Thrombocytopenia with and without thrombosis following COVID-19 vaccination: long-term management.

Background: Since administration of COVID-19 vaccines, there has been growing evidence of thrombotic and thrombocytopenic events following vaccination. However, there remains limited data on long-term management of these adverse hematologic events. Key Clinical Question: We report on 9 patients presenting with thrombocytopenia following COVID-19 vaccination, with 4 subsequently diagnosed with vaccine-induced thrombocytopenia and thrombosis (VITT) and 5 with immune thrombocytopenia. Clinical Approach: A retrospective chart review was completed for adults >18 years of age presenting to a tertiary care center with new-onset thrombocytopenia occurring 4 to 42 days following COVID-19 vaccination. Presenting symptoms, laboratory investigations, and response to treatment are described. Conclusion: Two of 4 patients with VITT developed refractory thrombocytopenia successfully treated with intravenous immunoglobulin, corticosteroids, and plasma exchange therapy. Patients with VITT remained on anticoagulation for at least 9 months due to persistently positive diagnostic tests. Four of 5 patients with immune thrombocytopenia received intravenous immunoglobulin and corticosteroids with good recovery. Patients who received a subsequent COVID-19 mRNA vaccine had no adverse hematologic effects.

Extended-duration thromboprophylaxis following major abdominopelvic surgery - For everyone or selected cases only?

Major abdominopelvic surgery is an important risk factor for postoperative venous thromboembolism (VTE). VTE is the leading cause of 30-day postoperative mortality in patients with cancer undergoing major abdominopelvic surgery. Randomized controlled trials have shown that extended duration thromboprophylaxis using a low molecular weight heparin or a direct oral anticoagulant significantly decreases the risk of overall VTE (symptomatic events and asymptomatic deep vein thrombosis). Hence, several clinical practice guidelines suggest the use of extended duration thromboprophylaxis for all high-risk patients undergoing major abdominopelvic surgery. Despite these recommendations by clinical practice guidelines, adoption of extended duration thromboprophylaxis in clinical practice remains low and clinical equipoise seems to persist. In this narrative review, we aim is to highlight and summarize the reasons that may explain discrepancy between clinical guideline recommendations and current practice regarding extended duration thromboprophylaxis in this patient population. We also aim to review different personalized approaches based on patients' individualized risk of VTE that may foster shared decision making and improve patient outcomes by reducing decisional conflict, increasing patient knowledge, and increasing risk perception accuracy.

Thromboprophylaxis of cancer patients undergoing systemic therapy in the ambulatory setting.

Cancer-associated Thrombosis (CAT) is a common complication among patients with cancer which is associated with significant morbidity and mortality. The risk of CAT varies widely depending on cancer types and treatments and its cumulative incidence increases over time. Although patients with cancer have a high risk of developing venous thromboembolism, pharmacological thromboprophylaxis is not routinely recommended for ambulatory patients receiving chemotherapy but is suggested for those deemed as high-risk. Risk assessment models can help clinicians identify ambulatory patients at high risk who would most benefit from thromboprophylaxis with low molecular weight heparin or direct oral anticoagulants (apixaban or rivaroxaban). This narrative review will summarize the data on pharmacological thromboprophylaxis in ambulatory patients with cancer, provide further insights into the safety and efficacy of different anticoagulants, and suggest implementation methods using a multidisciplinary approach leading to an optimization of preventative strategies in this patient population.

A pilot study investigating the feasibility of using a fully automatic software to assess the RENAL and PADUA score.

PURPOSE: Image-based morphometric scoring systems such as the RENAL and PADUA scores are useful to evaluate the complexity of partial nephrectomy for renal cell carcinoma (RCC). The main aim of this study was to develop a new imaging software to enable an automatic detection and a 3D visualization of RCC from CT angiography (CTA) and to address the feasibility to use it to evaluate the features of the RENAL and the PADUA scores. METHODS: A training dataset of 210 patients CTA-scans manually segmented was used to train a deep learning algorithm to develop the automatic detection and 3D-visualization of RCC. A trained operator blindly assessed the RENAL and PADUA scores on a testing dataset of 41 CTA from patients with RCC using a commercialized semi-automatic software (ground truth) and the new automatic software. Concordance between the two methods was evaluated. RESULTS: The median PADUA score was 9 (7-11) and the renal score was 8 (5.5-9). The automatic software enabled to automatically detect the tumoral kidney and provided a 3D-visualization in all cases, with a computational time less than 20 seconds. Concordances for staging the anatomical features of the RENAL scores were respectively: 87.8% for radius, 85.4% for exophytic rate, 82.9% for location to the polar lines and 92.7% for the antero-posterior location. For the PADUA scores, concordances were 90.2% for tumor size, 85.4% for exophytic rate, 87.8% for polar location and 100% for renal rim. CONCLUSION: By enabling an automatic 3D-visualization of tumoral kidney, this software could help to calculate morphometric scores, save time and improve reproducibility for clinicians.

Multicenter Evaluation of the Clinical Performance and the Neutralizing Antibody Activity Prediction Properties of 10 High-Throughput Serological Assays Used in Clinical Laboratories.

As the coronavirus disease 2019 (COVID-19) pandemic second wave is emerging, it is of the upmost importance to screen the population immunity in order to keep track of infected individuals. Consequently, immunoassays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high specificity and positive predictive values are needed to obtain an accurate epidemiological picture. As more data accumulate about the immune responses and the kinetics of neutralizing-antibody (nAb) production in SARS-CoV-2-infected individuals, new applications are forecast for serological assays such as nAb activity prediction in convalescent-phase plasma from recovered patients. This multicenter study, involving six hospital centers, determined the baseline clinical performances, reproducibility, and nAb level correlations of 10 commercially available immunoassays. In addition, three lateral-flow chromatography assays were evaluated, as these devices can be used in logistically challenged areas. All assays were evaluated using the same patient panels in duplicate, thus enabling accurate comparison of the tests. Seven immunoassays examined in this study were shown to have excellent specificity (98 to 100%) and good to excellent positive predictive values (82 to 100%) when used in a low (5%)-seroprevalence setting. We observed sensitivities as low as 74% and as high as 95% at ≥15 days after symptom onset. The determination of optimized cutoff values through receiver operating characteristic (ROC) curve analyses had a significant impact on the diagnostic resolution of several enzyme immunoassays by increasing the sensitivity significantly without a large trade-off in specificity. We found that spike-based immunoassays seem to be better correlates of nAb activity. Finally, the results reported here will add to the general knowledge of the interlaboratory reproducibility of clinical performance parameters of immunoassays and provide new evidence about nAb activity prediction.

Prescribing patterns and outcomes of venous thromboembolism prophylaxis in hospitalized medical and cancer patients: Observations from the Ottawa Hospital.

Guidelines suggest broad use of pharmacologic prophylaxis to prevent venous thromboembolism (VTE) in hospitalized medical patients, however little 'real-world' data exists to support this. Our goal was to describe the use of thromboprophylaxis among general medical and cancer patients admitted to hospital, compare VTE and bleeding outcomes according to use of thromboprophylaxis, and to determine what variables influence prescribing patterns and outcomes. Patients admitted to the general medical and oncology services at The Ottawa Hospital between 2010 and 2015 were retrospectively reviewed and classified according to whether they received initial, delayed, or no pharmacologic thromboprophylaxis during their first hospitalization. Patients with an alternate indication for anticoagulation or those admitted with a bleeding event were excluded from analysis. The primary efficacy outcome was any symptomatic VTE during index hospitalization or within 90 days of discharge, and the primary safety outcome was clinically relevant bleeding during the index hospitalization. 17,262 patients were included in our final analysis. General medical patients selected to receive no, initial, or delayed thromboprophylaxis had 0.4%, 0.7%, and 2.4% rates of VTE; and 0.2%, 0.7%, and 1.5% rates of clinically relevant bleeding complications, respectively. Cancer patients had significantly higher rates of VTE: 3.3%, 3.9%, and 5.0%; and 0.9%, 0.7%, and 3.0% rates of clinically relevant bleeding among those selected to receive no, initial, or delayed thromboprophylaxis, respectively. Overall, our study suggests that broad use of pharmacologic thromboprophylaxis may be unnecessary in select low-risk general medical patients and may be less effective in cancer patients in whom new studies are indicated.

Prevention and treatment of cancer-associated thrombosis.

Cancer is a hypercoagulable state with an associated increased risk of venous thromboembolism (vte) that is further amplified in individuals who undergo chemotherapy. Compared with patients having cancer alone or vte alone, patients who develop cancer-associated vte have a significantly poorer prognosis. The risks of recurrent vte despite appropriate anticoagulation therapy and of bleeding are also higher in patients with cancer than in those without. For those reasons, the prevention and appropriate management of cancer-associated thrombosis is of paramount importance. Although low-molecular-weight heparin has been the standard of care for the prevention and treatment of cancer-associated thrombosis, direct oral anticoagulants are increasingly being adopted as an effective and safe alternative.

Debate: Thromboprophylaxis should be considered in all patients with cancer - Yes.

Venous thromboembolism (VTE) is a common complication among patients with cancer that is associated with significant morbidity, mortality and health care costs. There is a significant lack of awareness among health care providers and patients leading to delays in seeking medical attention or diagnosis when signs and symptoms of suspected VTE occur as well as underappreciation of potential benefits of different thromboprophylaxis options. Clinical prediction rules (e.g. Khorana risk score) can be used by clinicians to stratify patients according to their underlying risk of VTE. Low-molecular-weight-heparin and direct oral anticoagulants (rivaroxaban and apixaban) have been shown to be safe and effective thromboprophylactic options in this patient population. Health care providers should educate all patients regarding VTE and consider thromboprophylaxis in patients at higher risk of VTE complications. Decisions about thromboprophylaxis should be made with the patients and include a discussion about relative benefits and harms, costs and duration.

Thromboembolism prophylaxis during L-asparaginase therapy in acute lymphoblastic leukemia - time to reconsider current approaches?

Acute Lymphoblastic Leukemia (ALL) is the commonest malignancy in childhood with a second incidence peak in adulthood. Improvements in pediatric therapy including the addition of L-asparaginase (L-ASP) have enabled cure rates in excess of 90% to be achieved in children. More recently L-ASP-containing pediatric protocols are being used to treat younger adults with ALL and have improved survival by approximately 2-fold. However, a toxicity associated with L-ASP-containing therapy in ALL is venous thromboembolism (VTE) which is associated with significant morbidity in this patient population and results in interruptions in L-ASP therapy that can impact on survival outcomes. The incidence of VTE among adult patients with ALL receiving L-ASP containing therapy has been reported to be as high as 43%. Despite this, there is a lack of evidence-based recommendations for VTE prophylaxis in this clinical context; low-molecular weight heparin (LMWH) and/or AT replacement have mostly been used. The low-quality data and inconveniences associated with these VTE prophylaxis regimens highlight the need to evaluate alternatives such as direct oral anticoagulants for the prevention of L-ASP-associated VTE in ALL. This narrative will review the body of evidence on primary thromboprophylaxis in adult patients with ALL receiving L-ASP containing therapy.

Development of a new patient-reported outcome measure to assess activities and participation in people with systemic sclerosis: the Cochin 17-item Scleroderma Functional scale.

BACKGROUND: Patient-reported outcome measures (PROMs) aimed at assessing people with systemic sclerosis (SSc) have rarely involved the target population in the item- and domain-generation stage of the instrument construction. OBJECTIVES: To develop a new PROM assessing activities and participation in people with SSc. METHODS: A provisional International Classification of Functioning, Disability and Health (ICF)-based 65-item questionnaire previously developed from interviews of people with SSc was sent by email to all patients followed in the internal medicine department of Cochin hospital (n = 184) and enrolled in the Scleroderma Patient-centered Intervention Network Cohort. Items were reduced according to their metric properties. Dimensional structure of the questionnaire was assessed by principal component analysis, convergent and divergent validities by Spearman's rank correlation coefficient, internal consistency by Cronbach's α, and reliability by a test-retest method using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Overall, 113 of 184 patients (61·4%) completed the provisional questionnaire. The item-reduction process resulted in a 17-item questionnaire, the Cochin 17-item Scleroderma Functional scale (CSF-17). Principal component analysis extracted two dimensions: 10 items related to mobility (CSF-17 section A) and seven items related to general tasks (CSF-17 section B). We observed convergent validity of the CSF-17 total score with global activity limitation, pain, depression and aesthetic burden, and divergent validity with anxiety. Cronbach's α was 0·94 for section A and 0·95 for section B. ICC (n = 25 patients) was 0·92 for the CSF-17 total score. Bland-Altman analysis did not reveal a systematic trend for the test-retest. CONCLUSIONS: The CSF-17 is a new PROM assessing activities and participation specifically in people with SSc. Its content and construct validities are very high. What is already known about this topic? In the earliest stages of construction patient-reported outcomes (PROMs) for people with systemic sclerosis (SSc) rarely involve the target population. Instruments able to capture the specific needs of people with SSc in terms of activities and participation are lacking. What does this study add? The Cochin 17-item Scleroderma Functional Scale (CSF-17) is a new PROM assessing global activities and participation specifically in people with SSc. Patients' perspectives were prioritized at all stages of construction. What are the clinical implications of this work? The CSF-17 could be used in clinical practice and research to assess the efficacy of complex multidisciplinary interventions targeting activity limitations and participation restriction in people with SSc. Linked Comment: Clark and Denton. Br J Dermatol 2020; 183:610.

Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Relationship between type of unprovoked venous thromboembolism and cancer location: An individual patient data meta-analysis.

BACKGROUND: Unprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to assess the period prevalence of occult cancer detection stratified by VTE location (deep vein thrombosis [DVT], pulmonary embolism [PE] or both) and the anatomical relationship between occult cancer and VTE. METHODS: Post-hoc analysis of a systematic review and individual patient data meta-analysis of adults with unprovoked VTE with at least 12 months of follow-up. Cancer types were grouped according to thoracic, abdomino-pelvic, or other locations. RESULTS: A total of 2300 patients were eligible including 1218 with DVT only (53%), 719 with PE only (31%), and 363 with both PE and DVT (16%). The pooled 12-month period prevalence of cancer in DVT only, PE only, and DVT + PE was 5.6% (95% CI, 4.4 to 7.2), 4.3% (95% CI, 2.7 to 6.9), and 5.6% (95% CI, 1.7 to 15.5), respectively. Most occult cancers were located in the abdomen (68.4%). The proportion of patients with an abdomino-pelvic cancer was not different in patients with DVT + PE (81%; 95% CI, 54 to 96) than in those with DVT (68%; 95% CI, 57 to 78) or PE alone (65%; 95% CI, 48 to 79). CONCLUSION: The 12-month prevalence of occult cancer was similar in patients with DVT only, PE only, or both. Most cancers were located in the abdomen, and there was no relationship between VTE type and cancer location.

Treatment algorithm in cancer-associated thrombosis: Canadian expert consensus.

Management of anticoagulant therapy for the treatment of venous thromboembolism (vte) in cancer patients is complex because of an increased risk of recurrent vte and major bleeding complications in those patients relative to the general population. Subgroups of patients with cancer also show variation in their risk for recurrent vte and adverse bleeding events. Accordingly, a committee of 10 Canadian clinical experts developed the consensus risk- stratification treatment algorithm presented here to provide guidance on tailoring anticoagulant treatment choices for the acute and extended treatment of symptomatic and incidental vte, to prevent recurrent vte, and to minimize the bleeding risk in patients with cancer. During a 1-day live meeting, a systematic review of the literature was performed, and a draft treatment algorithm was developed. The treatment algorithm was refined through the use of a Web-based platform and a series of online teleconferences. Clinicians using this treatment algorithm should consider the bleeding risk, the type of cancer, and the potential for drug-drug interactions in addition to informed patient preference in determining the most appropriate treatment for patients with cancer-associated thrombosis. Anticoagulant therapy should be regularly reassessed as the patient's cancer status and management change over time.

McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome.

Background The McMaster RARE-Bestpractices project group selected the catastrophic antiphospholipid syndrome (CAPS) for a pilot exercise in guideline development for a rare disease. Objectives The objectives of this exercise were to provide a proof of principle that guidelines can be developed for rare diseases and assist in clinical decision making for CAPS. Patients/Methods The GIN-McMaster Guideline Development checklist and GRADE methodology were followed throughout the guideline process. The CAPS guideline was coordinated by a steering committee, and the guideline panel was formed with representation from all relevant stakeholder groups. Systematic reviews were performed for the key questions. To supplement the published evidence, we piloted novel methods, including use of an expert-based evidence elicitation process and ad hoc analysis of registry data. Results This paper describes the CAPS guideline recommendations, including evidence appraisal and discussion of special circumstances and implementation barriers identified by the panel. Many of these recommendations are conditional, because of subgroup considerations in this heterogeneous disease, as well as variability in patient values and preferences. Conclusions The CAPS clinical practice guideline initiative met the objective of the successful development of a clinical practice guideline in a rare disease using GRADE methodology. We expect that clinicians caring for patients with suspected CAPS will find the guideline useful in assisting with diagnosis and management of this rare disease.

Risk stratification for the development of venous thromboembolism in hospitalized patients with cancer.

Essentials The Khorana score is validated for risk of venous thromboembolism (VTE) in cancer outpatients. We conducted a multicenter analysis of medically hospitalized cancer patients. Patients with a higher Khorana score on admission were more likely to develop VTE. The Khorana score is predictive of in-hospital, symptomatic VTE development. SUMMARY: Introduction The Khorana score is a validated risk assessment score for estimating the risk of symptomatic venous thromboembolism (VTE) in outpatients with cancer. The objective of this study was to assess the Khorana score for predicting the development of VTE in cancer patients during hospital admission. Methods We conducted an analysis of consecutive, adult cancer patients hospitalized for medical reasons between January and June 2010 in three academic medical centers. Information on objectively diagnosed, symptomatic VTE during hospitalization, use of anticoagulant thromboprophylaxis (TP) and Khorana score variables at the time of admission was collected. Results A total of 1398 patients were included. Mean age was 62 years, 51.2% were male, and mean BMI was 25.9 kg m-2 . The most frequent reasons for hospitalization were chemotherapy administration (22.3%), followed by pain control and palliation (21.4%). The overall incidence of VTE was 2.9% (95% CI, 2.0-3.8%), occurring in 5.4% (95% CI, 1.9-8.9%) of the high-, 3.2% (95% CI, 2.0-4.4%) of the intermediate- and 1.4% (95% CI, 0.3-2.6%), of the low-risk groups. High-risk patients were more likely than low-risk patients to have VTE (OR, 3.9; 95% CI, 1.4-11.2). Conclusion The Khorana score is predictive of in-hospital, symptomatic VTE development in cancer patients who are hospitalized for medical reasons and may be a useful tool for tailoring inpatient anticoagulant thromboprophylaxis.

McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome

Background The McMaster RARE-Bestpractices project group selected the catastrophic antiphospholipid syndrome (CAPS) for a pilot exercise in guideline development for a rare disease. Objectives The objectives of this exercise were to provide a proof of principle that guidelines can be developed for rare diseases and assist in clinical decision making for CAPS. Patients/Methods The GIN-McMaster Guideline Development checklist and GRADE methodology were followed throughout the guideline process. The CAPS guideline was coordinated by a steering committee, and the guideline panel was formed with representation from all relevant stakeholder groups. Systematic reviews were performed for the key questions. To supplement the published evidence, we piloted novel methods, including use of an expert-based evidence elicitation process and ad hoc analysis of registry data. Results This paper describes the CAPS guideline recommendations, including evidence appraisal and discussion of special circumstances and implementation barriers identified by the panel. Many of these recommendations are conditional, because of subgroup considerations in this heterogeneous disease, as well as variability in patient values and preferences. Conclusions The CAPS clinical practice guideline initiative met the objective of the successful development of a clinical practice guideline in a rare disease using GRADE methodology. We expect that clinicians caring for patients with suspected CAPS will find the guideline useful in assisting with diagnosis and management of this rare disease.