Pharmacology and Clinical Development of Factor XI Inhibitors.

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

Effects of COVID-19 vaccination on platelet counts and bleeding in children, adolescents, and young adults with immune thrombocytopenia.

Coronavirus disease 2019 (COVID-19) vaccines rarely cause de novo immune thrombocytopenia (ITP) but may worsen preexisting ITP in adults. Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines impact platelet counts and bleeding in children, adolescents, and young adults (C-AYA) with preexisting ITP is unknown. We report here the very limited effect of COVID-19 vaccination on platelet counts and bleeding in a single-center series of 2 C-AYA with ITP. No patient experienced worsening bleeding and only one child had a significant decrease in platelet count which improved spontaneously to her baseline without intervention. SARS-CoV2 vaccination was safe in C-AYA with ITP in this small cohort.

Hemorrhage, Disseminated Intravascular Coagulopathy, and Thrombosis Complications Among Critically Ill Patients with COVID-19: An International COVID-19 Critical Care Consortium Study.

OBJECTIVES: To determine the prevalence and outcomes associated with hemorrhage, disseminated intravascular coagulopathy, and thrombosis (HECTOR) complications in ICU patients with COVID-19. DESIGN: Prospective, observational study. SETTING: Two hundred twenty-nine ICUs across 32 countries. PATIENTS: Adult patients (≥ 16 yr) admitted to participating ICUs for severe COVID-19 from January 1, 2020, to December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: HECTOR complications occurred in 1,732 of 11,969 study eligible patients (14%). Acute thrombosis occurred in 1,249 patients (10%), including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial ischemia, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic strokes. Hemorrhagic complications were reported in 579 patients (4.8%), including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, 77 (13%) with pulmonary hemorrhage, and 68 (12%) with hemorrhage associated with extracorporeal membrane oxygenation (ECMO) cannula site. Disseminated intravascular coagulation occurred in 11 patients (0.09%). Univariate analysis showed that diabetes, cardiac and kidney diseases, and ECMO use were risk factors for HECTOR. Among survivors, ICU stay was longer (median days 19 vs 12; p < 0.001) for patients with versus without HECTOR, but the hazard of ICU mortality was similar (hazard ratio [HR] 1.01; 95% CI 0.92-1.12; p = 0.784) overall, although this hazard was identified when non-ECMO patients were considered (HR 1.13; 95% CI 1.02-1.25; p = 0.015). Hemorrhagic complications were associated with an increased hazard of ICU mortality compared to patients without HECTOR complications (HR 1.26; 95% CI 1.09-1.45; p = 0.002), whereas thrombosis complications were associated with reduced hazard (HR 0.88; 95% CI 0.79-0.99, p = 0.03). CONCLUSIONS: HECTOR events are frequent complications of severe COVID-19 in ICU patients. Patients receiving ECMO are at particular risk of hemorrhagic complications. Hemorrhagic, but not thrombotic complications, are associated with increased ICU mortality.

Emicizumab: a novel drug in hemophilia A prophylaxis - a narrative review.

INTRODUCTION: Hemophilia A is a genetically conditioned disease leading to hemostatic disorders due to factor VIII (FVIII) deficiency. The treatment of hemophilia has evolved throughout the past years and has significantly changed. One of the newest drugs for prophylactic treatment is the humanized bispecific IgG antibody - emicizumab, which binds with factor IXa and factor X, bridging those factors and thus mimicking the activity of factor VIII. AREAS COVERED: The literature search was done via the PubMed database, with the emphasis on clinical trials and case reports, describing the off-label emicizumab use. This review presents an extensive summary and considers the advantages and disadvantages (side-effects) of emicizumab, describing additional clinical situations, where emicizumab has been successfully used. In our review, we cover information about the mechanisms of action, indications, and efficacy and discuss some chosen case reports about off-label emicizumab use. EXPERT OPINION: Its convenient administration method (subcutaneous) and frequency of injections (from once a week to once a month) makes it a more comfortable treatment, limiting injection-site reactions, hospital stays, costs of prophylaxis, and significantly increasing patients' quality of life. Adverse effects are scarce and rarely serious - the most common ones are reactions at the injection-site and upper respiratory tract infections.

The presentation, etiologies, pathophysiology, and treatment of pulmonary renal syndrome: A review of the literature.

Pulmonary renal syndrome (PRS) is a constellation of different disorders that cause both rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. While antineutrophil cytoplasmic antibody associated vasculitis and anti-glomerular basement membrane disease are the predominant causes of PRS, numerous other mechanisms have been shown to cause this syndrome, including thrombotic microangiopathies, drug exposures, and infections, among others. This syndrome has high morbidity and mortality, and early diagnosis and treatment is imperative to improve outcomes. Treatment generally involves glucocorticoids and immunosuppressive agents, but treatment targeted to the underlying disorder can improve outcomes and mitigate side effects. Familiarity with the wide range of possible causes of PRS can aid the clinician in workup, diagnosis and early initiation of treatment. This review provides a summary of the clinical presentation, etiologies, pathophysiology, and treatment of PRS.

Use of nafamostat mesilate for anticoagulation during extracorporeal membrane oxygenation: A systematic review.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) represents an advanced option for supporting refractory respiratory and/or cardiac failure. Systemic anticoagulation with unfractionated heparin (UFH) is routinely used. However, patients with bleeding risk and/or heparin-related side effects may necessitate alternative strategies: among these, nafamostat mesilate (NM) has been reported. METHODS: We conducted a systematic literature search (PubMed and EMBASE, updated 12/08/2021), including all studies reporting NM anticoagulation for ECMO. We focused on reasons for starting NM, its dose and the anticoagulation monitoring approach, the incidence of bleeding/thrombosis complications, the NM-related side effects, ECMO weaning, and mortality. RESULTS: The search revealed 11 relevant findings, all with retrospective design. Of these, three large studies reported a control group receiving UFH, the other were case series (n = 3) or case reports (n = 5). The main reason reported for NM use was an ongoing or high risk of bleeding. The NM dose varied largely as did the anticoagulation monitoring approach. The average NM dose ranged from 0.46 to 0.67 mg/kg/h, but two groups of authors reported larger doses when monitoring anticoagulation with ACT. Conflicting findings were found on bleeding and thrombosis. The only NM-related side effect was hyperkalemia (n = 2 studies) with an incidence of 15%-18% in patients anticoagulated with NM. Weaning and survival varied across studies. CONCLUSION: Anticoagulation with NM in ECMO has not been prospectively studied. While several centers have experience with this approach in high-risk patients, prospective studies are warranted to establish the optimal space of this approach in ECMO.

Management of Dengue: An Updated Review.

Dengue is an important public health problem with a wide clinical spectrum. The World Health Organization classifies dengue into probable dengue, dengue with warning signs, and severe dengue. Severe dengue, characterized by plasma leakage, severe bleeding, or organ impairment, entails significant morbidity and mortality if not treated timely. There are no definitive curative medications for dengue; management is supportive. Judicious fluid resuscitation during the critical phase of dengue is the cornerstone of management. Crystalloids are the initial fluid of choice. Prophylactic platelet transfusion is not recommended. Organ involvement in severe dengue should be carefully looked for and managed. Secondary hemophagocytic lymphohistiocytosis is a potentially fatal complication of dengue that needs to be recognized, as specific management with steroids or intravenous immunoglobulin may improve outcomes. Several compounds with anti-dengue potential are being studied; no anti-dengue drug is available so far.

Dynamic coagulofibrinolytic responses under long-term VV-ECMO management without anticoagulation in a COVID-19-ARDS patient: A case report.

RATIONALE: Venovenous extracorporeal membrane oxygenation (ECMO) is recommended for the treatment of critically ill patients with acute respiratory distress syndrome due to coronavirus disease 2019 (COVID-19). However, ECMO management can cause both bleeding and thrombotic complications. There are insufficient coagulofibrinolytic data for appropriate ECMO management in patients with COVID-19. PATIENT CONCERNS: A 48-year-old man with severe COVID-19-acute respiratory distress syndrome underwent long-term venovenous ECMO management for 48 days. Refractory oronasal bleeding developed on day 13, so the administration of unfractionated heparin was ceased for 29 days. DIAGNOSIS: The patient showed dynamic coagulofibrinolytic responses associated with ECMO management, as shown by fibrin/fibrinogen degradation products, soluble fibrin, thrombin-antithrombin complex, and plasmin-α2-plasmin inhibitor complex elevations, suggesting the development of ECMO-induced coagulopathy. INTERVENTIONS: We assessed coagulofibrinolytic markers to decide the appropriate timing for controlling excessive activation of coagulation by exchanging ECMO circuits. Moreover, viscoelastic hemostatic assays were used for adequate transfusion of blood products. OUTCOMES: Safe long-term ECMO management was completed, which was withdrawn on day 48. The patient was weaned off mechanical ventilation on day 57 and was transferred to another hospital for rehabilitation. LESSONS: Monitoring the coagulofibrinolytic status using markers and viscoelastic hemostatic assays may be effective for safe long-term ECMO management even without anticoagulant therapy.

Mortality rate in patients with SAR-COV-2 infection treated with extracorporeal membrane oxygenator: A systematic review and meta-analysis.

BACKGROUND: Extracorporeal membrane oxygenator (ECMO) is one of the life-saving modalities for the treatment of multiple organs dysfunction, particularly the heart and the lungs. OBJECTIVE: To evaluate the benefit of ECMO for the treatment of SAR-COV-2 infection and its outcomes, complications, and mortality rate. METHODS: A comprehensive search for articles was performed using MEDLINE and SCOPUS from December 2019 to December 2020. Two independent reviewers selected eligible studies, extracted the data, assessed the quality of the studies, reviewed the full study protocols, and reported the findings according to the PRISMA protocol. The meta-analyses were performed using the Comprehensive Meta-Analysis software version 2.0. RESULTS: Pooled data from 57 studies was analyzed. There were 7,035 patients with SAR-COV-2 infection with event rate of ECMO treatment was 58.10% (95%CI: 43.70-71.20). The mortality rate was 16.66% (95%CI: 11.49-23.53). The mean mortality rate of ECMO supported patients was 35.60% (95%CI: 30.60 to 41.00). Thirty-one percent (95%CI: 24.50-38.40) of the patients had venous thromboembolic events, 30.90% (95%CI: 17.90-47.80) of the patients had ECMO circuit thrombosis, and 24.50% (95%CI: 12.50-42.40) of the patients had bleeding. In the subgroup analysis, the mortality rate was higher among patients who were treated with ECMO, the pooled odds ratio was 4.47 (95%CI: 2.39-8.35, p < 0.001), and was significantly higher in Asia with an odds ratio of 7.88 (95%CI: 2.40-25.85, p = 0.001). CONCLUSION: Mortality rate among patients who received ECMO therapy was high. A system of care, including patient selection, resource management and referral system, can impact the outcomes of ECMO therapy.

[Computed tomography and endovascular occlusion in diagnosis and treatment of spontaneous bleeding into soft tissues of abdominal, chest wall and retroperitoneal space in patients with COVID-19]. / Komp'yuternaya tomografiya i rentgenendovaskulyarnaya okklyuziya v diagnostike i lechenii spontannykh krovotechenii v myagkie tkani bryushnoi, grudnoi stenok i zabryushinnogo prostranstva u bol'nykh COVID-19.

OBJECTIVE: To investigate the results of therapeutic and prophylactic endovascular hemostasis of spontaneous bleeding into soft tissues of abdominal, chest wall and retroperitoneal space in patients with COVID-19. MATERIAL AND METHODS: We retrospectively studied 35 patients with COVID-19 complicated by spontaneous bleeding into soft tissues of abdominal, chest wall and retroperitoneal space. According to CT data, the volume of hematoma was 1193.4±706.1 ml. In all patients, CT signs of ongoing bleeding were detected. Moreover, contrast agent extravasation in all phases of examination was established in 15 patients. In other ones, extravasation was detected in late phases or study phase was not identified. All patients underwent angiography. Ongoing bleeding was detected in 12 (34.3%) patients (group 1). They underwent embolization of the target vessel. In 23 patients, bleeding was not established during angiography. Of these, 13 ones underwent prophylactic embolization (group 2). No embolization was carried out in 10 patients (group 3). All groups differed in hematoma localization and COVID-19 severity. RESULTS: Fourteen (40%) patients died in postoperative period. Mortality was similar in all groups. The most common cause of death was progressive respiratory failure following pneumonia. The last one was established by autopsy in 10 (71.4%) patients. CONCLUSION: Angiography confirmed MR signs of contrast agent extravasation in 34.3% of patients. In case of extravasation in all CT phases, ongoing bleeding was confirmed in 66.7% of patients. Endovascular embolization is effective for arterial bleeding into soft tissues. However, large-scale studies are needed to assess the effect of this technique on survival.

Lupus anticoagulant-hypoprothrombinemia syndrome with severe bleeding diathesis after coronavirus disease 2019: a case report.

Acquired antibodies against factor II (prothrombin) are rare and most commonly associated with severe liver disease or vitamin K antagonist treatment. In very rare cases, these antibodies and associated hypoprothrombinemia are found in patients with lupus anticoagulant (LAC), an antiphospholipid antibody that inhibits phospholipid-dependent coagulation tests. This uncommon entity, called lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS), may cause both severe, life-threatening bleeding and a predisposition to thrombosis. Coronavirus disease 2019 (COVID-19) is associated with a variety of coagulation abnormalities and an increased risk of thrombosis. Bleeding may occur, but it is less common than thromboembolism and has mostly been described in association with the severity of the disease and anticoagulation treatment in hospitalized patients, rarely in the post-acute phase of the disease. We report on a case of an 80-year-old man who developed LAHPS with prothrombin antibodies and severe bleeding after COVID-19.

Tracheostomy Practices and Outcomes in Children During Respiratory Extracorporeal Membrane Oxygenation.

OBJECTIVES: Children receiving prolonged extracorporeal membrane oxygenation (ECMO) support may benefit from tracheostomy during ECMO by facilitating rehabilitation; however, the procedure carries risks, especially hemorrhagic complications. Knowledge of tracheostomy practices and outcomes of ECMO-supported children who undergo tracheostomy on ECMO may inform decision-making. DESIGN: Retrospective cohort study. SETTING: ECMO centers contributing to the Extracorporeal Life Support Organization registry. PATIENTS: Children from birth to 18 years who received ECMO support for greater than or equal to 7 days for respiratory failure from January 1, 2015, to December 31, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three thousand six hundred eighty-five children received at least 7 days of ECMO support for respiratory failure. The median duration of ECMO support was 13.0 days (interquartile range [IQR], 9.3-19.9 d), and inhospital mortality was 38.7% (1,426/3,685). A tracheostomy was placed during ECMO support in 94/3,685 (2.6%). Of those who received a tracheostomy on ECMO, the procedure was performed at a median 13.2 days (IQR, 6.3-25.9 d) after initiation of ECMO. Surgical site bleeding was documented in 26% of children who received a tracheostomy (12% after tracheostomy placement). Among children who received a tracheostomy, the median duration of ECMO support was 24.2 days (IQR, 13.0-58.7 d); inhospital mortality was 30/94 (32%). Those that received a tracheostomy before 14 days on ECMO were older (median age, 15.8 yr [IQR, 4.7-15.5] vs 11.7 yr [IQR, 11.5-17.3 yr]; p =0.002) and more likely to have been supported on venovenous-ECMO (84% vs 52%; p = 0.001). Twenty-two percent (11/50) of those who received a tracheostomy before 14 days died in the hospital, compared with 19/44 (43%) of those who received a tracheostomy at 14 days or later (p = 0.03). CONCLUSIONS: Tracheostomies during ECMO were uncommon in children. One in four patients who received a tracheostomy on ECMO had surgical site bleeding. Children who had tracheostomies placed after 14 days were younger and had worse outcomes, potentially representing tracheostomy as a "secondary" strategy for prolonged ECMO support.

A case report of pediatric systemic lupus erythematosus with diffuse alveolar hemorrhage following COVID-19 infection: Causation, association, or chance?

RATIONALE: Diffuse alveolar hemorrhage (DAH) is a rare manifestation of childhood systemic lupus erythematosus (SLE) that can be life-threatening. Several reports have linked previous or concurrent coronavirus disease (COVID-19) infections with a high prevalence of autoimmune and autoinflammatory disorders. PATIENT CONCERNS: We report a case of a 13-year-old female who presented with DAH due to SLE 2 months after a laboratory-confirmed severe COVID-19 infection. DIAGNOSES: The patient was diagnosed with DAH due to SLE 2 months after a laboratory-confirmed severe COVID-19 infection. INTERVENTIONS AND OUTCOMES: The patient was treated with intravenous methylprednisolone pulse, broad-spectrum antibiotics, and supportive measures. In addition, she received 6 sessions of plasma exchange and maintenance methylprednisolone therapy (2 mg/kg/day). The patient then improved and was discharged on prednisolone, hydroxychloroquine, and azathioprine. LESSONS: We suggest plasmapheresis be considered a treatment for SLE-associated DAH in the context of active disease when conventional treatment has failed to induce a rapid response. In addition, further studies are needed to assess the role of COVID-19 as an autoimmune disease trigger, particularly for SLE.