Publications by authors named "Adam Cuker"

155 Publications

Heparin-induced thrombocytopenia and cardiovascular surgery.

Hematology Am Soc Hematol Educ Program 2021 12;2021(1):536-544

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Clinicians generally counsel patients with a history of heparin-induced thrombocytopenia (HIT) to avoid heparin products lifelong. Although there are now many alternative (nonheparin) anticoagulants available, heparin avoidance remains challenging for cardiac surgery. Heparin is often preferred in the cardiac surgery setting based on the vast experience with the agent, ease of monitoring, and reversibility. To "clear" a patient with a history of HIT for cardiac surgery, hematologists must first confirm the diagnosis of HIT, which can be challenging due to the ubiquity of heparin exposure and frequency of thrombocytopenia in patients in the cardiac intensive care unit. Next, the "phase of HIT" (acute HIT, subacute HIT A/B, or remote HIT) should be established based on platelet count, immunoassay for antibodies to platelet factor 4/heparin complexes, and a functional assay (eg, serotonin release assay). As long as the HIT functional assay remains positive (acute HIT or subacute HIT A), cardiac surgery should be delayed if possible. If surgery cannot be delayed, an alternative anticoagulant (preferably bivalirudin) may be used. Alternatively, heparin may be used with either preoperative/intraoperative plasma exchange or together with a potent antiplatelet agent. The optimal strategy among these options is not known, and the choice depends on institutional experience and availability of alternative anticoagulants. In the later phases of HIT (subacute HIT B or remote HIT), brief intraoperative exposure to heparin followed by an alternative anticoagulant as needed in the postoperative setting is recommended.
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http://dx.doi.org/10.1182/hematology.2021000289DOI Listing
December 2021

Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data.

Ann Intern Med 2021 Dec 7. Epub 2021 Dec 7.

University of Pennsylvania, Philadelphia, Pennsylvania (G.K.D., C.E.L., J.D.L., A.C.).

Background: Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited.

Objective: To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE.

Design: Retrospective new-user cohort study.

Setting: U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020.

Participants: Adults with VTE who were newly prescribed apixaban or rivaroxaban.

Measurements: The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding.

Results: Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation.

Limitation: Short follow-up.

Conclusion: In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M21-0717DOI Listing
December 2021

Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

J Thromb Thrombolysis 2021 Nov 24. Epub 2021 Nov 24.

Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.
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http://dx.doi.org/10.1007/s11239-021-02610-4DOI Listing
November 2021

Falsely positive heparin-induced thrombocytopenia antibody testing in severe hyperbilirubinemia.

Res Pract Thromb Haemost 2021 Oct 8;5(7):e12608. Epub 2021 Nov 8.

Hematology/Oncology Albert Einstein Medical Center Philadelphia Pennsylvania USA.

Heparin-induced thrombocytopenia (HIT) is a life-threatening pathologic reaction to heparin-based products. Diagnosis of this condition can be confounded by other comorbidities or by acute illness-oftentimes presenting challenging clinical dilemmas, particularly in critically ill patients. A 67-year-old woman was admitted with liver failure and severe hyperbilirubinemia. She developed thrombocytopenia after prophylactic heparin exposure. Subsequent quantitative latex immunoturbidimetric assay (LIA) HIT antibody testing was intermediately positive. Confirmatory serotonin release assay testing subsequently returned negative. Platelet factor4-dependent P-selectin expression assay also returned negative, suggesting false positivity of the initial LIA tests. Concern was raised that hyperbilirubinemia (total bilirubin, 55.5 mg/dL) interfered with the original assay. Further testing with a separate HIT ELISA assay, which includes multiple washes and dilutions of the serum in order to effectively remove bilirubin, returned negative. Medical providers must consider the possibility of false-positive LIA testing when evaluating for HIT in the setting of severe hyperbilirubinemia.
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http://dx.doi.org/10.1002/rth2.12608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576178PMC
October 2021

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

Blood Adv 2021 Nov 2. Epub 2021 Nov 2.

American University of Beirut, Lebanon.

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 three 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 one additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 being discharged from the hospital 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 post-discharge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.
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http://dx.doi.org/10.1182/bloodadvances.2021005945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566097PMC
November 2021

Psychometric Evaluation of ITP Life Quality Index (ILQI) in a Global Survey of Patients with Immune Thrombocytopenia.

Adv Ther 2021 12 27;38(12):5791-5808. Epub 2021 Oct 27.

Ostfold Hospital Trust, Gralum, Norway.

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disorder caused by immunologic destruction of otherwise normal platelets. Patients and physicians differ in their views pertaining to the limitations imposed on patients' daily lives by ITP and its treatment. Poor understanding of ITP symptoms can result in misdiagnosis and complex treatment patterns, and affect patient health-related quality of life (HRQoL). The ITP Life Quality Index (ILQI) is a 10-item patient-reported outcome measure developed for clinical practice to aid discussions between patients and physicians. This research aimed to validate the psychometric properties of the ILQI using data collected in the ITP World Impact Survey (I-WISh).

Methods: I-WISh data containing responses to the ILQI from 1507 patients with ITP across 13 countries worldwide was subject to psychometric analysis to evaluate the structure, reliability and validity of the ILQI and assess scoring cut-offs.

Results: The ILQI has an overarching unidimensional structure, supporting a total score including all 10 items. Reliability was supported (Cronbach's alpha = 0.90). ILQI scores monotonically increased with ITP severity. ILQI scores correlated with measures of fatigue and emotional well-being, supporting construct validity. Differential item functioning (DIF) analyses showed that ILQI item responses were interpreted similarly between the USA and other Western countries. It was suggested that previous clinical cut-off score of 20 for "impaired HRQoL" was reduced to 17 and a cut-off of 23-25 (rather than 30) was suggested to assess "significantly impaired HRQoL".

Conclusion: The validity and reliability of the ILQI to assess HRQoL of patients with ITP is supported. The revised cut-off scores for the ILQI will aid patient-centric decision-making.
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http://dx.doi.org/10.1007/s12325-021-01934-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572218PMC
December 2021

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation.

Ann Intern Med 2021 10;174(10):1490

Perelman School of Medicine and Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.7326/L21-0565DOI Listing
October 2021

SARS-CoV-2 Vaccination and Immune Thrombocytopenia in de novo and pre-existing ITP patients.

Blood 2021 Sep 29. Epub 2021 Sep 29.

Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medicine, New York, New York, United States.

Cases of de novo immune thrombocytopenia (ITP) - including a fatality - following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in pre-existing ITP. In this study, four data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a ten-center retrospective study of adults with pre-existing ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA, United States) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] x109/L approximately 1-week post-vaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 109 patients with pre-existing ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30x109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK ITP patients, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in pre-existing ITP or be identified de novo post-SARS-CoV2-vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those post-splenectomy and with more refractory disease, is indicated.
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http://dx.doi.org/10.1182/blood.2021013411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483984PMC
September 2021

Optimal Medical Therapy Following Deep Venous Interventions: Proceedings from the Society of Interventional Radiology Foundation Research Consensus Panel.

J Vasc Interv Radiol 2022 Jan 23;33(1):78-85. Epub 2021 Sep 23.

Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri.

The optimal medical management of patients following endovascular deep venous interventions remains ill-defined. As such, the Society of Interventional Radiology Foundation (SIRF) convened a multidisciplinary group of experts in a virtual Research Consensus Panel (RCP) to develop a prioritized research agenda regarding antithrombotic therapy following deep venous interventions. The panelists presented the gaps in knowledge followed by discussion and ranking of research priorities based on clinical relevance, overall impact, and technical feasibility. The following research topics were identified as high priority: 1) characterization of biological processes leading to in-stent stenosis/rethrombosis; 2) identification and validation of methods to assess venous flow dynamics and their effect on stent failure; 3) elucidation of the role of inflammation and anti-inflammatory therapies; and 4) clinical studies to compare antithrombotic strategies and improve venous outcome assessment. Collaborative, multicenter research is necessary to answer these questions and thereby enhance the care of patients with venous disease.
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http://dx.doi.org/10.1016/j.jvir.2021.09.009DOI Listing
January 2022

How to write a guideline: a proposal for a manuscript template that supports the creation of trustworthy guidelines.

Blood Adv 2021 11;5(22):4721-4726

Michael G. DeGroote Cochrane Canada and McMaster GRADE Centres and.

Trustworthy health guidelines should provide recommendations, document the development process, and highlight implementation information. Our objective was to develop a guideline manuscript template to help authors write a complete and useful report. The McMaster Grading of Recommendations Assessment, Development and Evaluation Centre collaborated with the American Society of Hematology (ASH) to develop guidelines for the management of venous thromboembolism. A template for reporting the guidelines was developed based on prior approaches and refined using input from other key stakeholders. The proposed guideline manuscript template includes: (1) title for guideline identification, (2) abstract, including a summary of key recommendations, (3) overview of all recommendations (executive summary), and (4) the main text, providing sufficient detail about the entire process, including objectives, background, and methodological decisions from panel selection and conflict-of-interest management to criteria for updating, as well as supporting information, such as links to online (interactive) tables. The template further allows for tailoring to the specific topic, using examples. Initial experience with the ASH guideline manuscript template was positive, and challenges included drafting descriptions of recommendations involving multiple management pathways, tailoring the template for a specific guideline, and choosing key recommendations to highlight. Feedback from a larger group of guideline authors and users will be needed to evaluate its usefulness and refine. The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines. Consistent application of the template may simplify the preparation of an evidence-based guideline manuscript and facilitate its use.
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http://dx.doi.org/10.1182/bloodadvances.2020003577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759117PMC
November 2021

Eltrombopag treatment of patients with secondary immune thrombocytopenia: retrospective EHR analysis.

Ann Hematol 2022 Jan 10;101(1):11-19. Epub 2021 Sep 10.

Department of Medicine and Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Immune thrombocytopenia (ITP) may occur in isolation (primary) or in association with a predisposing condition (secondary ITP [sITP]). Eltrombopag is a well-studied treatment for primary ITP, but evidence is scarce for sITP. We evaluated real-world use of eltrombopag for sITP using electronic health records. Eligible patients had diagnoses of ITP and a qualifying predisposing condition, and eltrombopag treatment. We described patient characteristics, treatment patterns, platelet counts, and thrombotic and bleeding events. We identified 242 eligible patients; the most common predisposing conditions were hepatitis C and systemic lupus erythematosus. Average duration of eltrombopag treatment was 6.1 months. Most (81.4%) patients achieved a platelet count ≥ 30,000/µL at a mean of 0.70 months, 70.2% reached ≥ 50,000/µL at a mean of 0.95 months, and 47.1% achieved a complete response of > 100,000/µL at a mean of 1.43 months after eltrombopag initiation. At eltrombopag discontinuation, 105 patients (43%) experienced a treatment-free period for a mean 3.3 months. Bleeding events occurred with similar frequency before and during eltrombopag treatment whereas thrombotic events were less frequent during eltrombopag treatment. Our results suggest similar rates of platelet response with eltrombopag in patients with sITP as compared with primary ITP. In addition, a treatment-free period is possible for a substantial minority of patients.
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http://dx.doi.org/10.1007/s00277-021-04637-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720735PMC
January 2022

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.

Blood Adv 2021 10;5(20):3951-3959

Michael G. DeGroote Cochrane Canada, McGRADE Centre, Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

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.
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http://dx.doi.org/10.1182/bloodadvances.2021005493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416320PMC
October 2021

Corticosteroid overuse in adults with immune thrombocytopenia: Cause for concern.

Res Pract Thromb Haemost 2021 Aug 25;5(6):e12592. Epub 2021 Aug 25.

Jane Anne Nohl Division of Hematology Department of Medicine Norris Cancer Center University of Southern California-Keck School of Medicine Los Angeles CA USA.

Corticosteroids remain a crucial component of first-line therapy for immune thrombocytopenia (ITP) due to low cost, high initial response rates, and acceptable short-term tolerability. However, extended and recurrent use of corticosteroids is associated with substantial toxicity. Survey studies indicate that >95% of patients with ITP treated with corticosteroids report adverse effects, more than one-third of whom require reduction or discontinuation of treatment. In light of the heavy treatment burden of prolonged corticosteroid exposure, clinical practice guidelines recommend limiting corticosteroid treatment to no more than 6 weeks in adults with ITP receiving initial therapy. For patients who require subsequent therapy, clinical practice guidelines recommend treatments more suitable for long-term disease control such as thrombopoietin receptor agonists, rituximab, other immune-modulating medications, or splenectomy, rather than repeated courses of corticosteroids. Despite these recommendations, real-world evidence suggests that corticosteroids remain the most frequently used treatment for adults with ITP, not only in the first line, but also in the second and third line. In this review, we summarize evidence on the efficacy, safety, and tolerability of corticosteroids; discuss the problem of overuse; and suggest strategies for curtailing the excessive use of corticosteroids in adults with ITP.
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http://dx.doi.org/10.1002/rth2.12592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387601PMC
August 2021

Cardiovascular and major bleeding outcomes with antiplatelet and direct oral anticoagulants in patients with acute coronary syndrome and atrial fibrillation: A population-based analysis.

Am Heart J 2021 12 24;242:71-81. Epub 2021 Aug 24.

Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA; Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Direct oral anticoagulants (DOACs) are replacing warfarin for stroke prevention in patients with atrial fibrillation (AF).

Objective: To assess the effectiveness and safety of concomitant treatment with antiplatelet-DOAC compared to antiplatelet-warfarin in patients with acute coronary syndrome (ACS) and AF.

Design: Retrospective propensity score-matched cohort study using United States-based commercial healthcare database from January 2016 to June 2019.

Participants: New-users of antiplatelet-DOAC and antiplatelet-warfarin who initiated the combined therapy within 30 days following incident ACS diagnosis.

Measurements: Primary study outcomes were recurrent cardiovascular diseases (CVD) (ie, a composite of stroke and myocardial infarction) and major bleeding events identified via discharge diagnoses. We controlled for potential confounders via propensity score matching (PSM). We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar time.

Results: After PSM, a total of 2,472 persons were included (1,236 users of antiplatelet-DOAC and 1,236 users of antiplatelet-warfarin). The use of antiplatelet-DOAC (vs. antiplatelet-warfarin) was associated with a reduced rate of recurrent CVD (adjusted HR 0.72, 95% confidence interval [CI], 0.56-0.92) and major bleeding events (adjusted HR, 0.49, 95% CI 0.33-0.72).

Limitations: Residual confounding.

Conclusions: In real-world data of AF patients with concurrent ACS, the use of antiplatelet-DOAC following ACS diagnosis was associated with a lower rate of recurrent CVD and major bleeding events compared with antiplatelet-warfarin. These findings highlight a potential promising role for DOACs in patients with ACS and AF requiring combined antiplatelet therapy.
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http://dx.doi.org/10.1016/j.ahj.2021.08.014DOI Listing
December 2021

Immune thrombocytopenia: vaccination does not equal causation

Haematologica 2021 08 26. Epub 2021 Aug 26.

Dept. of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.279727DOI Listing
August 2021

Carfilzomib-Induced Atypical Hemolytic Uremic Syndrome in a Patient With Heterozygous CFHR3/CFHR1 Deletion Treated With Eculizumab.

Clin Lymphoma Myeloma Leuk 2021 11 14;21(11):e845-e849. Epub 2021 Jul 14.

Hospital of the University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1016/j.clml.2021.06.019DOI Listing
November 2021

Definition of a critical bleed in patients with immune thrombocytopenia: Communication from the ISTH SSC Subcommittee on Platelet Immunology.

J Thromb Haemost 2021 08;19(8):2082-2088

Department of Medicine, McMaster Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada.

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. In preparation for an upcoming guideline, the ITP Emergency Management Guideline Panel, including clinical experts in hematology, emergency medicine, research methodology, and patient representatives, identified the need for a standardized definition of a critical ITP bleed. The goal of the definition was to distinguish critical bleeds from bleeds that may not require urgent treatment, typically in the context of severe thrombocytopenia.

Methods: The panel met in person and virtually to achieve consensus on the criteria for critical bleeding events among patients with ITP. Existing ITP bleeding scores and published definitions of major bleeds in patients receiving anticoagulation informed the definition of a critical ITP bleed. The Platelet Immunology Scientific Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis endorsed the definition.

Results: A critical ITP bleed was defined as: (a) a bleed in a critical anatomical site including intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or intramuscular with compartment syndrome; or (2) an ongoing bleed that results in hemodynamic instability or respiratory compromise.

Conclusion: The definition of a critical ITP bleed was developed by the ITP Emergency Management Guideline Panel and endorsed by the Platelet Immunology SSC. It incorporates both anatomic and physiologic risk and pertains to patients with confirmed or suspected ITP who typically have severe thrombocytopenia (platelet count below 20 × 10 /L).
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http://dx.doi.org/10.1111/jth.15368DOI Listing
August 2021

Self-reported positive impact of mentored clinical research training is associated with academic success in hematology.

Blood Adv 2021 07;5(14):2919-2924

Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada.

The American Society of Hematology Clinical Research Training Institute (CRTI) is a mentored training program for hematology fellows and junior faculty. Our objective was to determine whether the self-reported impact of CRTI on research retention, career development, and connectedness to hematology investigators was associated with academic success. A survey was distributed in January 2020 to alumni who participated in the program from 2003 to 2019. It focused on the impact of CRTI on retention in research, facilitation of career development, understanding of requirements to succeed, and feelings of connectedness to investigators. These questions were scored on a 5-point Likert scale ranging from strongly disagree to strongly agree. Outcomes were grants, publications, and invited lectures; these were abstracted from a submitted curriculum vitae. Of 334 eligible alumni, 321 responded (response rate of 96.1%). Of these, 250 (77.9%) agreed that CRTI was instrumental to research retention, 268 (83.5%) agreed that CRTI facilitated career development, 296 (92.2%) agreed that CRTI allowed a better understanding of requirements to succeed in research, and 289 (90.0%) agreed that CRTI increased connectedness to hematology investigators. Those who agreed with these CRTI impacts had significantly more first-author publications. Those who agreed that CRTI was instrumental to retention, facilitated career development, and increased connectedness had significantly more protected time for research. Self-reported perception that CRTI had an impact on research retention, career development, and connectedness to hematology investigators was significantly associated with more publications and percent effort in research. Clinical research training programs should identify and implement approaches to enhance these characteristics.
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http://dx.doi.org/10.1182/bloodadvances.2021004421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341353PMC
July 2021

Diagnosing heparin-induced thrombocytopenia: The need for accuracy and speed.

Int J Lab Hematol 2021 Jul;43 Suppl 1:96-102

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition resulting from pathogenic antibodies to complexes of heparin and platelet factor 4 (PF4). The diagnosis of HIT can be challenging due to the widespread use of heparin and the frequency of thrombocytopenia in hospitalized patients. Laboratory testing for HIT typically includes an immunoassay to detect antibodies to PF4-heparin and a functional assay. Current HIT diagnostic algorithms recommend using the 4Ts score to determine the need for HIT laboratory testing. Automated calculation of HIT clinical prediction scores in the electronic health record may improve the identification of patients who should undergo HIT testing. Another challenge in the management of patients with suspected HIT is the turnaround time of the laboratory testing needed to confirm the diagnosis. Due to the high daily thrombotic risk of HIT, clinicians must treat patients with intermediate to high pretest likelihood of HIT empirically while awaiting the test results. Treatment for HIT often involves alternative anticoagulants that lack reversal agents, which may increase bleeding risk, prolong hospital stays, and increase costs for patients suspected of having HIT. Rapid immunoassays hold promise to improve the speed of HIT diagnosis. These assays must retain a very high sensitivity for this "can't miss" diagnosis, yet have sufficient specificity to be of diagnostic value. A Bayesian approach has been proposed using two rapid immunoassays in succession, which decreased analytic turnaround time to 60 minutes. Such an approach has the potential to be a much-needed clinical advance in improving accuracy and speed in the diagnosis of HIT.
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http://dx.doi.org/10.1111/ijlh.13564DOI Listing
July 2021

A modeling approach to derive baseline risk estimates for GRADE recommendations: Concepts, development, and results of its application to the American Society of Hematology 2019 guidelines on prevention of venous thromboembolism in surgical hospitalized patients.

J Clin Epidemiol 2021 Dec 18;140:69-78. Epub 2021 Jul 18.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Canada; Institute for Evidence in Medicine, Medical Center & Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Objective: The goal of this study was to develop an approach that can be used where baseline risk estimates that are directly applicable to prioritized patient-important outcomes are not available from published studies.

Study Design: The McMaster University GRADE Centre and the ASH guideline panel for the prevention of VTE in surgical patients developed a modeling approach based on explicit assumptions about the distribution of symptoms, anatomical location, and severity of VTE events.

Results: We applied the approach to derive modeled estimates of baseline risk. These estimates were used to calculated absolute measures of anticipated effects that informed the discussion of the evidence and the formulation of 30 guideline recommendations.

Conclusion: Our approach can assist guideline developers facing a lack of information about baseline risk estimates that directly apply to outcomes of interest. The use of modeled estimates increases transparency in the process and makes the baseline risk used by guideline experts explicit during their decision-making.
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http://dx.doi.org/10.1016/j.jclinepi.2021.07.010DOI Listing
December 2021

Qualitative study to support the content validity of the immune thrombocytopenia (ITP) Life Quality Index (ILQI).

Br J Haematol 2021 08 15;194(4):759-766. Epub 2021 Jul 15.

Novartis Pharma AG, Global Value and Access, Oncology, Basel, Switzerland.

Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder. Bleeding is the primary symptom that presents in varying severities. ITP has a negative impact on health-related quality of life (HRQoL). The ITP Life Quality Index (ILQI) was developed as a 10-item patient-reported outcome measure to assess impact on HRQoL in ITP. The objective of the present study was to confirm the content validity of the ILQI with a qualitative interview study in the UK involving 15 adult participants with ITP. Combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted to explore the symptoms and impacts associated with ITP and confirm content validity of the draft ILQI. The CE phase elicited 14 ITP symptom concepts, including: bruising (all 15 patients, 100%), fatigue (14, 93·3%) and bleeding gums/blood blisters (13, 86·7%). Impacts included decreased ability to participate in sport (all 15 patients, 100%) and anxiety (12, 80%). The CD phase resulted in an adjustment to the ILQI recall period from 1 week to 'the past month'. Updates were made to improve relevance and response options. The qualitative interviews support the content validity of the ILQI and confirm that the concepts assessed are relevant and consistently understood and interpreted by adult patients with ITP.
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http://dx.doi.org/10.1111/bjh.17694DOI Listing
August 2021

Thrombosis with thrombocytopenia syndrome after COVID-19 vaccination.

Authors:
Adam Cuker

Clin Adv Hematol Oncol 2021 07;19(7):446-449

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

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July 2021

Thrombosis After Vaccination With Messenger RNA-1273: Is This Vaccine-Induced Thrombosis and Thrombocytopenia or Thrombosis With Thrombocytopenia Syndrome?

Ann Intern Med 2021 10 29;174(10):1468-1469. Epub 2021 Jun 29.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.7326/M21-2680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251937PMC
October 2021

Laboratory assessment of the direct oral anticoagulants: who can benefit?

Kardiol Pol 2021 24;79(6):622-630. Epub 2021 May 24.

Department of Medicine and Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.

Direct oral anticoagulants (DOACs), apixaban, dabigatran, edoxaban, and rivaroxaban, are widely used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation as well as for prevention and treatment of venous thromboembolism. Although DOACs do not require routine laboratory monitoring of anticoagulant effect, there are special situations in which laboratory assessment may be warranted. Laboratory tests include quantitative assays, which measure plasma DOAC levels, and qualitative or semi-quantitative assays, which may be used to screen for the presence of clinically relevant DOAC levels. Indications for laboratory assessment include emergent indications (serious bleeding, urgent surgery, acute ischemic stroke with consideration of thrombolysis) and elective indications (extremes of bodyweight, renal hypo- or hyperfunction, liver disease, suspected drug-drug interactions, suspected gastrointestinal malabsorption). In general, quantitative assays that measure DOAC levels may be used for elective indications, whereas screening assays may be necessary for emergent indications if a quantitative assay with sufficiently rapid turnaround time is not available. Therapeutic ranges for DOACs have not been defined. In lieu of therapeutic ranges, data from pharmacokinetic studies may be used to determine whether a patient's plasma DOAC level falls within the expected range. If it does not, a change in therapy may be warranted. Depending on the clinical scenario, a change in therapy may involve adjustment of the DOAC dose, a change to a different DOAC, or a change to a different class of anticoagulant.
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http://dx.doi.org/10.33963/KP.a2021.0021DOI Listing
July 2021

Comparative effectiveness and safety of anticoagulants for the treatment of heparin-induced thrombocytopenia.

Am J Hematol 2021 07 3;96(7):805-815. Epub 2021 May 3.

Department of Clinical Chemistry, Inselspital, Bern University Hospital, Bern, Switzerland.

Background: The effectiveness and safety of non-heparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT) are not fully established, and the optimal treatment strategy is unknown. In a systematic review and meta-analysis, we aimed to determine precise rates of platelet recovery, new or progressive thromboembolism (TE), major bleeding, and death for all non-heparin anticoagulants and to study potential sources of variability.

Methods: Following a detailed protocol (PROSPERO: CRD42020219027), EMBASE and Medline were searched for all studies reporting clinical outcomes of patients treated with non-heparin anticoagulants (argatroban, danaparoid, fondaparinux, direct oral anticoagulants [DOAC], bivalirudin, and other hirudins) for acute HIT. Proportions of patients with the outcomes of interest were pooled using a random-effects model for each drug. The influence of the patient population, the diagnostic test used, the study design, and the type of article was assessed.

Results: Out of 3194 articles screened, 92 studies with 119 treatment groups describing 4698 patients were included. The pooled rates of platelet recovery ranged from 74% (bivalirudin) to 99% (fondaparinux), TE from 1% (fondaparinux) to 7% (danaparoid), major bleeding from 1% (DOAC) to 14% (bivalirudin), and death from 7% (fondaparinux) to 19% (bivalirudin). Confidence intervals were mostly overlapping, and results were not influenced by patient population, diagnostic test used, study design, or type of article.

Discussion: Effectiveness and safety outcomes were similar among various anticoagulants, and significant factors affecting these outcomes were not identified. These findings support fondaparinux and DOACs as viable alternatives to conventional anticoagulants for treatment of acute HIT in clinical practice.
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http://dx.doi.org/10.1002/ajh.26194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252596PMC
July 2021

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study.

Ann Intern Med 2021 07 30;174(7):910-919. Epub 2021 Mar 30.

Perelman School of Medicine and Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania (G.K.D., C.E.L., J.D.L.).

Background: Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited.

Objective: To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF.

Design: New-user retrospective propensity score-matched cohort study.

Setting: U.S.-based commercial health care database from 1 January 2010 to 30 June 2019.

Participants: Adults with valvular AF who were newly prescribed DOACs or warfarin.

Measurements: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding.

Results: Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]).

Limitation: Relatively short follow-up; inability to ascertain disease severity.

Conclusion: In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M20-6194DOI Listing
July 2021

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

J Thromb Haemost 2021 06 7;19(6):1533-1545. Epub 2021 May 7.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1111/jth.15310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250316PMC
June 2021

Certainty of evidence and intervention's benefits and harms are key determinants of guidelines' recommendations.

J Clin Epidemiol 2021 08 1;136:1-9. Epub 2021 Mar 1.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Objective: Many factors are postulated to affect guidelines developments. We set out to identify the key determinants.

Study Design And Setting: a) Web-based survey of 12 panels of 153 "voting" members who issued 2941 recommendations; b) qualitative analysis of 13 panels of 311 attendees (panel members, systematic review teams and observers).

Results: Compared with "no recommendations", when intervention's benefit outweigh harms (BH-balance), probability of issuing strong recommendations in favor of intervention was 0.22 (95%CI: 0.08 to 0.36) when certainty of evidence (CoE) was very low; 0.5 (95%CI:0.36 to 0.63) when low; 0.74 (95%CI 0.61 to 0.87) when moderate and 0.85 (95%CI:0.71 to 1.00) when high. No other postulated factor significantly affected recommendations. The findings are consistent with a J- curve model when recommendations are issued in favor but not against an intervention. Panelists often changed their judgments as a result of the meeting discussion (67% for CoE to 92% for balance between benefits and harms). The panels spent over 50% of their time debating CoE; the chairs and co-chairs dominated discussion.

Conclusions: CoE and BH-balance are key determinants of recommendations in favor of an intervention. Chairs and co-chairs dominate discussion. Panelists often change their judgments as a result of panel deliberation.
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http://dx.doi.org/10.1016/j.jclinepi.2021.02.025DOI Listing
August 2021

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

Blood Adv 2021 02;5(3):872-888

Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.

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.
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http://dx.doi.org/10.1182/bloodadvances.2020003763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869684PMC
February 2021

Tapering thrombopoietin receptor agonists in primary immune thrombocytopenia: Expert consensus based on the RAND/UCLA modified Delphi panel method.

Res Pract Thromb Haemost 2021 Jan 8;5(1):69-80. Epub 2020 Dec 8.

Partnership for Health Analytic Research (PHAR), LLC Beverly Hills CA USA.

Background: Thrombopoietin receptor agonists (TPO-RAs) are used to treat primary immune thrombocytopenia (ITP). Some patients have discontinued treatment while maintaining a hemostatic platelet count.

Objectives: To develop expert consensus on when it is appropriate to consider tapering TPO-RAs in ITP, how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy.

Methods: We used a RAND/UCLA modified Delphi panel method. Ratings were completed independently by each expert before and after a meeting. Second-round ratings were used to develop the panel's guidance. The panel was double-blinded: The sponsor and nonchair experts did not know each other's identities.

Results: Guidance on when it is appropriate to taper TPO-RAs in children and adults was developed based on patient platelet count, history of bleeding, intensification of treatment, trauma risk, and use of anticoagulants/platelet inhibitors. For example, it is appropriate to taper TPO-RAs in patients who have normal/above-normal platelet counts, have no history of major bleeding, and have not required an intensification of treatment in the past 6 months; it is inappropriate to taper TPO-RAs in patients with low platelet counts. Duration of ITP, months on TPO-RA, or timing of platelet response to TPO-RA did not have an impact on the panel's guidance on appropriateness to taper. Guidance on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy is also provided.

Conclusion: This guidance could support clinical decision making and the development of clinical trials that prospectively test the safety of tapering TPO-RAs.
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http://dx.doi.org/10.1002/rth2.12457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845076PMC
January 2021
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