Characterization of the severe phenotype of pyruvate kinase deficiency

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/2/ajh25926.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/1/ajh25926_am.pd

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation

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

The Role of Direct Oral Anticoagulants in Treatment of Cancer-Associated Thrombosis

Venous thromboembolism (VTE) complicates the clinical course of approximately 5–10% of all cancer patients. Anticoagulation of the cancer patient often presents unique challenges as these patients have both a higher risk of recurrent VTE and a higher risk of bleeding than patients without cancer. Although low molecular weight heparins (LMWH) are the standard of care for the management of cancer-associated VTE, their use requires once or twice daily subcutaneous injections, which can be a significant burden for many cancer patients who often require a long duration of anticoagulation. The direct oral anticoagulants (DOACs) are attractive options for patients with malignancy. DOACs offer immediate onset of action and short half-lives, properties similar to LMWH, but the oral route of administration is a significant advantage. Given the higher risks of recurrent VTE and bleeding, there has been concern about the efficacy and safety of DOACs in this patient population. Data are now emerging for the use of DOACs in the cancer patient population from dedicated clinical trials. While recently published data suggest that DOACs hold promise for the treatment of cancer associated VTE, additional studies are needed to establish DOACs as the standard-of-care treatment. Many such studies are currently underway. The available data for the use of DOACs in the treatment of cancer-associated VTE will be reviewed, focusing on efficacy, safety, and other considerations relevant to the cancer patient

Clinical challenges and promising therapies for chemotherapy-induced thrombocytopenia

Introduction: Chemotherapy-induced thrombocytop enia (CIT) is a common complication of cancer treatment causing chemotherapy delays, dose reductions, and treatment discontinuation, negatively impacting treatment outcomes and putting patients at risk for bleeding complications. There is no FDA-approved agent available to manage CIT. Areas covered: This article covers the diagnosis, definitions, and clinical challenges of CIT, and then focuses on the therapeutics developed to manage CIT. The first-generation thrombopoietic agents (oprelvekin and recombinant human thrombopoietins) are reviewed for critical background and context, followed by a detailed discussion of the data for the thrombopoietin receptor agonists (TPO-RAs) to manage CIT. Efficacy of TPO-RAs in treatment and prevention of CIT, as well as safety concerns such as the risk of thromboembolic complications, are reviewed in detail. For this review, a PubMed/MEDLINE literature search was undertaken for relevant articles published from 1995-2021. Expert opinion: After over two decades of drug development for CIT, multiple clinical trials and observational studies have found TPO-RAs, in particular romiplostim, to be safe and effective agents to manage patients with CIT, although no agent is yet FDA-approved for this indication. Active management of CIT with TPO-RAs is likely to improve oncologic outcomes, although additional data are needed. Phase 3 trials are ongoing

Impact of Tumor Genomic Mutations on Thrombotic Risk in Cancer Patients

Venous thromboembolism (VTE) is common in patients with cancer and is an important contributor to morbidity and mortality in these patients. Early thromboprophylaxis initiated only in those cancer patients at highest risk for VTE would be optimal. Risk stratification scores incorporating tumor location, laboratory values and patient characteristics have attempted to identify those patients most likely to benefit from thromboprophylaxis but even well-validated scores are not able to reliably distinguish the highest-risk patients. Recognizing that tumor genetics affect the biology and behavior of malignancies, recent studies have explored the impact of specific molecular aberrations on the rate of VTE in cancer patients. The presence of certain molecular aberrations in a variety of different cancers, including lung, colon, brain and hematologic tumors, have been associated with an increased risk of VTE and arterial thrombotic events. This review examines the findings of these studies and discusses the implications of these findings on decisions relating to thromboprophylaxis use in the clinical setting. Ultimately, the integration of tumor molecular genomic information into clinical VTE risk stratification scores in cancer patients may prove to be a major advancement in the prevention of cancer-associated thrombosis