COVID-19 and venous thromboembolism: A narrative review

COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) is associated with coagulopathy through numerous mechanisms. The reported incidence of venous thromboembolism (VTE) in hospitalized patients with COVID-19 has varied widely, and several meta-analyses have been performed to assess the overall prevalence of VTE. The novelty of this coronavirus strain along with its unique mechanisms for microvascular and macrovascular thrombosis has led to uncertainty as to how to diagnose, prevent, and treat thrombosis in patients affected by this virus. This review discusses the epidemiology and pathophysiology of thrombosis in the setting of SARS-CoV-2 infection along with an updated review on the preventative and treatment strategies for VTE associated with SARS-CoV-2 infection

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

IMPORTANCE: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. OBJECTIVE: To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. EXPOSURE: Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. MAIN OUTCOMES AND MEASURES: Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. RESULTS: Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). CONCLUSIONS AND RELEVANCE: In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer

Loss of Gata1 but Not Gata2 Converts Erythropoiesis to Myelopoiesis in Zebrafish Embryos

AbstractThe differentiation of hematopoietic progenitors into erythroid or myeloid cell lineages is thought to depend upon relative levels of the transcription factors gata1 and pu.1. While loss-of-function analysis shows that gata1 is necessary for terminal erythroid differentiation, no study has demonstrated that loss of gata1 alters myeloid differentiation during ontogeny. Here we provide in vivo evidence that loss of Gata1, but not Gata2, transforms primitive blood precursors into myeloid cells, resulting in a massive expansion of granulocytic neutrophils and macrophages at the expense of red blood cells. In addition to this fate change, expression of many erythroid genes was found to be differentially dependent on Gata1 alone, on both Gata1 and Gata2, or independent of both Gata factors, suggesting that multiple pathways regulate erythroid gene expression. Our studies establish a transcriptional hierarchy of Gata factor dependence during hematopoiesis and demonstrate that gata1 plays an integral role in directing myelo-erythroid lineage fate decisions during embryogenesis

The CoVID- TE risk assessment model for venous thromboembolism in hospitalized patients with cancer and COVID- 19

BackgroundHospitalized patients with COVID- 19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well- known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID- 19 is lacking.ObjectivesTo assess the incidence of and risk factors for thrombosis in hospitalized patients with cancer and COVID- 19.MethodsAmong patients with cancer in the COVID- 19 and Cancer Consortium registry (CCC19) cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID- 19- associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap.ResultsFrom March 17, 2020 to November 30, 2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti- cancer therapy. A simplified RAM for VTE was derived and named CoVID- TE (Cancer subtype high to very- high risk by original Khorana score +1, VTE history +2, ICU admission +2, D- dimer elevation +1, recent systemic anti- cancer Therapy +1, and non- Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low- risk, 0- 2 points, n = 1423 vs. high- risk, 3+ points, n = 1034) where VTE occurred in 4.1% low- risk and 11.3% high- risk patients (c statistic 0.67, 95% confidence interval 0.63- 0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission.ConclusionsHospitalized patients with cancer and COVID- 19 have elevated thrombotic risks. The CoVID- TE RAM for VTE prediction may help real- time data- driven decisions in this vulnerable population.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170302/1/jth15463_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170302/2/jth15463.pd

Incidence of and Risk Factors for Venous Thromboembolism Among Hospitalized Patients with Cancer and COVID-19: Report from the COVID-19 and Cancer Consortium (CCC19) Registry

Introduction: Hospitalized patients with COVID-19 may have increased risk of venous thromboembolism (VTE) and pulmonary embolism (PE). Cancer and anti-cancer therapies are well-known additional risk factors for VTE. Nonetheless, the VTE risk in patients with both cancer and COVID-19 infection remains unknown as recent studies have not found an association due to sample size limitations. We report the incidence of and risk factors for VTE and PE among hospitalized patients with cancer and COVID-19. Methods: The COVID-19 and Cancer Consortium (CCC19) developed an international retrospective cohort study (NCT04354701) to investigate the clinical course and complications of COVID-19 among adult patients with an active or previous history of cancer. For the current study, cumulative incidences of clinically detected VTE and PE were analyzed among hospitalized patients with laboratory confirmed SARS-CoV-2. Pre-specified subgroup analysis was performed to examine the interaction between intensive care unit (ICU) admission and recent anti-cancer therapy on VTE outcomes. Bivariable logistic regression analyses were conducted to assess the association between baseline variables and VTE; unadjusted odds ratios (OR) and 95% confidence interval (CI) were reported. These variables included age, sex, obesity (BMI>30), race/ethnicity, performance status, comorbidities, blood type, history of VTE, recent surgery, recent anti-cancer therapy, cancer subtype VTE risk grouping (adapted from Khorana Score), pre-admission anticoagulant or antiplatelet use, and ICU admission status. Results: From March 17, 2020 to July 31, 2020, 3914 patients were enrolled in the CCC19 registry. For the present analysis, patients were excluded if they had inadequate follow-up <4 weeks (n=950), were not admitted to the hospital (n=1008), or had unknown VTE outcomes (n=327). Among the 1629 hospitalized patients, the median follow-up was 35 days. Patients were comprised from 3 countries (92% US, 6% Canada, 2% Spain), with a median age of 70, 45% female, and a median comorbidity score of 3. Racial/ethnic breakdown included 44% White, 26% Black, 14% Hispanic, and 13% Other. A past history of VTE was reported in 9% of patients; pre-admission anticoagulant use and antiplatelet use were reported in 25% and 35% of patients, respectively. The most common cancer types included prostate (18%), breast (15%), and lymphoma (14%). Based on the VTE risk grouping adapted from the original Khorana Score, 34% were low-risk, 29% were high-risk, and 6% were very high-risk. The receipt of anti-cancer therapy within 3 months of diagnosis was observed in 39% of patients (17% cytotoxic chemotherapy, 11% targeted therapy, 7% endocrine therapy, and 5% immunotherapy). The overall incidence of inhospital VTE and PE was 9.3% and 5.2%, respectively. The corresponding estimates were 13.4% and 7.9% among the ICU subgroup. On bivariable analysis, significant predictors of VTE included ICU admission, recent anti-cancer therapy, active cancer status, cancer subtype VTE risk grouping, and pre-admission antiplatelet use (Table 1). Pre-admission anticoagulant use had significant associations with PE but not VTE. Multivariable adjustment is ongoing to identify independent risk factor for VTE and clarify the impact of pre-admission anticoagulant/antiplatelet use controlled for other potential confounders. Both ICU admission status and anti-cancer therapy increased the risk of VTE independently. Non-ICU patients not on anti-cancer therapy had the lowest incidence of VTE (4.5%), whose estimate was similar to that reported in the non-cancer hospitalized population with COVID-19 infection. Patients with either ICU admission or recent anti-cancer therapy had the intermediate risk (11.0%), whereas ICU patients with recent anti-cancer therapy had the highest risk (16.7%). We did not observe confounding or effect modification by the ICU subgroup on the association between anti-cancer therapy and VTE. Conclusion: In this cohort study of hospitalized patients with cancer and COVID-19, recent anti-cancer therapy, active disease, high-risk VTE cancer subtypes, and ICU admission have increased risk of VTE and PE, while pre-admission anticoagulant/antiplatelet therapy may reduce the risk. This information will aid in developing a risk prediction tool for VTE in hospitalized patients with cancer and COVID-19. Disclosures Kuderer: G1 Therapeutics: Consultancy; Total Health: Consultancy; Invitae: Consultancy; Beyond Springs: Consultancy; Bristol-Myers Squibb: Consultancy; celldex: Consultancy; Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Janssen: Consultancy. Warner:HemOnc.orgLLC: Other: Shareholder/Stockholder/Stock options; IBM Watson Health: Consultancy; Westat: Consultancy; National Cancer Institute: Research Funding. Shah:American Cancer Society and the Hope Foundation for Cancer Research: Research Funding; National Cancer Institute: Research Funding. Zon:Amagma Therapeutics.: Consultancy, Other: stockholder. Shah:Aspen Pharma: Research Funding. Gulati:Puma Biotechnology: Consultancy; AstraZeneca: Research Funding; Isoray: Research Funding. Khaki:Merck: Other: share/stockholder; Pfizer: Other: share/stockholder. Thompson:AIM Specialty Health, BMS, GlaxoSmithKline, Takeda, Via Oncology: Membership on an entity's Board of Directors or advisory committees; Synapse Precision Medical Council: Other: Travel expenses; Doximity: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Grivas:Oncogenex: Research Funding; Immunomedics: Research Funding; Debiopharm: Research Funding; Bavarian Nordic,: Research Funding; QED Therapeutics: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria; Pfizer: Honoraria, Research Funding; Mirati Therapeutics: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria; Heron Therapeutics: Honoraria; GlaxoSmithKline: Honoraria; Genzyme: Honoraria; Genentech: Honoraria, Research Funding; Foundation Medicine: Honoraria; Exelixis: Honoraria; EMD Serono: Honoraria; Driver: Honoraria; Clovis Oncology: Honoraria, Research Funding; Bristol-Myers Squibb,: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biocept: Honoraria; Bayer: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding. de Lima Lopes:Bavarian Nordic: Research Funding; NOVARTIS: Research Funding; Tesaro: Research Funding; GSK: Research Funding; G1 Therapeutics: Research Funding; adaptimmune: Research Funding; BMS: Research Funding; Lilly: Research Funding; Merck Sharp & Dohme: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Boehringer Ingelheim: Honoraria; Janssen: Research Funding; rgenix: Research Funding; Blueprint Medicines: Research Funding; Genentech: Research Funding; Roche: Research Funding; EMD Serono: Research Funding. Shyr:Roche: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Johnson & Johnson: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Eisai: Speakers Bureau. Pennell:Merck: Consultancy; Cota: Consultancy; Inivata: Consultancy; G1 Therapeutics: Consultancy; Astrazeneca: Consultancy; BMS: Consultancy; Eli Lilly: Consultancy; Amgen: Consultancy; Genentech: Consultancy. Friese:Eli Lilly: Consultancy; Patient-Centered Outcomes Research Institute: Membership on an entity's Board of Directors or advisory committees; Agency for Healthcare Research and Quality: Research Funding; National Cancer Institute: Research Funding; Merck Foundation: Research Funding; National Comprehensive Cancer Network: Research Funding; Pfizer: Research Funding; Eli Lilly: Consultancy. Patel:reast Cancer Research Foundation: Research Funding; Sanofi: Research Funding; Odonate Therapeutics: Research Funding; Radius: Honoraria; Genentech: Research Funding. Halmos:Foundation Medicine: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Guardant Health: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Boehringer-Ingelheim: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Eli-Lilly: Research Funding; Advaxis: Research Funding; Mirati: Research Funding; Takeda: Research Funding; GSK: Research Funding; AbbVie: Research Funding; Genentech: Consultancy; TPT: Consultancy. Choueiri:Pfizer: Consultancy, Honoraria, Research Funding; Pionyr: Consultancy, Other; Merck: Consultancy, Honoraria, Research Funding; Roche Products Limited: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Lilly: Consultancy, Research Funding; Peloton: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Tempest: Consultancy, Other; Lilly Ventures: Consultancy; International Patent Application No. PCT/US2018/12209, entitled "PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response," filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017: Patents & Royalties; Prometheus Labs: Consultancy, Honoraria, Research Funding; Corvus: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb/ER Squibb and sons LLC: Consultancy, Honoraria, Research Funding; Cerulean: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; oundation Medicine Inc.: Consultancy, Honoraria, Research Funding; International Patent Application No. PCT/US2018/058430, entitled "Biomarkers of Clinical Response and Ben

Transferrin-a modulates hepcidin expression in zebrafish embryos

The iron regulatory hormone hepcidin is transcriptionally up-regulated in response to iron loading, but the mechanisms by which iron levels are sensed are not well understood. Large-scale genetic screens in the zebrafish have resulted in the identification of hypochromic anemia mutants with a range of mutations affecting conserved pathways in iron metabolism and heme synthesis. We hypothesized that transferrin plays a critical role both in iron transport and in regulating hepcidin expression in zebrafish embryos. Here we report the identification and characterization of the zebrafish hypochromic anemia mutant, gavi, which exhibits transferrin deficiency due to mutations in transferrin-a. Morpholino knockdown of transferrin-a in wild-type embryos reproduced the anemia phenotype and decreased somite and terminal gut iron staining, while coinjection of transferrin-a cRNA partially restored these defects. Embryos with transferrin-a or transferrin receptor 2 (TfR2) deficiency exhibited low levels of hepcidin expression, however anemia, in the absence of a defect in the transferrin pathway, failed to impair hepcidin expression. These data indicate that transferrin-a transports iron and that hepcidin expression is regulated by a transferrin-a–dependent pathway in the zebrafish embryo