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in category hematology

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1: Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
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Posted 12 Feb 2020

Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
9,389 downloads medRxiv hematology

Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, Mao Qiang, Jianglin Xiang, Bangshuo Zhang, Yongping Chen

BackgroundTo explore the cellular immunity and cytokines status of NCP patients and to predict the correlation between the cellular immunity levels, cytokines and the severity of patients. Methods123 NCP patients were divided into mild and severe groups. Peripheral blood was collected, lymphocyte subsets and cytokines were detected. Correlation analysis was performed on the lymphocyte subsets and cytokines, and the differences between the indexes of the two groups were analyzed. Results102 mild and 21 severe patients were included. Lymphocyte subsets were reduced in two groups. The proportion of CD8 + T reduction in the mild and severe group was 28.43% and 61.9%, respectively; The proportion of B cell reduction was 25.49% and 28.57%; The proportion of NK cell reduction was 34.31% and 47.62%; The detection value of IL-6 was 0 in 55.88% of the mild group, mild group has a significantly lower proportion of patients with IL-6 higher than normal than severe group; There was no significant linear correlation between the lymphocyte subsets and cytokines, while significant differences were noticed between the two groups in CD4 + T, CD8 + T, IL-6 and IL-10. ConclusionsLow levels of CD4+T and CD8+T are common in severe NCP. IL-6 and IL-10 levels were higher in severe patients. T cell subsets and cytokines can be used as one of the basis for predicting the transition from mild to severe. Large number of samples are still needed to confirm the "warning value" of CD4 + T, CD8 + T IL-6 and IL-10.

2: Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients
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Posted 30 Jun 2020

Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients
4,264 downloads medRxiv hematology

Tiffany Thomas, Davide Stefanoni, Monika Dzieciatkowska, Aaron Issaian, Travis Nemkov, Ryan C Hill, Richard O Francis, Krystalyn E Hudson, Paul W Buehler, James C Zimring, Eldad A Hod, Kirk C Hansen, Steven L Spitalnik, Angelo D'Alessandro

The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly-diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, especially short and medium chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, and mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading, RBCs from COVID-19 patients may be incapable of responding to environmental variations in hemoglobin oxygen saturation when traveling from the lungs to peripheral capillaries and, as such, may have a compromised capacity to transport and deliver oxygen.

3: Recommendations for standardized management of CML patients in the core epidemic area of COVID-19(Multi-center survey results in Hubei Province, China)
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Posted 16 Mar 2020

Recommendations for standardized management of CML patients in the core epidemic area of COVID-19(Multi-center survey results in Hubei Province, China)
4,149 downloads medRxiv hematology

Dan-Yu Wang, Jing-Ming Guo, Zhuang-Zhi Yang, Guo-Lin Yuan, Li Meng, Wei-Ming Li

BackgroundSince late December 2019, the outbreak of the novel coronavirus disease, COVID-19, that began in Wuhan, has become endemic in China and more than 100 countries and regions in the world. There is no report about the prevalence of COVID-19 in CML patients untill now. We aimed to describe the clinical course, outcomes of CML patients with COVID-19 and prevalence of COVID-19 in CML patients. MethodsIn this multi-center survey, cross-sectional survey, observational study, the clinical data of CML patients with COVID-19 in each center were collected. Simultaneously, an online survey was conducted for information about the CML patients under the management at each center by asking the CML patients to complete a questionnaire,from February 15, 2020 to February 21, 2020. The questionnaire includes demographic data, place of residence, smoking status, CML diagnosis and treatment, comorbidities, combined medications, epidemiological history, symptoms(fever, cough, shortness of breath, etc) during the epidemic. Additional clinical data was collected on respondents suspected or confirmed to have COVID-19. We described and analyzed the prevalence of COVID-19 in CML patients, and focus on the clinical characteristics and outcomes of COVID-19 patients. Data were compared between the CML patients with optimal response and those with non-optimal response. The primary outcome was prevalence of COVID-19 in CML patients, as of Feb 21, 2020. Secondary outcomes included the history of epidemiology of CML patients, the clinical characteristics and outcomes of CML patients with COVID-19. FindingsOf 392 respondents, 223(56.9%) were males, and 240(61.2%) were 50 years or younger. Only 10 patients took drugs irregularly due to the influence of the epidemic because of traffic control, pharmacies unable to operate normally, etc. In the history of epidemiology, there were 4 patients with definite contact with COVID-19, of which 3 were remote contact and 1 was close contact. 12 respondents had fever, cough or shortness of breath during the epidemic, 1 case (common type) was confirmed with COVID-19 and cured after treatment. 1 patient was clinically diagnosed and succumbed. 1 of 299 (0.3%) patients with an optimal response was diagnosed with COVID-19. Of the 50 patients who failed to respond to CML treatment or had a poor response, 1 patient (2%) had a clinical diagnosis of COVID-19. InterpretationWhile the 392 CML respondents required regular referrals to hospitals, they did not have much contact with COVID-19 patients during the outbreak. Patients who failed to achieved an optimal response to CML therapy appear more likely to have a symptomatic infection with SARS-CoV-2. Older patients with comorbidities are at increased risk of death. FundingThis work was supported by grants from the National Natural Science Foundation of China(NSFC)(81873440&81700142).

4: Delayed-Phase Thrombocytopenia in Patients of Coronavirus Disease 2019 (COVID-19)
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Posted 15 Apr 2020

Delayed-Phase Thrombocytopenia in Patients of Coronavirus Disease 2019 (COVID-19)
4,048 downloads medRxiv hematology

Hao Zhou, Wanxin Chen, Ziping Li, Bohan Yang, Qiong Zhou, Ping Wang, Jianhua Zhu, Xuexing Chen, Peng Yang

The pandemic COVID19 pneumonia has engulfed the entire world. Hematopoietic system can also be affected by COVID19. Thrombocytopenia at admission was prevalent, while late phase or delayed phase thrombocytopenia is obscure. This retrospective case series analyzed patients with COVID19 at the Union Hospital, Wuhan, China, from January 25th to March 9th, 2020. Analysis began on March 11th, 2020. COVID19 associated delayed phase thrombocytopenia was occurred in 11.8% percent of enrolled patients. The delayed phase thrombocytopenia in COVID19 is prone to develop in elderly patients or patients with low lymphocyte count on admission. The delayed-phase thrombocytopenia is significantly associated with increased length of hospital stay and higher ICU admission rate. Delayed phase nadir platelet counts demonstrated a high and significantly negative linear correlation with B cell percentages and serum IL 6 levels. We also presented bone marrow aspiration pathology of three patients with delayed phase thrombocytopenia, showing impaired maturation of megakaryocytes. We speculated that the delayed phase platelet destruction might be mediated by antibodies, and suggest immunoregulatory treatment in severe patients to improve outcomes. Besides, clinicians need to pay attention to the delayed phase thrombocytopenia especially at 3 to 4 weeks after symptom onset.

5: Meta-Analysis of Risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia Following ChAdOx1-S Recombinant Vaccine
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Posted 08 May 2021

Meta-Analysis of Risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia Following ChAdOx1-S Recombinant Vaccine
3,233 downloads medRxiv hematology

Benjamin T.B. Chan, Pavlos Bobos, Ayodele Odutayo, Menaka Pai

Context: Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported after administering ChAdOx1-S recombinant COVID-19 vaccine (marketed as Vaxzevira by Astra Zeneca, Covishield). Estimates of incidence vary between countries, due to different age distributions chosen, case definitions and choice of denominator (persons vaccinated vs immunizations given). This study clarifies these estimates by pooling data from ten countries and examining differences by age group. Methods: We examined case reports, press releases and immunization data and calculated pooled estimates of VITT incidence using random effects models. Sensitivity analyses considered different combinations of countries and varying assumptions on time between vaccination and reporting of cases. Results: Pooling all countries, VITT incidence was 0.73 per 100,000 persons receiving first dose of Covishield/Vaxzevira [95% CI .43,1.23]. Incidence for age 65 and over was 0.11 per 100,000 persons [95% CI .05-.26], and significantly higher among those under age 55: 1.67 per 100,000 persons [95% CI 1.30-2.14] in the UK, 5.06 per 100,000 persons in Norway [95% CI 2.16, 11.86]. The latter had the best data on counts of persons vaccinated. Incidence for age 55 to 64 years was 0.34 [95% CI 0.13, 0.85] in the UK, lower than for under age 55. Conclusion: VITT is a rare vaccine-associated adverse event. Incidence estimates vary between jurisdictions. However, even the highest reported incidence from Norway is low - and in settings with high community transmission, lower than risk of serious outcomes associated with Covid-19. Policymakers and individuals can use these data to calculate risk-benefit ratios and better target vaccine distribution.

6: Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients
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Posted 15 May 2021

Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients
3,191 downloads medRxiv hematology

Adolfo Aleman, Oliver Van Oekelen, Bhaskar Upadhyaya, Sarita Agte, Katerina Kappes, Katherine Beach, Komal Srivastava, Charles R Gleason, PVI study group, Bo Wang, Tarek H Mouhieddine, Kevin Tuballes, Daniel Geanon, Zenab Khan, Ana S. Gonzalez-Reiche, Harm van Bakel, Konstantinos Mouskas, Nicole W. Simons, Alexander W Charney, Seunghee Kim-Schulze, Adeeb H Rahman, Emilia M. Sordillo, Florian M Krammer, Carlos Cordon-Cardo, Nina Bhardwaj, Sacha Gnjatic, Miriam Merad, Brian D. Brown, Larysa Sanchez, Ajai Chari, Sundar Jagannath, Viviana Simon, Ania Wajnberg, Samir Parekh

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly effective in healthy individuals. Patients with multiple myeloma (MM) are immunocompromised due to defects in humoral and cellular immunity as well as immunosuppressive therapies. The efficacy after two doses of SARS-CoV-2 mRNA vaccination in MM patients is currently unknown. Here, we report the case of a MM patient who developed a fatal SARS-CoV-2 infection after full vaccination while in remission after B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T treatment. We show that the patient failed to generate antibodies or SARS-CoV-2-specific B and T cell responses, highlighting the continued risk of severe coronavirus disease 2019 (COVID-19) in vaccine non-responders. In the largest cohort of vaccinated MM patients to date, we demonstrate that 15.9% lack SARS-CoV-2 spike antibody response more than 10 days after the second mRNA vaccine dose. The patients actively receiving MM treatment, especially on regimens containing anti-CD38 and anti-BCMA, have lower antibody responses compared to healthy controls. Thus, it is of critical importance to monitor this patient population for serological responses. Non-responders may benefit from ongoing public health measures and from urgent study of prophylactic treatments to prevent SARS-CoV-2 infection.

7: COVID-19 infections and outcomes in patients with multiple myeloma in New York City: a cohort study from five academic centers
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Posted 11 Jun 2020

COVID-19 infections and outcomes in patients with multiple myeloma in New York City: a cohort study from five academic centers
2,286 downloads medRxiv hematology

Malin Hultcrantz, Joshua Richter, Cara Rosenbaum, Dhwani Patel, Eric Smith, Neha Korde, Sydney Lu, Sham Mailankody, Urvi Shah, Alexander Lesokhin, Hani Hassoun, Carlyn Tan, Francesco Maura, Andriy Derkach, Benjamin Diamond, Adriana Rossi, Roger N Pearse, Deppu Madduri, Ajai Chari, David Kaminetzky, Marc Braunstein, Christian Gordillo, Faith Davies, Sundar Jagannath, Ruben Niesvizky, Suzanne Lentzsch, Gareth Morgan, Ola Landgren

Importance: New York City is a global epicenter for the SARS-CoV-2 outbreak with a significant number of individuals infected by the virus. Patients with multiple myeloma have a compromised immune system, due to both the disease and anti-myeloma therapies, and may therefore be particularly susceptible to coronavirus disease 2019 (COVID-19); however, there is limited information to guide clinical management. Objective: To assess risk factors and outcomes of COVID-19 in patients with multiple myeloma. Design: Case-series. Setting: Five large academic centers in New York City. Participants: Patients with multiple myeloma and related plasma cell disorders who were diagnosed with COVID-19 between March 10th, 2020 and April 30th, 2020. Exposures: Clinical features and risk factors were analyzed in relation to severity of COVID-19. Main Outcomes and Measures: Descriptive statistics as well as logistic regression were used to estimate disease severity reflected in hospital admissions, intensive care unit (ICU) admission, need for mechanical ventilation, or death. Results: Of 100 multiple myeloma patients (male 58%; median age 68, range 41-91) diagnosed with COVID-19, 74 (74%) were admitted; of these 13 (18%) patients were placed on mechanical ventilation, and 18 patients (24%) expired. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes (ICU-admission, mechanical ventilation, or death): hypertension (N=56) odds ratio (OR) 2.3 (95% confidence interval [CI] 0.9-5.9); diabetes (N=18) OR 1.1 (95% CI 0.3-3.2); age >65 years (N=63) OR 2.0 (95% CI 0.8-5.3); high dose melphalan with autologous stem cell transplant <12 months (N=7) OR 1.2 (95% CI 0.2-7.4), IgG<650 mg/dL (N=42) OR=1.2 (95% CI 0.4-3.1). In the entire series of 127 patients with plasma cell disorders, hypertension was significantly associated with the combined end-point (OR 3.4, 95% CI 1.5-8.1). Conclusions and Relevance: Although multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.

8: Integrated analysis of bulk multi omic and single-cell sequencing data confirms the molecular origin of hemodynamic changes in Covid-19 infection explaining coagulopathy and higher geriatric mortality
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Posted 29 Apr 2020

Integrated analysis of bulk multi omic and single-cell sequencing data confirms the molecular origin of hemodynamic changes in Covid-19 infection explaining coagulopathy and higher geriatric mortality
2,222 downloads medRxiv hematology

Shreya Johri, Deepali Jain, Ishaan Gupta

Besides severe respiratory distress, recent reports in Covid-19 patients have found a strong association between platelet counts and patient survival. Along with hemodynamic changes such as prolonged clotting time, high fibrin degradation products and D-dimers, increased levels of monocytes with disturbed morphology have also been identified. In this study, through an integrated analysis of bulk RNA-sequencing data from Covid-19 patients with data from single-cell sequencing studies on lung tissues, we found that most of the cell-types that contributed to the altered gene expression were of hematopoietic origin. We also found that differentially expressed genes in Covid-19 patients formed a significant pool of the expressing genes in phagocytic cells such as Monocytes and Platelets. Interestingly, while we observed a general enrichment for Monocytes in Covid-19 patients, we found that the signal for FCGRA3+ Monocytes was depleted. Further, we found evidence that age-associated gene expression changes in Monocytes and Platelets, associated with inflammation, mirror gene expression changes in Covid-19 patients suggesting that pro-inflammatory signalling during aging may worsen the infection in older patients. We identified more than 20 genes that change in the same direction between Covid-19 infection and aging cells that may act as potential therapeutic targets. Of particular interest were IL2RG, GNLY and GMZA expressed in Platelets, which facilitates cytokine signalling in Monocytes through an interaction with Platelets. To understand whether infection can directly manipulate the biology of Monocytes and Platelets, we hypothesize that these non-ACE2 expressing cells may be infected by the virus through the phagocytic route. We observed that phagocytic cells such as Monocytes, T-cells, and Platelets have a significantly higher expression of genes that are a part of the Covid-19 viral interactome. Hence these cell-types may have an active rather than a reactive role in viral pathogenesis to manifest clinical symptoms such as coagulopathy. Therefore, our results present molecular evidence for pursuing both anti-inflammatory and anticoagulation therapy for better patient management especially in older patients.

9: In-depth Analysis of Laboratory Parameters Reveals the Interplay Between Sex, Age and Systemic Inflammation in Individuals with COVID-19
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Posted 11 Aug 2020

In-depth Analysis of Laboratory Parameters Reveals the Interplay Between Sex, Age and Systemic Inflammation in Individuals with COVID-19
2,076 downloads medRxiv hematology

Felipe ten-Caten, Patricia Gonzalez-Dias, Icaro Castro, Rodrigo Ogava, Jeevan Giddaluru, Juan CS Silva, Felipe Martins, Andre NA Goncalves, Andre G Costa-Martins, Jose D Araujo, Ana C Viegas, Fernando Q. Cunha, Sandra Farsky, Fernando A. Bozza, Anna S Levin, Pia S Pannaraj, Thushan I de Silva, Paola Minoprio, Bruno B. Andrade, Fabiano P da Silva, Helder I Nakaya

Introduction: The progression and severity of the coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), varies significantly in the population. While the hallmarks of SARS-CoV-2 and severe COVID-19 within routine laboratory parameters are emerging, little is known about the impact of sex and age on these profiles. Methods: We performed multidimensional analysis of millions of records of laboratory parameters and diagnostic tests for 178,887 individuals, of which 33,266 tested positive for SARS-CoV-2. These included complete blood cell count, electrolytes, metabolites, arterial blood gases, enzymes, hormones, cancer biomarkers, and others. Results: COVID-19 induced more alterations in the laboratory parameters in males compared to females between 13 and 60 years old, in contrast to older individuals, where several parameters were altered by COVID-19 in both men and women. Biomarkers of inflammation, such as C-reactive protein (CRP) and ferritin, were increased especially in older men with COVID-19, whereas other markers such as abnormal liver function tests were common across several age groups, except for young women. Low peripheral blood basophils and eosinophils were also more common in the elderly with COVID-19. Both male and female COVID-19 patients admitted to the intensive care unit (ICU) displayed alterations in the coagulation system, and higher levels of neutrophils, CRP, lactate dehydrogenase (LDH), among others. Discussion: Our study uncovers the laboratory profile of a large cohort of COVID-19 patients that underly discrepancies influenced by aging and biological sex. These profiles directly link COVID-19 disease presentation to an intricate interplay between sex, age and the immune response.

10: Blood group A Secretors are associated with a higher risk of COVID-19 cardiovascular disease complications
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Posted 19 Dec 2020

Blood group A Secretors are associated with a higher risk of COVID-19 cardiovascular disease complications
1,322 downloads medRxiv hematology

TJ Mankelow, BK Singleton, PL Moura, CJ Stevens-Hernandez, NM Cogan, G Gyorffy, S Kupzig, L Nichols, C Asby, J Pooley, G Ruffino, F Hosseini, F Moghaddas, M Attwood, A Noel, Alan Cooper, D Arnold, F Hamilton, C Hyams, A Finn, AM Toye, DJ Anstee

The SARS-CoV-2 virus causes COVID-19, an infection capable of causing severe disease and death but which may also be asymptomatic or oligosymptomatic in many individuals. While several risk factors, including age, have been described, the mechanisms of this variation are poorly understood. Several studies have described associations between blood group and COVID-19 severity, while others do not. Expression of ABO glycans on secreted proteins and non-erythroid cells is controlled by a fucosyltransferase (FUT2). Inactivating mutations result in a non-secretor phenotype which is known to protect against some viral infections. We investigated whether ABO or secretor status was associated with COVID-19 severity. Data combined from healthcare records and laboratory tests (n=275) of SARS-CoV-2 PCR positive patients hospitalised with COVID-19, confirmed higher than expected numbers of blood group A individuals compared to O (RR=1.24, CI 95% [1.05,1.47], P=0.0111). There was also a significant association between group A and COVID-19-related cardiovascular complications (RR=2.56, CI 95% [1.43,4.55], P=0.0011) which is independent of gender. Molecular analysis of phenotype revealed that group A patients who are non-secretors are significantly less likely to be hospitalised than secretors. In a larger cohort of 1000 convalescent plasma donors, among whom the majority displayed COVID-19 symptoms and only a small minority required hospitalisation, group A non-secretors were slightly over-represented. Our findings indicate that group A non-secretors are not resistant to infection by SARS-CoV-2, but they are likely to experience a less severe form of its associated disease. Key PointsO_LIBlood group type A is associated with an increased risk of cardiovascular complications in COVID-19 patients. C_LIO_LIFUT2 "non-secretor" status reduces the risk of severe COVID-19 outcomes in patients with blood group A. C_LI

11: Red blood cell distribution width (RDW) in Hospitalized COVID-19 Patients
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Posted 03 Jul 2020

Red blood cell distribution width (RDW) in Hospitalized COVID-19 Patients
1,290 downloads medRxiv hematology

Preethi Ramachandran, Mahesh Gajendran, Abhilash Perisetti, Karim Osama Elkholy, Abhishek Chakraborti, Giuseppe Lippi, Hemant Goyal

Introduction: Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing dramatic morbidity and mortality worldwide. The Red Blood Cell Distribution Width (RDW) has been strongly associated with increased morbidity and mortality in multiple diseases. Objective: To assess if elevated RDW is associated with unfavorable outcomes in hospitalized COVID-19. Methods: We retrospectively studied clinical outcomes of hospitalized COVID-19 patients for their RDW values. In-hospital mortality was defined as primary outcome, while septic shock, need for mechanical ventilation, and length of stay (LOS) were secondary outcomes. Results- A total of 294 COVID-19 patients were finally studied. Overall prevalence of increased RDW was 49.7% (146/294). RDW was associated with increased risk of in-hospital mortality (aOR, 4.5; 95%CI, 1.4-14.3) and septic shock (aOR, 4.6; 95%CI, 1.4-15.1) after adjusting for anemia, ferritin, and lactate. The association remained unchanged even after adjusting for other clinical confounders such as age, sex, body mass index, coronary artery disease, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease. No association was found instead with mechanical ventilation and median LOS. Conclusion: Elevated RDW in hospitalized COVID-19 patients is associated with a significantly increased risk of mortality and septic shock.

12: Correlation of coagulation parameters with clinical outcomes in Coronavirus-19 affected minorities in United States: Observational cohort
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Posted 06 May 2020

Correlation of coagulation parameters with clinical outcomes in Coronavirus-19 affected minorities in United States: Observational cohort
1,197 downloads medRxiv hematology

Morayma Reyes Gil, Jesus D Gonzalez-Lugo, Shafia Rahman, Mohammad Barouqa, James Szymnaski, Kenji Ikemura, Yungtai Lo, Henny H. Billett

Importance: COVID-19 has caused a worldwide illness and New York has become the epicenter of COVID-19 in the United States. Currently Bronx has the highest prevalence per capita in New York. Objective: To investigate the coagulopathic presentation of COVID and its natural course and to investigate whether hematologic and coagulation parameters can be used to assess illness severity and death. Design: Retrospective case study of positive COVID inpatients between 3/20/2020-3/31/2020. Setting: Montefiore Health System main hospital, Moses, a large tertiary care center in the Bronx. Participants: Adult inpatients with positive COVID tests hospitalized at MHS. Exposure (for observational studies): Datasets of participants were queried for physiological, demographic (age, sex, socioeconomic status and self-reported race and/or ethnicity) and laboratory data. Main Outcome and Measures: Relationship and predictive value of measured parameters to mortality and illness severity. Results: Of the 217 in this case review, 70 died during hospitalization while 147 were discharged home. Only the admission PT and first D-Dimer could very significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 1.65 mcg/mL. Conclusions: We describe here a comprehensive assessment of hematologic and coagulation parameters in COVID and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments.

13: Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with Acute Myeloid Leukaemia
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Posted 10 Jan 2020

Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with Acute Myeloid Leukaemia
1,117 downloads medRxiv hematology

Stefanos A. Bamopoulos, Aarif M. N. Batcha, Vindi Jurinovic, Maja Rothenberg-Thurley, Hanna Janke, Bianka Ksienzyk, Julia Philippou-Massier, Alexander Graf, Stefan Krebs, Helmut Blum, Stephanie Schneider, Nikola Konstandin, Maria Cristina Sauerland, Dennis Goerlich, Wolfgang E. Berdel, Bernhard J. Woermann, Stefan K Bohlander, Stefan Canzar, Ulrich Mansmann, Wolfgang Hiddemann, Jan Braess, Karsten Spiekermann, Klaus H. Metzeler, Tobias Herold

Previous studies have demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies. Their clinical characteristics and aberrant splicing patterns have been explored in myelodysplasia, however, their functional consequences in acute myeloid leukaemia are largely unknown. The aim of this study was the comprehensive clinical and functional analysis of mutations in the three most commonly afflicted splicing factor genes: SRSF2, U2AF1 and SF3B1. To this end, we examined the prognostic role of splicing factor mutations in two large independent cohorts, encompassing a total of 2678 acute myeloid leukaemia patients treated with intensive chemotherapy. The clinical analysis was complemented by RNA-sequencing of 246 patients to identify targets of splicing dysregulation. Results were validated in an additional RNA-sequencing dataset of 177 patients. Patients with splicing factor mutations show inferior relapse-free and overall survival, however, these mutations do not represent independent prognostic markers. Differential isoform expression analysis revealed a characteristic expression profile for each splicing factor mutation with a strong dysregulation of several isoforms. Furthermore, by establishing a custom differential splice junction usage pipeline we accurately detected aberrant splicing in splicing factor mutated samples. Mutated samples were characterized by predominantly decreased splice junction utilization of a large number of genes. A large proportion of differentially used spliced junctions were novel. Targets of splicing dysregulation included several genes with a known role in acute myeloid leukaemia. In SRSF2(P95H) mutants we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Taken together, our findings suggest that splicing factor mutations does not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.

14: Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis
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Posted 15 Jan 2021

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis
956 downloads medRxiv hematology

Matthew L. Meizlish, George Goshua, Yiwen Liu, Rebecca Fine, Kejal Amin, Eric Chang, Nicholas DeFilippo, Craig Keating, Yuxin Liu, Michael Mankbadi, Dayna McManus, Stephen Wang, Christina Price, Robert D. Bona, Cassius Ochoa Chaar, Hyung J. Chun, Alexander B. Pine, Henry M. Rinder, Jonathan Siner, Donna S. Neuberg, Kent A. Owusu, Alfred Ian Lee

Background: Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. Research Question: How does in-hospital mortality compare with intermediate- versus prophylactic-dose anticoagulation, and separately with in-hospital aspirin versus no antiplatelet therapy, in treatment of COVID-19? Study Design and Methods: Using data from 2785 hospitalized adult COVID-19 patients, we established two separate, nested cohorts of patients (1) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (2) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). Propensity score matching utilizing various markers of illness severity and other patient-specific covariates yielded treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Results: Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). Interpretation: In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

15: Dynamics of coagulopathy in patients with different COVID-19 severity
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Posted 04 Jul 2020

Dynamics of coagulopathy in patients with different COVID-19 severity
918 downloads medRxiv hematology

Anna Kalinskaya, Oleg Dukhin, Ivan Molodtsov, Alexandra Maltseva, Denis Sokorev, Antonina Elizarova, Olga Sapozhnikova, Ksenia Glebova, Daria Stonogina, Soslan Shakhidzhanov, Evgeniy Nikonov, Alexey Mazus, Ilia Spiridonov, Fazly Ataullakhanov, Leonid Margolis, Alexander Shpektor, Elena Vasilieva

With the progress of COVID-19 studies, it became evident that SARS-CoV-2 infection is often associated with thrombotic complications. The goal of our present study was to evaluate which component of clot formation process including endothelial function, platelets aggregation and plasma coagulation, as well as endogenous fibrinolysis in patients with COVID-19 correlates with the severity of the disease. We prospectively included 58 patients with COVID-19 and 47 healthy volunteers as a control group that we recruited before the pandemic started. It turns out that plasma coagulation with subsequent platelet aggregation, but not endothelial function, correlates with the severity of the COVID-19. IL-6 blockade may play a beneficial role in COVID-19 induced coagulopathy.

16: Panel Based Error Corrected Next Generation Sequencing versus Flow Cytometry to Detect Measurable Residual Disease in Acute Myeloid Leukemia
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Posted 25 Aug 2020

Panel Based Error Corrected Next Generation Sequencing versus Flow Cytometry to Detect Measurable Residual Disease in Acute Myeloid Leukemia
890 downloads medRxiv hematology

Nikhil Patkar, Chinmayee Kakirde, Anam Fatima Shaikh, Rakhi Salve, Prasanna Bhanshe, Gaurav Chatterjee, Sweta Rajpal, Swapnali Joshi, Shruti Chaudhary, Rohan Kodgule, Sitaram Ghoghale, Nilesh Deshpande, Dhanalaxmi Shetty, Khizer Syed Hasan, Hasmukh Jain, Bhausaheb Bagal, Hari Menon, Navin Khattry, Manju Sengar, Prashant Tembhare, Papagudi Subramanian, Sumeet Gujral

A 35 gene error corrected next generation sequencing (NGS) panel was created using single molecule molecular inversion probes with applicability to 83% of acute myeloid leukemia (AML). We accrued 201 patients of adult AML treated with conventional therapy, in morphological remission and evaluated measurable residual disease using NGS (NGS-MRD) as well as multiparameter flow cytometry (FCM-MRD) at post induction (PI) and consolidation (PC) time points. A total of 344 mutations were detected [median VAF of 0.95% (0.76% after excluding mutations in DNMT3A, TET2, ASXL1)] during assessment of MRD. Nearly 71% of patients harbored PI NGS-MRD (and 40.9% harbored PC-MRD). Patients harboring NGS-MRD had a significantly higher cumulative incidence of relapse (CIR), inferior overall survival (OS) and relapse free survival (RFS) as compared to NGS-MRD negative patients at PI and PC time points. NGS-MRD was predictive of inferior outcome in intermediate cytogenetic risk and demonstrated potential in favorable cytogenetic risk AML. Patients who cleared PI NGS-MRD (and stayed negative) had a significantly improved survival as compared to patients who became negative subsequently indicating that kinetics of NGS-MRD clearance was of paramount importance. NGS-MRD identified over 80% of cases identified by flow cytometry at PI time point whereas FCM identified 49.3% identified by NGS. Both FCM and NGS MRD were important in predicting outcome however, PI NGS-MRD emerged as the most important independent prognostic factor predictive of inferior outcome. We demonstrate that panel based NGS-MRD is highly predictive of outcome and advantageous when compared to FCM-MRD in AML treated with conventional therapies.

17: The immune profile of the gut microbiome in graft versus host disease patients
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Posted 11 Apr 2020

The immune profile of the gut microbiome in graft versus host disease patients
878 downloads medRxiv hematology

Marcel A. de Leeuw, Manuel X. Duval

Background. Gut microbiota (GM) composition has been associated with acute Graft-versus-Host Disease (aGvHD), however, current knowledge is insufficient to target the GM. Methods. A relevant series of microbiome data sets were combined and reanalyzed, with resolution of species level changes in the GM. Results. GM composition was found strongly correlated with aGvHD status after one month post stem cell infusion (R2=0.51). The predicted average biological safety level, indicative of antibiotic resistance, was found increased in aGvHD cases (p=1.6E-4). Using in silico modelling, we formulated a probiotic composition putatively competing with mortality and aGvHD associated species. Implications. Supplementation with Bifidobacterium longum and Bifidobacterium breve is proposed as a prophylactic treatment alongside with prebiotics and an adapted antibiotics course.

18: Platelet-to-lymphocyte ratio (PLR), a novel biomarker to predict the severity of COVID-19 patients: a systematic review and meta-analysis
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Posted 24 Aug 2020

Platelet-to-lymphocyte ratio (PLR), a novel biomarker to predict the severity of COVID-19 patients: a systematic review and meta-analysis
796 downloads medRxiv hematology

Daniel Martin Simadibrata, Bashar Adi Wahyu Pandhita, Muammar Emir Ananta, Tamara Tango

Background Platelet-to-lymphocyte ratio (PLR), a novel inflammatory marker, has been suggested to be able to predict the severity of COVID-19 patients. This systematic review aims to evaluate the association between PLR levels on admission and the severity of COVID-19 patients. Methods A systematic literature search was done on 23 July 2020 to identify peer-reviewed studies across four different databases (Ovid MEDLINE, EMBASE, SCOPUS, and the Cochrane Library), preprints from two databases (MedRxiv and SSRN), and grey literature from two databases (WHO COVID-19 Global Research Database and Center for Disease Control and Prevention COVID-19 Research Article). Research articles comparing the PLR value on admission in adult patients with COVID-19 with varying degrees of severity were included in the analysis. The following keywords were used for the search: 'COVID-19', 'PLR', 'severity', and 'mortality'. The inverse variance method was used to calculate the pooled effect standardized mean difference (SMD) along with its 95% confidence interval (CI). Results A total of seven studies were included in the meta-analysis, six of which were conducted in China. From a total of 998 participants included, 316 (31.7%) had severe diseases; and those in the severe group were generally older and had underlying diseases compared to the non-severe group. In comparison to non-severe patients, the meta-analysis showed that severe COVID-19 patients had higher PLR levels on admission (SMD 0.68; 95%CI 0.43-0.93; I2 =58%). Conclusion High PLR levels on admission were associated with severe COVID-19 cases. Therefore, on-admission PLR level is a novel, cost-effective, and readily available biomarker with a promising prognostic role for determining the severity of COVID-19 patients.

19: Severe COVID-19 infection is associated with increased antibody-mediated platelet apoptosis
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Posted 05 Sep 2020

Severe COVID-19 infection is associated with increased antibody-mediated platelet apoptosis
781 downloads medRxiv hematology

Karina Althaus, Irene Marini, Jan Zlamal, Lisann Pelzl, Helene Haeberle, Martin Mehrlaender, Stefanie Hammer, Harald Schulze, Michael Bitzer, Nisar Malek, Dominik Rath, Hans Boesmueller, Bernard Nieswandt, Meinrad Gawaz, Tamam Bakchoul, Peter Rosenberger

The pathophysiology of COVID-19 associated thrombosis seems to be multifactorial, involving interplay between cellular and plasmatic elements of the hemostasis. We hypothesized that COVID-19 is accompanied by platelet apoptosis with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential ({Delta}{Psi}m), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization by flow cytometry. Platelets from intensive care unit (ICU) COVID-19 patients (n=21) showed higher {Delta}{Psi}m depolarization, cytosolic Ca2+ concentration and PS externalization, compared to healthy controls (n=18) and COVID-19 non-ICU patients (n=4). Moreover significant higher cytosolic Ca2+ concentration and PS was observed compared to septic ICU control group (ICU control). In ICU control group (n=5; non-COVID-19 ICU) cytosolic Ca2+ concentration and PS externalization was comparable to healthy control, with an increase in {Delta}{Psi}m depolarization. Sera from ICU COVID-19 patients induced significant increase in apoptosis markers ({Delta}{Psi}m depolarization, cytosolic Ca2+ concentration and PS externalization) compared to healthy volunteer and septic ICU control. Interestingly, immunoglobulin G (IgG) fractions from COVID-19 patients induced an Fc gamma receptor IIA dependent platelet apoptosis ({Delta}{Psi}m depolarization, cytosolic Ca2+ concentration and PS externalization). Enhanced PS externalization in platelets from ICU COVID-19 patients was associated with increased sequential organ failure assessment (SOFA) score (r=0.5635) and D-Dimer (r=0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared to those without. The strong correlations between apoptosis markers and increased D-Dimer levels as well as the incidence of thrombosis may indicate that antibody-mediated platelet apoptosis potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

20: Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 20.6 million people in six European countries
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Posted 13 May 2021

Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 20.6 million people in six European countries
779 downloads medRxiv hematology

Edward Burn, Xintong Li, Kristin Kostka, Henry Morgan Stewart, Christian Reich, Sarah Seager, Talita Duarte-Salles, Sergio Fernandez-Bertolin, María Aragón, Carlen Reyes, Eugenia Martinez-Hernandez, Edelmira Marti, Antonella Delmestri, Katia Verhamme, Peter Rijnbeek, Daniel Prieto-Alhambra

Background Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries. Methods Electronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner. Findings A total of 20,599,134 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 1.5 (1.0 to 2.0) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 1.4 (1.1 to 1.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 0.7 (0.5 to 0.9) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 4.4 (3.9 to 5.0) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.0 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event. Interpretation Although rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population. Funding This study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3).

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