC95% 0.13-2%). The female gender represents 72%. The median age at the event was 67 years (IIQ 25-75% 56-73).Five patients (27%) were on ACO prior to the event, mainly for atrial fibrillation, and 3(18%) suffered a previous VTE.The most frequent risk factors were recent hospitalization (44%) and iron deficiency anemia (44%), immobility (33%), recent surgery (18%), as well as cancer (5%) and recent travel (5%) patient each.Fifteen (83%) patients received ACO, 10(55%) received LMH followed by acenocumarol, 3(30%) of which had to be stopped due to nose or gastrointestinal bleeding.In 5 (27%) a cava vein filter were inserted, of which 3 are under anticoagulation therapy.Conclusion: VTE incidence in our study was significantly higher than reported in general population at similar age. However, the inclusion of more symptomatic and serious HHT patients could be selection bias. The low number of patients, may influence the results. IDA and hospitalization were the most important associated conditions. Most patients tolerated well the anticoagulation therapy. DisclosuresNo relevant conflicts of interest to declare.

Immune Mediated Cytopenia's Following Cord Blood Transplantation for Hurler's Syndrome: A Failure of Pre-Transplant Immune Suppression

Background: Hurler's syndrome is the most severe phenotype of Mucopolysaccharidosis 1 (MPS1H) with severe deficiency of the lysosomal enzyme alpha-L-iduronidase causing heparan and dermatan sulfate accumulation, CNS and somatic manifestations and premature death. Haematopoeitic Stem Cell Transplant (HSCT) alters the disease phenotype and prevents early death, and is standard of care in this condition. The use of an established ‘donor hierarchy’ recommending Unrelated Cord Blood Transplantation (UCBT) in the absence of a HLA-matched, non-carrier sibling, has resulted in improved engrafted and surviving rates and better post-enzyme levels with improved somatic and CNS clinical outcomes. However, UCBT for malignant and non-malignant conditions has led to high rates of post-transplant autoimmune disease, most frequently Autoimmune Cytopenia (AIC). We report a large cohort of MPS1H patients receiving busulfan-based UCBT and show that AIC is a frequently encountered complication of treatment with significant associated morbidity and we identify important risk factors for its occurrence.Methods: This was a retrospective observational study of patients undergoing first UCBT for Hurler's Syndrome at the Royal Manchester Children's Hospital between 30th September 2004 and 15th March 2018. An episode of AIC was defined as an episode of single or multi-lineage cytopenia occurring post-engraftment, confirmed by the presence of antibodies or diagnosed on the basis of clinical, biochemical and pathologic features. All patients received pK targeted busulfan to achieve myeloablative levels between 80-90 mg/L x hr. Conditioning between 2004 and May 2010 was with Busulfan and Cyclophosphamide (BuCy), and Fludarabine and Busulfan (FluBu) thereafter based on the reported equivocal efficacy and favourable toxicity profile of FluBu conditioning. All patients received serotherapy with Anti-Thymocyte Globulin (ATG) 10mg/kg for In Vivo T-Cell depletion. Timing of ATG was either distal (day -4 to -1) or proximal (day - 9 to -6) in accordance with international consensus at the time. Variables assessed in statistical analysis were conditioning drugs, ATG timing, Absolute Lymphocyte Count pre-conditioning, age-at-transplant, Graft-versus-Host Disease (GVHD) and Total Nucleated Cell dose.Results and Discussion: Thirty-six patients underwent first UCBT for Hurler's Syndrome. There were 8 episodes of AIC (22%), with median onset post-UCBT of 66 days (range 22-236 days). The median number of therapies required was 4 (range 0-8), with duration of illness ranging from 10 to 215 days. There were no deaths, though there were 2 episodes of life-threatening bleeding. Absolute Lymphocyte Count pre-conditioning (p=0.004), FluBu conditioning (p=0.03) and use of proximal-ATG (p=0.016) were significant risk factors for AIC in univariate analysis(see figure 1). Absolute Lymphocyte Count pre-conditioning was the most significant predictor in multivariable analysis (AOR 5.796, CI 0.921-36.474). This confirms that AIC is a frequent, serious but survivable complication of UCBT for Hurler's Syndrome. This data indicates that the balance between recipient immunity and graft immunity impacts AIC risk and severity, mandating a larger international review of registry data to define the frequency of AIC in this population, and an analysis of the risk factors that predispose to it. By better defining these risk factors, we can identify patients in whom conditioning might be altered to reduce risk.Figure 1. Univariate analysis of variables predicting an episode of Autoimmune Cytopenia. ALC (p=0.004), ATG timing (0.016) and Conditioning drugs (p=0.032) were significant risk factors. GVHD= Graft-versus-Host Disease ATG= Anti-Thymocyte Globulin [Display omitted] DisclosuresWynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy.

Management of rare coagulation disorders in 2018

Rare bleeding disorders (RBDs) comprise inherited deficiencies of factors I (fibrinogen), II (prothrombin), V, VII, X, XI, and XIII as well as combined factor V + VIII and vitamin K-dependent factors. They represent 3–5% of all congenital bleeding disorders and are usually transmitted as autosomal recessive traits. These disorders often manifest during childhood and have varied clinical presentations from mucocutaneous bleeding to life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Bleeding manifestations generally vary within the same RBD and may also vary from 1 RBD to the other. Laboratory diagnosis is based on coagulation screening tests and specific factor assays, with molecular techniques providing diagnostic accuracy and enabling prenatal counseling. The approach to treatment of bleeding episodes and invasive procedures needs to be individualized and depends on the severity, frequency and procedure-related risk of bleeding. The first line of treatment of RBDs is replacement of the deficient factor, using specific plasma-derived or recombinant products and using fresh frozen plasma or cryoprecipitate when specific products are not available or in resource-limited countries. Prophylaxis may be considered in individuals with recurrent serious bleeding and especially after life-threatening bleeding episodes. Novel no-replacement strategies promoting hemostasis by through different mechanisms need to be studied in RBDs as alternative therapeutic options.

Combined life-threatening thromboses and hemorrhages in a patient with afibrinogenemia and antithrombin deficiency

BackgroundPatients with congenital afibrinogenemia suffer from spontaneous recurrent severe bleeding. While fibrinogen concentrates are known to effectively treat bleeding episodes, thrombotic complications often occur upon replacement therapy, rendering clinical management highly challenging.Case PresentationWe hereby report a case of combined afibrinogenemia and congenital antithrombin deficiency manifested by recurrent life-threatening bleeding, as well as spontaneous severe arterial occlusion, such as acute coronary syndrome and stroke, and venous thromboses like pulmonary embolism.Secondary fibrinogen prophylaxis is recommended following any initial life-threatening bleeding episode in patients with afibrinogenemia, yet the high associated risk of thrombosis illustrates the complexity of choosing the most effective prophylaxis strategy combining fibrinogen concentrate with antithrombotic agent for optimal protection against the risk of both severe bleeding and thrombosis. For our patient, the thrombin generation assay objectively confirmed her prothrombotic tendency.ConclusionThis case may help us better understand the pathophysiology of arterial thrombosis in afibrinogenemia, while highlighting the difficulty of managing such complications.