Efficacy of emicizumab therapy in two adult patients with type 3 von Willebrand disease.

Type 3 von Willebrand disease (T3VWD) is a rare inherited bleeding disorder caused by the absence of von Willebrand factor (VWF). The traditional treatment for T3VWD has been VWF concentrates, but their effectiveness may be limited due to the development of alloantibodies. Emicizumab, a bispecific mAb, has shown promise in treating hemophilia A and is being studied as prophylaxis for T3VWD. In this case series, two patients with T3VWD received emicizumab prophylaxis and experienced a significant reduction in bleeding episodes and improved quality of life with fewer healthcare encounters. Although breakthrough bleeding was rare, one patient experienced a terminal intracranial bleed. Despite limited clinical experience with emicizumab in T3VWD, these cases suggest that emicizumab may be a valuable prophylactic option for patients with T3VWD. Further research is needed to determine the long-term efficacy and safety profile of emicizumab and optimal therapy for breakthrough bleeds in this patient population.

Silent cerebral infarction during immune TTP remission: prevalence, predictors, and impact on cognition.

Immune thrombotic thrombocytopenic purpura (iTTP) survivors have increased risk of cardiovascular disease, including strokes, and report persistent cognitive difficulties during remission. We conducted this prospective study involving iTTP survivors during clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neurodeficits. We also tested the hypothesis that SCI is associated with cognitive impairment, assessed using the National Institutes of Health ToolBox Cognition Battery. For cognitive assessments, we used fully corrected T scores adjusted for age, sex, race, and education. Based on the diagnostic and statistical manual 5 criteria, we defined mild and major cognitive impairment as T scores with a 1 or 2 standard deviation (SD) and >2 SD below the mean on at least 1 test, respectively. Forty-two patients were enrolled, with 36 completing MRIs. SCI was present in 50% of the patients (18), of which 8 (44.4%) had prior overt stroke including during acute iTTP. Patients with SCI had higher rates of cognitive impairment (66.7% vs 27.7%; P = .026), including major cognitive impairment (50% vs 5.6%; P = .010). In separate logistic regression models, SCI was associated with any (mild or major) cognitive impairment (odds ratio [OR] 10.5 [95% confidence interval (95% CI), 1.45-76.63]; P = .020) and major cognitive impairment (OR 7.98 [95% CI, 1.11-57.27]; P = .039) after adjusting for history of stroke and Beck depression inventory scores. MRI evidence of brain infarction is common in iTTP survivors; the strong association of SCI with impaired cognition suggests that these silent infarcts are neither silent nor innocuous.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. MATERIALS AND METHODS: As part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. RESULTS: Here we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. CONCLUSIONS AND RELEVANCE: TTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.

Updates in the Management of Warm Autoimmune Hemolytic Anemia.

Warm autoimmune hemolytic anemia (wAIHA) is an uncommon and heterogeneous disorder caused by autoantibodies to RBC antigens. Initial evaluation should involve the DAT, with wAIHA typically IgG positive with or without C3 positivity, and a search for underlying conditions associated with secondary wAIHA, which comprise 50% of cases. First-line therapy involves glucocorticoids, increasingly with rituximab, though a chronic relapsing course is typical. While splenectomy and a number of immunosuppressive therapies have been used in the setting of relapsed and refractory disease, the optimal choice and sequence of therapies is unknown, and clinical trials should be offered when available. Newer investigational targets include spleen tyrosine kinase inhibitors, monoclonal antibodies targeting CD38, Bruton's tyrosine kinase inhibitors, complement inhibitors, and antibodies against neonatal Fc receptors.

Case Series of Thrombosis With Thrombocytopenia Syndrome After COVID-19 Vaccination-United States, December 2020 to August 2021.

BACKGROUND: Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. It presents similarly to spontaneous heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis after vaccination with the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson) have previously been described. OBJECTIVE: To describe surveillance data and reporting rates of all reported TTS cases after COVID-19 vaccination in the United States. DESIGN: Case series. SETTING: United States. PATIENTS: Case patients receiving a COVID-19 vaccine from 14 December 2020 through 31 August 2021 with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction) reported to the Vaccine Adverse Event Reporting System. If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for antiplatelet factor 4 antibodies or functional heparin-induced thrombocytopenia platelet test result was required. MEASUREMENTS: Reporting rates (cases per million vaccine doses) and descriptive epidemiology. RESULTS: A total of 57 TTS cases were confirmed after vaccination with Ad26.COV2.S (n = 54) or a messenger RNA (mRNA)-based COVID-19 vaccine (n = 3). Reporting rates for TTS were 3.83 per million vaccine doses (Ad26.COV2.S) and 0.00855 per million vaccine doses (mRNA-based COVID-19 vaccines). The median age of patients with TTS after Ad26.COV2.S vaccination was 44.5 years (range, 18 to 70 years), and 69% of patients were women. Of the TTS cases after mRNA-based COVID-19 vaccination, 2 occurred in men older than 50 years and 1 in a woman aged 50 to 59 years. All cases after Ad26.COV2.S vaccination involved hospitalization, including 36 (67%) with intensive care unit admission. Outcomes of hospitalizations after Ad26.COV2.S vaccination included death (15%), discharge to postacute care (17%), and discharge home (68%). LIMITATIONS: Underreporting and incomplete case follow-up. CONCLUSION: Thrombosis with thrombocytopenia syndrome is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The different demographic characteristics of the 3 cases reported after mRNA-based COVID-19 vaccines and the much lower reporting rate suggest that these cases represent a background rate. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

De novo isolated myeloid sarcoma: comparative analysis of survival in 19 consecutive cases.

Institutional database search (1999-2020) for acute myeloid leukaemia (AML) identified 109 cases of myeloid sarcoma (MS), of which 19 were isolated and presented de novo. The latter displayed longer survival (median 78 months), compared to MS with synchronous intramedullary AML (n = 32; median 16 months) and de novo AML without MS (n = 729; median 22 months; P = 0·13). However, the difference in survival was no longer apparent after accounting for bone marrow cytogenetic risk status (P = 0·67). Treatment-induced MS tumour resolution was not affected by the presence of intramedullary disease (P = 0·61). The current study clarifies the prognosis of de novo isolated MS, in the context of AML.

Continuous-infusion von Willebrand factor concentrate is effective for the management of acquired von Willebrand disease.

Acquired von Willebrand disease (aVWD) is a rare disorder associated with a reduction in von Willebrand factor (VWF) activity, leading to increased bleeding risk. Monoclonal gammopathy of undetermined significance (MGUS) is the most common cause of lymphoproliferative disorder-associated aVWD and is caused by accelerated clearance of circulating VWF. Standard VWF replacement protocols for congenital VWD based on intermittent bolus dosing are typically less effective for aVWD because of antibody-mediated clearance. Intermittent bolus dosing of VWF concentrates often leads to inadequate peak response and profoundly shortened VWF half-life in aVWD. Intravenous immune globulin (IVIG) has demonstrated efficacy in aVWD; however, treatment effect is delayed up to 4 days, limiting its efficacy in acutely bleeding patients. We report the successful use of continuous-infusion VWF concentrate (with or without concomitant IVIG) in 3 patients with MGUS-associated aVWD who had demonstrated an inadequate response to bolus dosing. VWF concentrate doses required in this cohort were higher than typical doses for bleeding treatment in congenital VWD. This report illustrates that continuous-infusion VWF concentrate administration with or without intravenous immunoglobulin rapidly achieves target ristocetin cofactor activity and provides adequate hemostasis in aVWD associated with immunoglobulin G MGUS.

Bleeding risk by intensity of anticoagulation in critically ill patients with COVID-19: A retrospective cohort study.

BACKGROUND: Studies report hypercoagulability in coronavirus disease 2019 (COVID-19), leading many institutions to escalate anticoagulation intensity for thrombosis prophylaxis. OBJECTIVE: To determine the bleeding risk with various intensities of anticoagulation in critically ill patients with COVID-19 compared with other respiratory viral illnesses (ORVI). PATIENTS/METHODS: This retrospective cohort study compared the incidence of major bleeding in patients admitted to an intensive care unit (ICU) within a single health system with COVID-19 versus ORVI. In the COVID-19 cohort, we assessed the effect of anticoagulation intensity received on ICU admission on bleeding risk. We performed a secondary analysis with anticoagulation intensity as a time-varying covariate to reflect dose changes after ICU admission. RESULTS: Four hundred and forty-three and 387 patients were included in the COVID-19 and ORVI cohorts, respectively. The hazard ratio of major bleeding for the COVID-19 cohort relative to the ORVI cohort was 1.26 (95% confidence interval [CI]: 0.86-1.86). In COVID-19 patients, an inverse-probability treatment weighted model found therapeutic-intensity anticoagulation on ICU admission had an adjusted hazard ratio of bleeding of 1.55 (95% CI: 0.88-2.73) compared with standard prophylactic-intensity anticoagulation. However, when anticoagulation was assessed as a time-varying covariate and adjusted for other risk factors for bleeding, the adjusted hazard ratio for bleeding on therapeutic-intensity anticoagulation compared with standard thromboprophylaxis was 2.59 (95% CI: 1.20-5.57). CONCLUSIONS: Critically ill patients with COVID-19 had a similar bleeding risk as ORVI patients. When accounting for changes in anticoagulation that occurred in COVID-19 patients, therapeutic-intensity anticoagulation was associated with a greater risk of major bleeding compared with standard thromboprophylaxis.

Deferasirox-associated Fanconi syndrome in adult patients with transfusional iron overload.

BACKGROUND AND OBJECTIVES: Deferasirox is an oral chelator approved for iron overload, which has a potential side effect of renal Fanconi syndrome, with proximal tubular dysfunction and tubular acidosis. Monitoring of renal function is recommended, though no standard for monitoring exists. We aim to describe cases of deferasirox-associated Fanconi syndrome in adults and the renal monitoring required to detect these findings. MATERIALS AND METHODS: We present a review of the literature and six cases from our institution of deferasirox-associated partial Fanconi syndrome in adult patients with transfusional iron overload secondary to ß-thalassemia or Diamond Blackfan Anaemia. RESULTS: While prior cases in the literature occurred at high doses of deferasirox, our series included patients on doses as low as deferasirox 10 mg/kg who had been aggressively chelated. All patients had resolution of laboratory abnormalities with drug interruption. CONCLUSION: Rather than chelating to normal iron levels, this series supports prior suggestions that deferasirox dose be reduced if ferritin <500-1000 ng/ml, and also supports dose reduction if liver iron content <3 mg iron per g dry weight or for those undergoing aggressive chelation with rapid decrease in iron. Monitoring with metabolic panel and urinalysis were sufficient to detect clinically significant proximal tubular dysfunction, but should be followed up with additional studies to confirm the diagnosis while deferasirox dose is decreased or held.

Arthrocentesis and Joint Injection in Patients Receiving Direct Oral Anticoagulants.

Anticoagulation is common in patients undergoing arthrocentesis and joint injections. Previous studies have established the safety of continuing anticoagulation with warfarin before joint aspirations/injections with only a small increased risk of bleeding, but no data are available regarding the use of direct oral anticoagulants (DOACs) and joint aspirations/injections. The objective of this study was to determine the rate of bleeding complications associated with arthrocentesis and joint injection in patients receiving DOACs. We performed a retrospective review of adult patients at Mayo Clinic in Rochester, Minnesota, who were being treated with DOACs and underwent outpatient joint aspiration and/or injection between October 1, 2010, and October 31, 2016. In 1050 consecutive procedures, there were no bleeding complications. Arthrocentesis and joint injections in patients receiving DOAC therapy are safe procedures, and there is no need to withhold anticoagulation treatment before the procedure.