Advanced practice providers in hematology: actionable findings from national paired APP and physician surveys.

ABSTRACT: Advanced practice providers (APPs) are critical to the hematology workforce. However, there is limited knowledge about APPs in hematology regarding specialty-specific training, scope of practice, challenges and opportunities in APP-physician interactions, and involvement with the American Society of Hematology (ASH). We conducted APP and physician focus groups to elucidate major themes in these areas and used results to inform development of 2 national surveys, 1 for APPs and 1 for physicians who work with APPs. The APP survey was distributed to members of the Advanced Practitioner Society of Hematology and Oncology, and the physician survey was distributed to physician members of ASH. A total of 841 APPs and 1334 physicians completed the surveys. APPs reported most hematology-specific knowledge was obtained via on-the-job training and felt additional APP-focused training would be helpful (as did physicians). Nearly all APPs and physicians agreed that APPs were an integral part of their organizations and that physician-APP collaborations were generally positive. A total of 42.1% of APPs and 29.3% of physicians reported burnout, and >50% of physicians felt that working with APPs had reduced their burnout. Both physicians and APPs reported interest in additional resources including "best practice" guidelines for APP-physician collaboration, APP access to hematology educational resources (both existing and newly developed resources for physicians and trainees), and greater APP integration into national specialty-specific professional organizations including APP-focused sessions at conferences. Professional organizations such as ASH are well positioned to address these areas.

Efficacy and safety evaluation of avatrombopag in immune thrombocytopenia: analyses of a phase III study and long-term extension.

Avatrombopag is an oral thrombopoietin receptor agonist approved for chronic immune thrombocytopenia (ITP). This is a post hoc analysis of the pivotal phase III study (NCT01438840) evaluating additional endpoints not previously described. Thirty-two ITP patients were randomized to avatrombopag and 17 were randomized to placebo during a 26-week core study period (with 21 study visits), followed by an open-label extension period, in which all patients received avatrombopag for varying lengths of time. In this analysis, we evaluated previously unreported response rates at the study visit level, durability of response, and reduction in corticosteroid use with avatrombopag treatment. In the core study, more avatrombopag-treated patients achieved either response (Plt ≥50 000/µL) or complete response (Plt ≥100 000/µL) than placebo-treated patients by day 8 (65.6% vs. 0%; P < .0001 for response; 37.5% vs. 0%; P < .0001 for complete response), day 28 (84.4% vs. 0%; P < .0001 for response; 71.9% vs. 0%; P < .0001 for complete response), and month 6 (87.5% vs. 5.9%; P < .0001 for response; 81.3% vs. 5.9%; P < .0001 for complete response). Durable responders from the core study achieved response and complete response at 96.1% and 60.1% of extension phase visits, respectively. Durable clinically relevant response (Plt ≥30 000/µL for 6 of the final 8 weeks of the core study) occurred in 64.0% of avatrombopag-treated patients versus 0% of placebo-treated patients. More than half (57.1%) of patients on chronic corticosteroids reduced or discontinued corticosteroids. In conclusion, avatrombopag enabled most patients with ITP to achieve clinically meaningful and durable platelet count improvements.

Angiotensin-converting enzyme (ACE) inhibitors for proteinuria and microalbuminuria in people with sickle cell disease.

BACKGROUND: Sickle cell disease is a group of disorders characterized by deformation of erythrocytes. Renal damage is a frequent complication in sickle cell disease as a result of long-standing anemia and disturbed circulation through the renal medullary capillaries. Due to the improvement in life expectancy of people with sickle cell disease, there has been a corresponding significant increase in the incidence of renal complications. Microalbuminuria and proteinuria are noted to be a strong predictor of subsequent renal failure. There is extensive experience and evidence with angiotensin-converting enzyme (ACE) inhibitors over many years in a variety of clinical situations for patients who do not have sickle cell disease, but their effect in people with this disease is unknown. It is common practice to administer ACE inhibitors for sickle nephropathy due to their renoprotective properties; however, little is known about their effectiveness and safety in this setting. This is an update of a Cochrane Review first published in 2013 and 2015. OBJECTIVES: To determine the effectiveness of ACE inhibitor administration in people with sickle cell disease for decreasing intraglomerular pressure, microalbuminuria and proteinuria and to to assess the safety of ACE inhibitors as pertains to their adverse effects. SEARCH METHODS: The authors searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Hameoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of the most recent search: 18 October 2021. We also searched clinical trial registries. Date of the most recent search: 22 August 2021. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of ACE inhibitors designed to reduce microalbuminuria and proteinuria in people with sickle cell disease compared to either placebo or standard treatment regimen. DATA COLLECTION AND ANALYSIS: Three authors independently applied the inclusion criteria in order to select studies for inclusion in the review. Two authors assessed the risk of bias of studies and extracted data and the third author verified these assessments. MAIN RESULTS: Seven studies were identified through the searches. Six studies were excluded. The included study randomized 22 participants (7 males and 15 females) having proteinuria or microalbuminuria with sickle cell disease and treated the participants for six months (median length of follow up of three months) with captopril or placebo. Overall, the certainty of the evidence provided in this review was very low, since most risk of bias domains were judged to have either an unclear or a high risk of bias. Because of this, we are uncertain whether captopril makes any difference, in total urinary albumin excretion (at six months) as compared to the placebo group, although it yielded a mean difference of -49.00 (95% confidence interval (CI) -124.10 to 26.10) or in the absolute change score, although it yielded a mean difference of -63.00 (95% CI -93.78 to -32.22). At six months albumin excretion in the captopril group was noted to decrease from baseline by a mean (standard deviation) of 45 (23) mg/day and the placebo group was noted to increase by 18 (45) mg/day. Serum creatinine and potassium levels were reported constant throughout the study (very low-certainty evidence). The potential for inducing hypotension should be highlighted; the study reported a decrease of 8 mmHg in systolic pressure and 5 mmHg in diastolic and mean blood pressure (very low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, we judged the certainty of the evidence to be very low. The included study selectively reported its results, was not powered to detect a group difference, should it exist, and otherwise did not offer enough information to allow us to judge the bias inherent in the study. Indirectness (in relation to the limited age and type of population included) and imprecision (wide confidence intervals around the effect estimate) were observed. More long-term studies involving multiple centers and larger cohorts using a randomized-controlled design are warranted, especially among the pediatric age group. Detailed reporting of each outcome measure is necessary to allow a clear cut interpretation in a systematic review. One of the difficulties encountered in this review was the lack of detailed data reported in the included study. Overall, we judged the certainty of this evidence to be very low.

Perspectives on the quality and utility of letters conforming to the AAIM guidelines.

Background Standardized letters of recommendation (SLOR) have become common features of the medical school to residency transition. Research has shown many advantages over the narrative letter of recommendation including improved letter-writing efficiency, ease of interpretation, and improved reliability as performance predictors. Currently, at least four specialties require fellowship SLORs. Internal medicine adopted its SLOR in 2017. Previous research showed fellowship program directors' satisfaction with the 2017 guidelines. Little is known about residency program directors' acceptance and adherence to the guidelines. Objectives The study sought to assess the adoption rate of each component, barriers to adoption, time commitment, and alignment with intended goals of the guidelines. Methods Anonymous survey links were posted to an internal medicine discussion forum prior to the guidelines in spring 2017 and twice following the guidelines in fall 2018 and winter 2019. Two-sample tests of proportions were used to compare respondent characteristics with known survey population data. Pre- and post-survey comparisons were assessed for statistical significance with Pearson chi-squared statistic. Results The response rate varied from 30% to 35% for each survey period. Medical knowledge, patient care, interpersonal and communication skills, professionalism, and scholarly activity were reported frequently (>96%) at baseline. Inclusion of residency program characteristics, systems-based practice, practice-based learning and improvement, and skills sought to master increased over the study period. Conclusions The new guidelines improved uniform reporting of all core competency data. Overall, the gains were modest, as many pre-survey respondents reported high rates of including components within the guidelines.

Comparison of low fixed dose versus standard-dose rituximab to treat thrombotic thrombocytopenic purpura in the acute phase and preemptively during remission.

The standard dose of rituximab used in B-cell hematological malignancies, 375 mg/m2 weekly, may be excessive for autoimmune conditions. Successful use of a low, fixed dose of 100-200 mg of rituximab, weekly for 4 weeks, has been reported in the literature in the treatment of autoimmune thrombotic thrombocytopenic purpura (aTTP). We retrospectively analyzed our rituximab data in aTTP over a 13-year-period for 39 patients, with the aim of comparing response and outcomes with a standard lymphoma-dose course versus a low fixed 100 mg-dose course. Compared to the standard dose (17 patients, 17 courses of 4 infusions), our patients who received a low dose (8 patients, 9 courses of 4 infusions) had a possibly lower baseline risk but did achieve a similar time to remission and number of plasma exchange procedures to remission. Preemptive low-dose courses for ADAMTS13 activity <50 % during remission (6 patients, 10 courses of 4 infusions) achieved a median peak ADAMTS13 activity of 99 %, in a median of 1 month, with no clinical relapses. Our results provide additional evidence for the efficacy of low-dose rituximab, with the benefit of much lower cost, less infusion time, and theoretically lower risk of toxicity.

miR-125a-5p regulates megakaryocyte proplatelet formation via the actin-bundling protein L-plastin.

There is heritability to interindividual variation in platelet count, and better understanding of the regulating genetic factors may provide insights for thrombopoiesis. MicroRNAs (miRs) regulate gene expression in health and disease, and megakaryocytes (MKs) deficient in miRs have lower platelet counts, but information about the role of miRs in normal human MK and platelet production is limited. Using genome-wide miR profiling, we observed strong correlations among human bone marrow MKs, platelets, and differentiating cord blood-derived MK cultures, and identified MK miR-125a-5p as associated with human platelet number but not leukocyte or hemoglobin levels. Overexpression and knockdown studies showed that miR-125a-5p positively regulated human MK proplatelet (PP) formation in vitro. Inhibition of miR-125a-5p in vivo lowered murine platelet counts. Analyses of MK and platelet transcriptomes identified LCP1 as a miR-125a-5p target. LCP1 encodes the actin-bundling protein, L-plastin, not previously studied in MKs. We show that miR-125a-5p directly targets and reduces expression of MK L-plastin. Overexpression and knockdown studies show that L-plastin promotes MK progenitor migration, but negatively correlates with human platelet count and inhibits MK PP formation (PPF). This work provides the first evidence for the actin-bundling protein, L-plastin, as a regulator of human MK PPF via inhibition of the late-stage MK invagination system, podosome and PPF, and PP branching. We also provide resources of primary and differentiating MK transcriptomes and miRs associated with platelet counts. miR-125a-5p and L-plastin may be relevant targets for increasing in vitro platelet manufacturing and for managing quantitative platelet disorders.

Thrombin Generation in a patient with Triple Positive Antiphospholipid Syndrome Treated with Three Different Anticoagulants.

INTRODUCTION: Venous and arterial thrombosis is one of the hallmarks of Antiphospholipid Antibody Syndrome (APS). The traditional treatment for individuals with APS and venous thrombosis has been vitamin K antagonists. However, with the widespread use of direct oral anticoagulants (DOACs) there has been conflicting evidence regarding their safety and failure rate as alternatives to warfarin. Reasons for this failure remain elusive. We utilized the thrombin generation assay (TGA) to investigate the anticoagulation efficacy of three different agents in a patient with triple-positive APS to acquire a better understanding of the pathophysiology of APS. METHODS: Blood samples were obtained from a single patient with APS at five distinct time points while on three different anticoagulants: rivaroxaban, warfarin, and enoxaparin. The effects of these anticoagulants on TG potential were evaluated using the TGA. RESULTS: In the presence of thrombomodulin, rivaroxaban had the highest endogenous thrombin potential, thrombin peak, velocity index, and thrombin inactivation velocity (821.9 nMmin, 121.5 nM, 36.44 nM/min, 7.19 nM/min) when compared to warfarin (121-367 nMmin, 13.85-121.5 nM, 3.02-3.85 nM/min, 0.64-4.55 nM/min) and enoxaparin (242-378.8 nM min, 21.33-23.78 nM, 2.87-3.85 nM/min, 0.747-0.784 nM/min). This trend was also observed in the absence of thrombomodulin. CONCLUSIONS: These results suggest that patients with APS treated with rivaroxaban may be at greater risk for thrombosis compared to warfarin or enoxaparin. The findings may provide insight into the recent studies in patients with triple positive APS randomized to different anticoagulants demonstrating high rates of thrombosis with rivaroxaban. Further studies are necessary to elucidate the clinical significance.

Sighting acute myocardial infarction through platelet gene expression.

Acute myocardial infarction is primarily due to coronary atherosclerotic plaque rupture and subsequent thrombus formation. Platelets play a key role in the genesis and progression of both atherosclerosis and thrombosis. Since platelets are anuclear cells that inherit their mRNA from megakaryocyte precursors and maintain it unchanged during their life span, gene expression profiling at the time of an acute myocardial infarction provides information concerning the platelet gene expression preceding the coronary event. In ST-segment elevation myocardial infarction (STEMI), a gene-by-gene analysis of the platelet gene expression identified five differentially expressed genes: FKBP5, S100P, SAMSN1, CLEC4E and S100A12. The logistic regression model used to combine the gene expression in a STEMI vs healthy donors score showed an AUC of 0.95. The same five differentially expressed genes were externally validated using platelet gene expression data from patients with coronary atherosclerosis but without thrombosis. Platelet gene expression profile highlights five genes able to identify STEMI patients and to discriminate them in the background of atherosclerosis. Consequently, early signals of an imminent acute myocardial infarction are likely to be found by platelet gene expression profiling before the infarction occurs.

Bleeding due to acquired dysfibrinogenemia as the initial presentation of multiple myeloma.

Patients with multiple myeloma (MM) are at risk for acquired dysfibrinogenemia resulting in laboratory abnormalities and/or bleeding complications. We describe a 63-year-old man who presented with bleeding diathesis in the presence of a low fibrinogen activity level with a normal fibrinogen antigen level. Further studies revealed elevated levels of lambda free light chains, and he was diagnosed with MM. Despite initiating treatment with bortezomib/dexamethasone, he continued to have recurrent bleeds along with hypofibrinogenaemia, prompting a switch to carfilzomib/dexamethasone. The patient responded with improvement in bleeding symptoms, normalisation of fibrinogen activity and a decrease in serum free light chains.

Role of Platelet Transfusion in the Reversal of Anti-Platelet Therapy.

Antiplatelet therapy is extensively used in the primary and secondary prophylaxis of arterial thrombotic disorders. Aspirin, the most commonly used antiplatelet agent, is a cyclooxygenase-1 inhibitor and considered a mild to moderate inhibitor of platelet function. Therefore, often a second antiplatelet agent is necessary in certain clinical conditions requiring greater inhibition of platelet function. An adenosine diphosphate (ADP) receptor, P2Y12, is an important target for this purpose; several agents inhibit this receptor providing potent antiplatelet effect. One of the side effects of these agents is bleeding, which in some patients may require reversal of antiplatelet effect. Similarly, patients undergoing emergent surgeries may benefit from reversal of antiplatelet effect to avoid excessive surgical bleeding. This article reviews current literature on this topic.

What's in a name? The heterogeneous clinical spectrum and prognostic factors in a cohort of adults with hemophagocytic lymphohistiocytosis.

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) in adults is rare but frequently fatal. Diagnosis is often delayed and treatment approaches vary significantly in contrast to the protocol-driven approach typically used in pediatric HLH. To improve care of these complex patients, this study retrospectively examined the prevalence, clinical characteristics, therapies and outcomes of adult HLH patients at two large tertiary care centers. METHODS: Adult patients with HLH confirmed by retrospective review of electronic medical records using HLH2004 criteria during admissions to the University of Texas Southwestern and Parkland Memorial Hospitals between June 2007 and June 2017 were studied. RESULTS: Of 31 patients included, 67.7% were male with mean age of 46 years. Average time from admission to diagnosis was 10.5 days. 48% of patients had malignancy, with T-cell lymphoma being most common. Infections were seen in 70%. Autoimmune disorders were found in 9.6%. In total, 13 patients survived (44.8%). Median survival was 8 months with increased mortality in malignancy-associated HLH (median 0.56 months versus 36.5 months, p < 0.001). T-cell lymphoma carried a worse prognosis than other malignancies. Central nervous system disease, hypoalbuminemia, elevated bilirubin, elevated soluble interleukin 2 receptor, and elevated lactate dehydrogenase, were also associated with poor survival. Treatment varied significantly. No individual treatment improved survival. CONCLUSION: This study corroborates prior limited data in adult HLH patients regarding poor survival, particularly in malignancy-associated HLH. Earlier recognition of this disease and a multidisciplinary approach to streamline diagnosis and optimize treatment are needed to improve outcomes in adult HLH patients.

Drugs for preventing red blood cell dehydration in people with sickle cell disease.

BACKGROUND: Sickle cell disease is an inherited disorder of hemoglobin, resulting in abnormal red blood cells. These are rigid and may block blood vessels leading to acute painful crises and other complications. Recent research has focused on therapies to rehydrate the sickled cells by reducing the loss of water and ions from them. Little is known about the effectiveness and safety of such drugs. This is an updated version of a previously published review. OBJECTIVES: To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched online trials registries for any ongoing trials (01 July 2018).Last search of the Group's Haemoglobinopathies Trials Register: 08 October 2018. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies for inclusion, assessed study quality and extracted data. MAIN RESULTS: Of the 51 studies identified, three met the inclusion criteria, including 524 people with sickle cell disease aged between 12 and 65 years of age. One study tested the effectiveness of zinc sulphate as compared to placebo and the remaining two assessed senicapoc versus placebo. No deaths were seen in any of the studies (low-quality evidence). The zinc sulphate study showed a significant reduction in painful crises (in a total of 145 participants) over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, analysis was restricted due to limited statistical data. Changes to red blood cell parameters and blood counts were inconsistent (very low-quality evidence). No serious adverse events were noted in the study. The Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo showed that the high dose senicapoc showed significant improvement in change in hemoglobin level, the number and proportion of dense red blood cells, red blood cell count and indices and hematocrit value (very low-quality evidence). The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups (low-quality evidence). A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises. AUTHORS' CONCLUSIONS: While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red blood cell survival (depending on dose), this did not lead to fewer painful crises.Given this is no longer an active area of research, this review will no longer be regularly updated.

Recent advances in understanding and management of acquired thrombocytopenia.

There are numerous congenital and acquired causes of thrombocytopenia. Thrombocytopenia could be a result of decreased bone marrow production, increased consumption, increased destruction, splenic sequestration or a combination of these causes. In this review, we have focused on some of the serious acquired causes of thrombocytopenia. There have been some significant advances in our understanding of the pathophysiology, diagnostic testing, and treatment of immune thrombocytopenia, heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, and atypical hemolytic uremic syndrome over the past five years. These advances have resulted in a significant decrease in mortality and morbidity of patients with these disorders. Despite these advances, we are still faced with numerous unanswered questions in the pathophysiology and management of these complex thrombocytopenic disorders.

Thyroid storm and warm autoimmune hemolytic anemia.

Graves' disease is often associated with other autoimmune disorders, including rare associations with autoimmune hemolytic anemia (AIHA). We describe a unique presentation of thyroid storm and warm AIHA diagnosed concurrently in a young female with hyperthyroidism. The patient presented with nausea, vomiting, diarrhea and altered mental status. Laboratory studies revealed hemoglobin 3.9g/dL, platelets 171×109L-1, haptoglobin <5mg/dL, reticulocytosis, and positive direct antiglobulin test (IgG, C3d, warm). Additional workup revealed serum thyroid stimulating hormone (TSH) <0.01µIU/mL and serum free-T4 (FT4) level 7.8ng/dL. Our patient was diagnosed with concurrent thyroid storm and warm AIHA. She was started on glucocorticoids to treat both warm AIHA and thyroid storm, as well as antithyroid medications, propranolol and folic acid. Due to profound anemia and hemodynamic instability, the patient was transfused two units of uncrossmatched packed red blood cells slowly and tolerated this well. She was discharged on methimazole as well as a prolonged prednisone taper, and achieved complete resolution of the thyrotoxicosis and anemia at one month. Hyperthyroidism can affect all three blood cell lineages of the hematopoietic system. Anemia can be seen in 10-20% of patients with thyrotoxicosis. Several autoimmune processes can lead to anemia in Graves' disease, including pernicious anemia, celiac disease, and warm AIHA. This case illustrates a rarely described presentation of a patient with Graves' disease presenting with concurrent thyroid storm and warm AIHA.