Caroline Cromwell

Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura

Anti-ADAMTS13 autoantibodies are the main cause of acquired thrombotic thrombocytopenic purpura. Binding of these antibodies to ADAMTS13 eventually results in the formation of antigen-antibody immune complexes. Circulating ADAMTS13-specific immune complexes have been described in patients with acquired thrombotic thrombocytopenic purpura, although the prevalence and persistence of these immune complexes over time have hitherto remained elusive. Here, we analyzed a large cohort of patients with acquired thrombotic thrombocytopenic purpura for the presence of free and complexed anti-ADAMTS13 antibodies. In the acute phase (n=68), 100% of patients had free IgG antibodies and 97% had ADAMTS13-specific immune complexes. In remission (n=28), 75% of patients had free antibodies (mainly IgG) and 93% had ADAMTS13-specific immune complexes. Free antibodies were mainly of subclasses IgG1 and IgG4, whereas IgG4 was by far the most prevalent in ADAMTS13-specific immune complexes. Comparison of ADAMTS13 inhibitor and anti-ADAMTS13 IgG (total and subclasses) antibody titers in acute phase and in remission samples showed a statistically significant decrease in all parameters in remission. Although non-significant, a trend towards reduced or undetectable titers in remission was also observed for ADAMTS13-specific immune complexes of subclasses IgG1, IgG2 and IgG3. No such trend was discernible for IgG4; IgG4 immune complexes persisted over years, even in patients who had been treated with rituximab and who showed no features suggesting relapse.

FEIBA: a prohemostatic agent.

Factor eight inhibitor bypassing activity (FEIBA), Anti-Inhibitor Coagulation Complex has been used for over 30 years in hemophiliac patients with inhibitors. The history of its use is reviewed here, including issues related to thrombosis, efficacy, and comparison to alternative bypassing agents. The need for surrogate assays to monitor effective hemostasis with the use of FEIBA remains.

Acquired hemophilia: a rare but life-threatening potential cause of bleeding in the intensive care unit

ObjectiveThere are a number of potential etiologies of severe bleeding encountered in the intensive care unit. Although rare, acquired hemophilia is one such etiology that often presents with major bleeding requiring intensive care. Despite the introduction of effective treatments, the reported mortality rate of patients with acquired hemophilia ranges from 6 to 8% and is in part attributable to sequential delays in diagnosis and appropriate treatment. The purpose of this review is to familiarize the intensive care specialist with this underrecognized cause of bleeding, with an emphasis on diagnosis and treatment.MethodsAs the objective of this article was to provide a concise overview of the diagnosis and management of acquired hemophilia, a directed search of English-language literature was undertaken using the PubMed database, targeting such topics as the differential diagnosis of bleeding in the intensive care unit and the epidemiology, diagnosis, and treatment of acquired hemophilia. Clinical study findings pertaining to the efficacy of specific treatments for acquired hemophilia were summarized.Results and conclusionRecognition of acquired hemophilia presents a clinical challenge, given the rarity of this condition, a general lack of familiarity with acquired hemophilia, and the potential for confusion with other more common causes of bleeding in the intensive care unit. Nevertheless, there are sentinel clinical and laboratory findings that should raise suspicion of this diagnosis. The treatment of acquired hemophilia is a multi-step, physiologically focused process aimed at controlling both active and recurrent bleeding. Therefore, prompt diagnosis is central to prognosis. Consultation with a hematologist may facilitate efficient diagnosis and management.

Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: A triple‐blind, randomized trial

Clinical and preclinical data demonstrate that altered pulmonary physiology (including increased inflammation, increased blood flow, airway resistance, and hyper‐reactivity) is an intrinsic component of Sickle Cell Disease (SCD) and may contribute to excess SCD morbidity and mortality. Inhaled corticosteroids (ICS), a safe and effective therapy for pulmonary inflammation in asthma, may ameliorate the altered pulmonary physiologic milieu in SCD. With this single‐center, longitudinal, randomized, triple‐blind, placebo controlled trial we studied the efficacy and feasibility of ICS in 54 nonasthmatic individuals with SCD. Participants received once daily mometasone furoate 220 mcg dry powder inhalation or placebo for 16 weeks. The primary outcome was feasibility (the number who complete the trial divided by the total number enrolled) with prespecified efficacy outcomes including daily pain score over time (patient reported) and change in soluble vascular cell adhesion molecule (sVCAM) levels between entry and 8‐weeks. For the primary outcome of feasibility, the result was 96% (52 of 54, 95% CI 87%‐99%) for the intent‐to‐treat analysis and 83% (45 of 54, 95% CI 71%‐91%) for the per‐protocol analysis. The adjusted treatment effect of mometasone was a reduction in daily pain score of 1.42 points (95%CI 0.61‐2.21, P = 0.001). Mometasone was associated with a reduction in sVCAM levels of 526.94 ng/mL more than placebo (95% CI 50.66‐1003.23, P = 0.03). These results support further study of ICS in SCD including multicenter trials and longer durations of treatment. www.clinicaltrials.gov (NCT02061202)

Whole-exome sequencing in evaluation of patients with venous thromboembolism

Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) (P < .0001). Clinical laboratory-based thrombophilia testing identified a heritable thrombophilia in only 14 of 54 study patients (25.9%). The majority of WES variants were either associated with thrombosis based on prior reports in the literature or predicted to affect protein structure based on protein modeling performed as part of this study. Variants were found in major thrombophilia genes, various SERPIN genes, and highly conserved areas of other genes with established or potential roles in coagulation or fibrinolysis. Ten patients (15.6%) had >1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias.

Acquired Hemophilia Presenting as Profound Hematuria: Evaluation, Diagnosis, and Management of Elusive Cause of Bleeding in the Emergency Department Setting

BACKGROUND There are numerous causes of bleeding that may present to the Emergency Department (ED). Although rare, acquired hemophilia is a potentially life-threatening bleeding disorder, with reported mortality rates ranging from 6% to 8% among patients who received proper diagnosis and treatment. Approximately two thirds of patients with this condition will present with major bleeding, the magnitude of which may necessitate urgent evaluation and care. OBJECTIVES The aim of this article is to provide an overview of the evaluation, differential diagnosis, and management of acquired hemophilia for the emergency physician. CASE REPORT A case report of a patient who presented to the ED with gross hematuria secondary to undiagnosed acquired hemophilia is described to facilitate a review of the laboratory evaluation, differential diagnosis, and treatment of acquired hemophilia. CONCLUSION Patients with acquired hemophilia-related bleeding may present to the ED for care, given the often serious nature of their bleeding. Delayed diagnosis may postpone the initiation of targeted, effective treatments for achieving hemostasis, with potentially catastrophic consequences, particularly in patients who require emergent invasive procedures. Recognition of the potential for an underlying bleeding disorder and subsequent consultation with a hematologist are critical first steps in effectively identifying and managing a patient with acquired hemophilia who presents with bleeding.

Application of phospho-CyTOF to characterize immune activation in patients with sickle cell disease in an ex vivo model of thrombosis

Sickle cell disease (SCD) is a genetic disease caused by mutations in the beta globin gene, and inflammation plays a key role in driving many aspects of disease pathology. Early immune activation is believed to be associated with hemodynamic stresses and thrombus formation as cells traffic through blood vessels. We applied an extracorporeal perfusion system to model these effects ex vivo, and combined this with a phospho-CyTOF workflow to comprehensively evaluate single-cell signatures of early activation across all major circulating immune subsets. These approaches showed immune activation following passage through the perfusion chamber, most notably in monocytes, which exhibited platelet aggregation and significantly elevated expression of multiple phospho-proteins. Overall, these studies outline a robust and broadly applicable workflow to leverage phospho-CyTOF to characterize immune activation in response to ex vivo or in vivo perturbations and may facilitate identification of novel therapeutic targets in SCD and other inflammatory diseases.

The Impact of Factor VIII/von Willebrand Factor Concentrate in Inhibitor Development and Management of Patients with Hemophilia A with Inhibitors

The development of inhibitor antibodies that bind to active sites on the factor VIII (FVIII) molecule and neutralize its function and/or accelerate its clearance is the most serious adverse event and safety issue associated with the treatment of hemophilia A. Inhibitor development complicates hemostasis management and increases morbidity and the cost of treatment because bleeding episodes do not respond to standard replacement therapy. Risk factors for inhibitor development include genetic and non-genetic factors. Immunogenicity of the type of product used for replacement therapy may also play a role. Within the category of human-derived products, the presence of von Willebrand factor (vWF) bound to FVIII (vWF/FVIII products) may reduce its immunogenicity. The challenge for inhibitors is to reduce their incidence and, when present, to facilitate their eradication. Factor-bypassing agents have been used to treat acute bleeds in patients who have inhibitors. Immune tolerance induction (ITI) therapy is an alternative approach whose goal is to create tolerance to inhibitors and return patients to their native state. The use of ITI therapy has raised many questions, including the optimal regimen and cost. The basic science data on reduced immunogenicity of vWF/FVIII-containing products and their success in achieving ITI have given us an incentive to continue to explore this approach to both primary and secondary ITI.