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Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding. Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years;incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p<0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality;the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. [Formula presented] Disclosures: Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy;Bayer: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees;Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Calithera: Membership on an entity's Board of Directors or advisory committees;Tempus: Research Funding;Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees;Tempus: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Dendreon: Consultancy;Caris: Other: Serves as a molecular tumor board;Vividion: Consultancy;Sorrento Therapeutics: Consultancy;Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria;CSL Behring: Research Funding;Alnylam: Consultancy;Bristol-Myers Squibb: Honoraria;takeda: Honoraria;Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding;BMS: Consultancy, Research Funding;Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees;Do a: Consultancy, Membership on an entity's Board of Directors or advisory committees.
ABSTRACT
Introduction: Circulating Cellular Clusters (CCCs) have been studied in the context of cancer;however, CCCs in other inflammatory conditions, such as COVID-19, have not been explored. Hypothesis: CCC phenotypes play a role in immunothrombosis and in the development of adverse events. Methods: Blood samples were collected from patients with a positive SARS-CoV2 PCR treated at the Massachusetts General Hospital. Imaging flow cytometry was used to characterize CCCs, including: platelet-leukocyte aggregates (PLAs), leukocyte clusters (LCs) and platelet-erythrocyte aggregates (PEAs) (Fig1A). CCC phenotypes were compared with controls and were correlated with clinical outcomes. CCCs identified to be significant were used to guide a computational model investigating the mechanism of CCC formation and their behavior in circulation (Fig1C). Results: Forty-six COVID-19 and 12 control samples were analyzed. Statistically significant positive correlations were identified between CCCs and clinical outcomes in patients with COVID19 (Fig1B). Using these data as inputs, computational simulations illustrated that CCCs may form in the circulation and be recruited by existing thrombi and sites of inflammation, or may detach from thrombogenic sites (Fig1D). Conclusions: CCCs are correlated with the development of significant clinical outcomes and cluster phenotypes appear to be associated with specific outcomes. CCCs may form de novo in the circulation or via the detachment from a thrombus. These CCCs may subsequently attach to a second thrombus downstream or serve as their own nidus for thrombus development, resulting in vessel lumen occlusion. Computational modeling serves as a powerful tool for the exploration of the pathophysiological mechanism by which CCCs contribute to thrombus formation. These findings may serve as novel biomarkers and aid in the identification of new drug targets for immunothrombotic complications in severe inflammatory conditions.
ABSTRACT
Introduction: Severe COVID-19 has been associated with aberrant coagulation factor activities, particularly in patients with a thrombotic event (TE). Management of anticoagulant is critical in the care of hospitalized patients with COVID-19.Hypothesis: Evaluation of a point-of-care (POC), functional, clot-time-based coagulation test to detect the anticoagulant effect of therapeutic unfractionated heparin (UFH) in hospitalized SARS-CoV-2-positive patients who developed a TE. Methods: An IRB-approved analysis of 36 citrated plasma specimens from 26 SARS-CoV-2-positive patients and 10 matched negative controls was performed. A Clotting Time Score (CTS), a measure of factor-specific inhibition (i.e. anticoagulant activity), was derived for each patient. CTS results were compared with traditional coagulation tests. Five UFH COVID-19 samples with low CTS scores (<10) were spiked with uniform dosing of UFH, low molecular weight heparin (LMWH), apixaban, or argatroban and retested to assess anticoagulation response. Results: The CTS detected subtherapeutic UFH anticoagulation levels more frequently in COVID-19 cases compared with controls (76% vs. 17%). Prothrombin Times, activated Partial Thromboplastin Times, anti-Xa levels, and antithrombin activity did not correlate with each other or with the CTS in the COVID-19 samples. CTS correlated with both FV and Factor X activity (R =0.49, Spearman R=-0.68), which form the prothrombinase complex. The CTS was 94% sensitive and 67% specific for the occurrence of TEs in patients on UFH. CTS demonstrated a consistent anticoagulant response only to argatroban (100%) compared with other anticoagulants (60%). Conclusions: The CTS, generated using a novel, low-volume, rapid POC coagulation test is a strong indicator of the therapeutic effect of UFH anticoagulation in COVID-19 patients and may provide a predictive measure of TEs potentially occurring from anticoagulation resistance.
ABSTRACT
[Formula presented] Background: Coronavirus disease-2019 (COVID-19) is an inflammatory, multisystem infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) and is associated with increased risk of thrombosis, particularly among critically ill patients. The myeloproliferative neoplasms (MPNs) include Philadelphia chromosome-negative (Ph-negative) MPNs polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), and Philadelphia-chromosome positive chronic myeloid leukemia (CML). Patients with MPNs, especially PH-negative, have increased risk of thrombotic complications. Given the increased propensity of thrombosis and prognostic significance of thrombosis in both COVID and MPNs, defining the risk of thrombotic complications in this patient population compared to the general population is important. Methods: Using an institutional database within the Mass General Brigham integrated health network, we retrospectively analyzed 63 consecutive patients with MPN who were ≥ 18 years old and tested positive for SARS-COV-2 infection based on polymerase chain reaction (PCR) testing from March 1, 2020 to January 1, 2021. We compared patients admitted to the hospital in our “MPN cohort” with patients admitted to the hospital from a separate COVID-19 (non-MPN cohort) Mass General Brigham registry of 1114 consecutive patients who tested positive for SARS-COV-2 infection based on PCR testing from March 13, 2020 to April 3, 2020. Care was taken to ensure the cohorts were mutually exclusive. The 90-day primary outcome for MPN cohort was a composite of all-cause death, any thrombosis (composite of arterial and venous thromboembolism [VTE]), International Society on Thrombosis and Haemostasis (ISTH) defined major and clinically relevant non-major bleeding. To identify risk factors for primary outcome in MPN cohort we used a multivariable logistic regression using age, sex, hospital admission status, MPN type, cytoreduction for MPN, hypertension, smoking status, baseline anticoagulation (AC), prior thrombosis (stroke, myocardial infarction or VTE) as co-variables. The 90-day outcomes of interest in our MPN vs non-MPN cohort analysis were any thrombosis, death, ISTH major and clinically relevant non-major bleeding and readmission for any reason. To assess impact of MPN status in hospitalized patients in our MPN vs non-MPN comparison, we used a multivariable logistic regression using age, sex, race, Hispanic ethnicity, ICU admission, treatment with steroids and/or Remdesivir, baseline AC and aspirin use, prior thrombosis (stroke, myocardial infarction or VTE), diabetes, heart failure, admission hematocrit, platelet count and D-dimer as co-variables. Continuous variables were compared using student t-test and categorical variables were compared using Fischer's Exact Test with a p value of < 0.05 considered significant. Results: Of the 63 patients with MPN (23 with PV, 17 ET, 4 PMF, 15 CML, 4 other), 27 (43%) were admitted to the hospital for COVID-19 and 5 (8%) required ICU admission. The mean age of all MPN patients was 66, 84% were White, 8% Black and 10% Hispanic. Primary 90-day outcome occurred in 12 (19%) of MPN patients. In multivariable analysis, only admission to hospital was associated with increased odds of composite (aOR 21.11, 95% CI 2.38 - 546.40), Figure 1A. In patients with (n = 27) and without MPN (n = 399) who were admitted to the hospital, patients with MPN were older (mean age 70 vs 61, p = 0.0076), more likely to be White (89% vs 54%, p = 0.0004) and less likely to be Hispanic (7% vs 29%, p = 0.0158), less likely to be admitted to the ICU (19% vs 43%, p = 0.0138), and more likely to be treated with corticosteroids (30% vs 14%, p = 0.025) or remdesivir (41% vs 13%, p < 0.0001). After multivariable logistic regression, diagnosis of MPN was significantly associated with increased odds of thrombosis (aOR 5.38, 95% CI 1.15-25.38) and readmission (aOR 6.28, 95% CI 1.60-24.88), but not bleeding (aOR 3.51, 95% CI 0.62-18.87) or death (aOR 4.29, 95% CI 0.95-18.9 ), Figure 1B. Conclusions: Thrombotic complications are common in patients with MPN and COVID-19, particularly if hospitalized for COVID-19. After multivariable analysis, MPN patients admitted for COVID-19 had a significantly increased risk of thrombotic complications compared with non-MPN patients. [Formula presented] Disclosures: Al-Samkari: Dova/Sobi: Consultancy, Research Funding;Novartis: Consultancy;Argenx: Consultancy;Rigel: Consultancy;Amgen: Research Funding;Agios: Consultancy, Research Funding;Moderna: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding;BMS: Consultancy, Research Funding;Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees;Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fathi: Agios/Servier: Consultancy, Other: Clinical Trial Support;BMS: Consultancy, Other: Clinical Trial Support;AbbVie: Consultancy, Other: Clinical Trial Support;Pfizer: Consultancy;Trillium: Consultancy;Kura: Consultancy;Blueprint Medicines Corporation: Consultancy;Genentech: Consultancy;Novartis: Consultancy;Trovagene: Consultancy;Daiichi Sankyo: Consultancy;Novartis: Consultancy;Morphosys: Consultancy;Kite: Consultancy;Foghorn: Consultancy;Takeda: Consultancy;Amgen: Consultancy;Seattle Genetics: Consultancy;NewLink Genetics: Consultancy;Forty Seven: Consultancy;Ipsen: Consultancy. Goldhaber: Bayer: Consultancy, Research Funding;Boehringer-Ingelheim: Consultancy, Research Funding;BMS: Research Funding;Boston Scientific BTG EKOS: Research Funding;Daiichi: Research Funding;Janssen: Research Funding;Pfizer: Consultancy, Research Funding;Agile: Consultancy. Piazza: Portola: Research Funding;Bayer: Research Funding;Amgen: Research Funding;BMS: Research Funding;Janssen: Research Funding;BSC: Research Funding. Hobbs: Celgene/Bristol Myers Squibb: Consultancy;Novartis: Consultancy;Merck: Research Funding;Constellation Pharmaceuticals: Consultancy, Research Funding;Bayer: Research Funding;Incyte Corporation: Research Funding;AbbVie.: Consultancy.
ABSTRACT
Background : COVID-19 triggers a pro-inflammatory and prothrombotic state. The role of circulating cellular clusters in the setting of COVID-19 remains unclear. Aims : This study explores the phenotype of circulating clusters and their potential relationship with clinical outcomes in COVID-19 patients. Methods : Blood samples were collected between July -August 2020 from patients with a positive SARS-CoV2 PCR treated at a large academic medical center. Imaging flow cytometry was used to detect various circulating cellular clusters, including: platelet (plt)-leukocyte aggregates (PLAs: 1 leukocyte + plt), leukocyte clusters (LC: ≥2 leukocytes ± any other cell) and platelet-erythrocyte aggregates (PEAs: ≥1 erythrocyte + plt) (Figure 1). Cluster phenotypes were compared in patients with and without COVID-19 and were retrospectively correlated with clinical outcomes. Results : Forty-six COVID and 12 non-COVID samples were analyzed. Patients with COVID-19 had higher circulating PEAs (2.58% ± 0.12% vs 1.41% ± 0.72%, P = .001) and manually-counted PLAs (0.15% ± 0.11% vs. 0.06% ± 0.03% P = .007) compared to healthy controls. Table 1 shows the relationship between specific populations of clusters and clinical outcomes in patients with COVID-19. The presence of LCs, in particular, significantly correlated with thrombotic events ( P = 0.006), whereas PLAs and PEAs did not ( P = 0.73 and P = 0.9, respectively). Blood type was also correlated to LCs ( P = 0.021), with Type O having the least LCs, followed by Types A, AB and B. Conclusions : Circulating cellular clusters are correlated with significant clinical outcomes and cluster phenotypes appear to be associated with specific outcomes, including thrombotic events. These immuno-thrombotic complexes may play a significant role in the development of thrombosis and resultant end-organ damage. Further study of the role of the cellular component in COVID-19 may lead to the development of prediction models and help identify novel drug targets for inflammation-related thrombosis.
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Background: Patients (pts) with cancer have a high risk of venous thromboembolic (VTE) complications, further enhanced by anti-cancer treatments, specifically hormonal therapies, targeted therapies (VEGF inhibitors, other TKIs) and immune checkpoint inhibitors (ICIs). We hypothesized that high-risk therapies would predispose pts with cancer and COVID-19 to higher risk of VTE complications. Methods: CCC19 is the largest international registry (NCT04354701) recording outcomes of pts with cancer and COVID-19. The registry was queried for hospitalized pts who developed VTE and received systemic cancer treatment in the year prior to COVID-19. Incidence of VTE was analyzed as the primary endpoint;30-day any cause mortality & need for ICU admission at baseline were secondary endpoints in pts with and without VTE respectively. Pts were stratified by treatment type and time from last treatment dose: <2 wk, 2-4 wk, 1-3 months (mos), 3-12 mos. Results: As of February 9th 2021, 4217 hospitalized pts with complications data were present in the registry. 1867 (44%) pts had received systemic anti-cancer therapy within the year prior to COVID-19 and were analyzed. There were a total of 186 (10%) VTE events. Of these, VTE incidence was 141 (10.5%) in pts with solid tumors and 57 (9%) in pts with hematologic malignancies. Overall 30-day mortality was 20% and 22% in pts with and without VTE respectively, while direct admission to ICU at presentation was seen in 17% and 10% of pts with and without VTE, respectively. Treatment timing and drug exposures are below (Table). Receipt of systemic anti-cancer treatment within 3 mos vs 3-12 mos was associated with increased rate of VTE, OR 2.44, 95% CI 1.18-5.84, p=0.011 (univariate Fisher test). Conclusions: We describe the incidence of VTE events in pts with cancer and COVID-19 with recent systemic cancer therapy. ICI and VEGFi were associated with numerically higher rates of VTE;other examined drugs and drug classes were not. Timing of therapy appears to modify risk of VTE. Although retrospective, with possible selection and confounding biases, our analysis suggests that factors other than anticancer drug exposures may drive VTE events in this population.