A New High Affinity Hemoglobin Variant: Hb San Francisco-KP (HBB: c.104T>C).

The evaluation of erythrocytosis can fail to detect hemoglobin (Hb) variants if a thorough and systemic investigation is not undertaken. Here we report the identification of a novel high-oxygen affinity Hb that was previously misclassified as polycythemia vera (PV). Given that treatment recommendations can vary significantly based on the etiology of erythrocytosis, familiarity with reference laboratories and their methodologies is of crucial importance to conducting a precise consultation, as in the case of our Hb variant, named Hb San Francisco-KP [ß34(B16)Val→Ala, HBB: c.104T>C] for the city and medical center where it was discovered. The Mayo Clinic's (Rochester, MN, USA) Erythrocytosis Evaluation (REVE) panel was instrumental in establishing a final diagnosis. Of note, the patient's clinical response to phlebotomy distinguishes this subtype from many of the other high affinity Hbs where the erythrocytosis is primarily compensatory and not in need of venesection.

Assessment of the Risk of Venous Thromboembolism in Nonhospitalized Patients With COVID-19.

Importance: Patients hospitalized with COVID-19 have higher rates of venous thromboembolism (VTE), but the risk and predictors of VTE among individuals with less severe COVID-19 managed in outpatient settings are less well understood. Objectives: To assess the risk of VTE among outpatients with COVID-19 and identify independent predictors of VTE. Design, Setting, and Participants: A retrospective cohort study was conducted at 2 integrated health care delivery systems in Northern and Southern California. Data for this study were obtained from the Kaiser Permanente Virtual Data Warehouse and electronic health records. Participants included nonhospitalized adults aged 18 years or older with COVID-19 diagnosed between January 1, 2020, and January 31, 2021, with follow-up through February 28, 2021. Exposures: Patient demographic and clinical characteristics identified from integrated electronic health records. Main Outcomes and Measures: The primary outcome was the rate per 100 person-years of diagnosed VTE, which was identified using an algorithm based on encounter diagnosis codes and natural language processing. Multivariable regression using a Fine-Gray subdistribution hazard model was used to identify variables independently associated with VTE risk. Multiple imputation was used to address missing data. Results: A total of 398 530 outpatients with COVID-19 were identified. The mean (SD) age was 43.8 (15.8) years, 53.7% were women, and 54.3% were of self-reported Hispanic ethnicity. There were 292 (0.1%) VTE events identified over the follow-up period, for an overall rate of 0.26 (95% CI, 0.24-0.30) per 100 person-years. The sharpest increase in VTE risk was observed during the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% CI, 0.51-0.67 per 100 person-years vs 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days). In multivariable models, the following variables were associated with a higher risk for VTE in the setting of nonhospitalized COVID-19: age 55 to 64 years (HR 1.85 [95% CI, 1.26-2.72]), 65 to 74 years (3.43 [95% CI, 2.18-5.39]), 75 to 84 years (5.46 [95% CI, 3.20-9.34]), greater than or equal to 85 years (6.51 [95% CI, 3.05-13.86]), male gender (1.49 [95% CI, 1.15-1.96]), prior VTE (7.49 [95% CI, 4.29-13.07]), thrombophilia (2.52 [95% CI, 1.04-6.14]), inflammatory bowel disease (2.43 [95% CI, 1.02-5.80]), body mass index 30.0-39.9 (1.57 [95% CI, 1.06-2.34]), and body mass index greater than or equal to 40.0 (3.07 [1.95-4.83]). Conclusions and Relevance: In this cohort study of outpatients with COVID-19, the absolute risk of VTE was low. Several patient-level factors were associated with higher VTE risk; these findings may help identify subsets of patients with COVID-19 who may benefit from more intensive surveillance or VTE preventive strategies.

Adding a Clinical Hemophilia Pharmacist to the Hemophilia Comprehensive Care Model Improves Health Care-Related Outcomes and Drug-Related Costs in an Integrated Health Care System.

IntroductionThe National Hemophilia Foundation has advocated for a comprehensive care model in caring for patients with hemophilia. Currently pharmacists are not included as part of the team, and the impact of specific team members on patient outcomes is unknown. The authors designed an intervention to add a clinical pharmacist to this care model. The authors evaluated the impact of this intervention on bleeding outcomes, medication access and adherence, and cost within an integrated health care system. MethodsThe authors performed a multicenter, retrospective analysis of all hemophilia A and B patients enrolled in the hemophilia pharmacy service between March 2017 and February 2019. The authors analyzed data prior to and after this quality improvement project, encompassing the period between March 2016 and February 2020. Primary outcomes included an evaluation of the annualized bleed rates, emergency department visits, and hospitalizations. ResultsIn the cohort of patients with hemophilia A and B, the overall bleed rate was reduced from 40 per 100 patient-years to 37.6 per 100 patient-years. Similarly, emergency department visits were reduced from 22.7 to 18.3 per 100 patient-years, and hospitalizations reduced from 6.4 to 3.0 per 100 patient-years (p values >.05). This was augmented by the use of a unique factor recycling program that saved $900,000 in medication costs over a 12-month period. DiscussionThis study shows that the addition of a clinical pharmacist to the core hemophilia team leads to positive trends toward improved bleeding outcomes for patients, improved medication access and adherence, and substantial cost savings to the health system.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: January 2022 update on the use of therapeutic-intensity anticoagulation in acutely ill patients.

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19. METHODS: ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 as part of the living phase of these guidelines. RESULTS: The panel made one additional recommendation. The panel issued a conditional recommendation in favor of therapeutic-intensity over prophylactic-intensity anticoagulation in patients with COVID-19-related acute illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of risk of thrombosis and bleeding. The panel also noted that heparin (unfractionated or low molecular weight) may be preferred because of a preponderance of evidence with this class of anticoagulants. CONCLUSION: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation in patients with COVID-19-related acute illness.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis for patients with COVID-19: March 2022 update on the use of anticoagulation in critically ill patients.

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for patients with COVID-19. METHODS: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing systematic evidence reviews (up to January 2022). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 and May 2021 as part of the living phase of these guidelines. RESULTS: The panel made 1 additional recommendation: a conditional recommendation for the use of prophylactic-intensity over therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of thrombotic and bleeding risk. CONCLUSIONS: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation for patients with COVID-19-related critical illness.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis.

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation. CONCLUSIONS: This recommendation was based on very low certainty in the evidence, underscoring the need for high-quality randomized controlled trials assessing the role of postdischarge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.

COVID-19 and Risk of VTE in Ethnically Diverse Populations.

BACKGROUND: Limited existing data suggest that the novel COVID-19 may increase risk of VTE, but information from large, ethnically diverse populations with appropriate control participants is lacking. RESEARCH QUESTION: Does the rate of VTE among adults hospitalized with COVID-19 differ from matched hospitalized control participants without COVID-19? STUDY DESIGN AND METHODS: We conducted a retrospective study among hospitalized adults with laboratory-confirmed COVID-19 and hospitalized adults without evidence of COVID-19 matched for age, sex, race or ethnicity, acute illness severity, and month of hospitalization between January 2020 and August 2020 from two integrated health care delivery systems with 36 hospitals. Outcomes included VTE (DVT or pulmonary embolism ascertained using diagnosis codes combined with validated natural language processing algorithms applied to electronic health records) and death resulting from any cause at 30 days. Fine and Gray hazards regression was performed to evaluate the association of COVID-19 with VTE after accounting for competing risk of death and residual differences between groups, as well as to identify predictors of VTE in patients with COVID-19. RESULTS: We identified 6,319 adults with COVID-19 and 6,319 matched adults without COVID-19, with mean ± SD age of 60.0 ± 17.2 years, 46% women, 53.1% Hispanic, 14.6% Asian/Pacific Islander, and 10.3% Black. During 30-day follow-up, 313 validated cases of VTE (160 COVID-19, 153 control participants) and 1,172 deaths (817 in patients with COVID-19, 355 in control participants) occurred. Adults with COVID-19 showed a more than threefold adjusted risk of VTE (adjusted hazard ratio, 3.48; 95% CI, 2.03-5.98) compared with matched control participants. Predictors of VTE in patients with COVID-19 included age ≥ 55 years, Black race, prior VTE, diagnosed sepsis, prior moderate or severe liver disease, BMI ≥ 40 kg/m2, and platelet count > 217 k/µL. INTERPRETATION: Among ethnically diverse hospitalized adults, COVID-19 infection increased the risk of VTE, and selected patient characteristics were associated with higher thromboembolic risk in the setting of COVID-19.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate-intensity anticoagulation in critically ill patients.

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021. RESULTS: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE. CONCLUSIONS: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.

American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-related critical illness and acute illness are associated with a risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis for patients with COVID-19-related critical illness and acute illness who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel and applied strict management strategies to minimize potential bias from conflicts of interest. The panel included 3 patient representatives. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic evidence reviews (up to 19 August 2020). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 2 recommendations. The panel issued conditional recommendations in favor of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness or acute illness who do not have confirmed or suspected VTE. CONCLUSIONS: These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation. They will be updated using a living recommendation approach as new evidence becomes available.

Temporal trends in first-line outpatient anticoagulation treatment for cancer-associated venous thromboembolism.

BACKGROUND: First-line treatment and secondary prevention of venous thromboembolism (VTE) in patients with cancer consisted, historically, of unfractionated heparin or low-molecular weight heparin (LMWH). With recent clinical trials of direct oral anticoagulants (DOAC) showing similar efficacy as LMWH, little is known about anticoagulant prescribing patterns in patients with cancer and a VTE. This study characterized the temporal trends in first-line outpatient anticoagulation therapy for cancer-associated VTE. MATERIALS AND METHODS: This retrospective cohort study of patients who were hospitalized for a cancer-associated venous thromboembolism (VTE) between 01/01/2000 and 10/31/2017 identified patients from the cancer registries at two regions of an integrated healthcare delivery system. The primary outcome was the trend in age- and sex-adjusted rates of first-line anticoagulant therapy during the 30 days post-hospital discharge. Therapies were categorized as 1) injectable LMWH monotherapy, 2) warfarin ± injectable, 3) injectable fondaparinux monotherapy, or 4) DOAC ± injectable. RESULTS: Overall, 9816 patients were included with a mean age of 66 ± 13 years and 54% were female. From 2000 to 2003, warfarin ± injectable was used in ≈90% of cases. After 2003, there was a steady decline in warfarin use (25% in 2017) corresponding with increased LMWH use: 11% in 2003 to 55% in 2017. The DOAC ± injectable use has rapidly increased from <1% in 2014 to 20% in 2017. CONCLUSIONS: From 2000 to 2017, first-line anticoagulant therapy for cancer-associated VTE has experienced a substantial increase in LMWH and DOAC use with a resultant decline in warfarin use.

Evolving epidemiologic trends in nonclear cell renal cell cancer: an analysis of the California Cancer Registry.

OBJECTIVE: To evaluate the California Cancer Registry in order to define nonclear cell renal cell cancer (RCC) clinical features and outcomes, identify prognostic variables, and generate hypotheses for further study. METHODS: Patients with invasive RCC tumors in the California Cancer Registry from 1998 to 2009 (n = 38,251) were analyzed, of which 4483 (11.7%) were of the nonclear cell type. Baseline clinical demographics and tumor characteristics were collected. Primary outcome measures were 3-year cause-specific survival (CSS) and overall survival (OS). RESULTS: Of 4483 nonclear cell RCC cases, 3304 (73.7%) were diagnosed between 2004 and 2009. Histologic distribution was as follows: papillary 63.9%, chromophobe 33.6%, and "other" 2.5% (including medullary and collecting duct tumors). Univariate analysis showed that chromophobe histology, female sex, and higher socioeconomic status were associated with significantly better OS and CSS. Patients in the later era (2004-2009) appeared to have better OS. Multivariate analysis showed the following to be independently associated with outcomes (hazard ratios shown for CSS and OS, respectively): chromophobe (0.48, 0.56; P <.001), medullary/collecting duct (2.99, 2.42; P <.001), no nephrectomy (2.84, 3.18; P <.001), regional stage (5.84, 1.98; P <.001), distant stage (25.7, 7.67; P <.001), and non-Hispanic blacks (1.5, P = .006; 1.25, P = .03). CONCLUSION: This large registry analysis demonstrated emerging epidemiologic trends in this uncommon RCC subset. Clinical variables associated with CSS and OS were identified that can potentially inform the design of future clinical trials in nonclear cell RCC.

Parallel synthesis of indolylquinones and their cell-based insulin mimicry.

A synthetic route to bis-indolyldihydroxybenzoquinones was adapted for parallel organic synthesis. The route involves selective conjugate addition of an indole to dichlorobenzoquinone promoted by Brønsted acid, followed by a Lewis acid-promoted conjugate addition of a second indole and a final hydrolysis. Methods for high-throughput purification of the products of this synthesis were also developed. Using these methods, we prepared a library whose structures are based on asterriquinone natural products, which have a wide range of biological activities. In this report, the activities of the library members in activation of the insulin receptor on mammalian cells were examined. Novel compounds were discovered that fall outside earlier developed structure-activity relationships for insulin mimics, supporting the value of systematic investigation (inspired by Nature) for the discovery of novel biologically active molecules.

Identification of novel orally available small molecule insulin mimetics.

Oral hypoglycemic agents have great potential for the treatment of both type 1 and type 2 diabetes. Here we report the identification of novel, small-molecule, insulin mimetics that activate the insulin receptor (IR) in vivo and in vitro, stimulate the Akt and extracellular signal-regulated kinase pathways downstream of the IR, and mimic the ability of insulin to stimulate glucose uptake, glycogen synthesis, and lipid synthesis in 3T3-L1 adipocytes. However, the compounds do not mimic the mitogenic effect of insulin. In animals, these compounds have oral hypoglycemic effects in both normal C57BL6 mice and diabetic db/db mice. Quantitative structure activity relationship modeling on data from a library of 60 compounds has highlighted structural features that are important for IR agonist activity that can be used to guide design of second and third generation compounds with greater potency and specificity.