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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)
9,148 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
4,111 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)
4,097 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)
3,813 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: 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
2,160 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.

6: 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
2,129 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.

7: 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
2,008 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 de Silva, Paola Minoprio, Bruno Bezerril 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.

8: 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
1,163 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.

9: 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
1,152 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.

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
1,069 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: 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
1,043 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.

12: 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
833 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.

13: 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
811 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.

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
807 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
798 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: The Lebanese Cohort for COVID-19; A Challenge for the ABO Blood Group System
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Posted 04 Aug 2020

The Lebanese Cohort for COVID-19; A Challenge for the ABO Blood Group System
744 downloads medRxiv hematology

Athar Khalil, Mahmoud Hassoun, Rita Feghali

A sudden outbreak of pneumonia caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread all over the world facilitating the declaration of the resultant disease as a pandemic in March,2020. In Lebanon, the fast action of announcing a state of emergency with strict measures was among the factors that helped in achieving a successful containment of the disease in the country. Predisposing factors for acquiring COVID-19 and for developing a severe form of this disease were postulated to be related to epidemiological and clinical characteristics as well as the genomics signature of a given population or its environment. Biological markers such as the ABO blood group system was amongst those factors that were proposed to be linked to the variability in the disease course and/or the prevalence of this infection among different groups. We therefore conducted the first retrospective case-control study in the Middle-East and North Africa that tackles the association between the blood group types and the susceptibility as well as the severity of SARS-CoV2 infection. Opposing to the current acknowledged hypothesis, our results have challenged the association significance of this system with COVID-19. Herein, we highlighted the importance of studying larger cohorts using more rigorous approaches to diminish the potential confounding effect of some underlying comorbidities and genetic variants that are known to be associated with the ABO blood group system.

17: Multiple Myeloma and SARS-CoV-2 Infection: Clinical Characteristics and Prognostic Factors of Inpatient Mortality
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Posted 30 Jun 2020

Multiple Myeloma and SARS-CoV-2 Infection: Clinical Characteristics and Prognostic Factors of Inpatient Mortality
741 downloads medRxiv hematology

Joaquin Martinez-Lopez, Maria-Victoria Mateos, Cristina Encinas, Anna Sureda, Jose Angel Hernandez-Rivas, Ana Lopez de la Guia, Diego Conde, Isabel Krsnik, Elena Prieto, Rosalia Riaza Grau, Mercedes Gironella, Maria Jesus Blanchard, Nerea Caminos, Carlos Fernandez de Larrea, Maria Alicia Senin, Fernando Escalante, Jose Enrique de la Puerta, Eugenio Gimenez, Pilar Martinez-Barranco, Juan Jose Mateos, Luis Felipe Casado, Joan Blade, Juan Jose Lahuerta, Javier De La Cruz, Jesus San-Miguel

There is limited information on the characteristics, pre-admission prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with coronavirus disease 2019 (COVID-19). This retrospective case series investigated characteristics and outcomes of 167 MM patients hospitalized with COVID-19 reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in Spain between March 1 and April 30, 2020. Outcomes were compared with a randomly selected contemporary cohort of 167 age-/sex-matched non-cancer patients with COVID-19 admitted at 6 participating hospitals. Common demographic, clinical, laboratory, treatment, and outcome variables were collected; specific disease status and treatment data were collected for MM patients. Among the MM and non-cancer patients, median age was 71 years and 57% of patients were male in each series, and 75% and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77% and 89% of patients and critical in 8% and 4%, respectively. Supplemental oxygen was required by 47% and 55% of MM and non-cancer patients, respectively, and 21%/9% vs 8%/6% required non-invasive/invasive ventilation. Inpatient mortality was 34% and 23% in MM and non-cancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors of inpatient mortality on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19.

18: 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
691 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.

19: Platelet Activating Immune Complexes Identified in COVID-19 Associated Coagulopathy
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Posted 06 Nov 2020

Platelet Activating Immune Complexes Identified in COVID-19 Associated Coagulopathy
689 downloads medRxiv hematology

Ishac Nazy, Stefan D Jevtic, Jane C Moore, Angela Huynh, James W Smith, John G Kelton, Donald M Arnold

Thrombosis is a prominent feature of coronavirus disease 2019 (COVID-19) and often occurs in patients who are critically ill; however, the mechanism is unclear. This COVID-19 associated coagulopathy (CAC) shares features with heparin-induced thrombocytopenia (HIT), including mild thrombocytopenia and thrombosis. We thus tested 10 CAC patients for anti-PF4/heparin antibodies and functional platelet activation. HIT was excluded in all samples based on anti-PF4/heparin antibody and serotonin release assay results. Of note, 6 CAC patients demonstrated platelet activation by the serotonin release assay that was inhibited by Fc{gamma}RIIA receptor blockade, confirming an IgG-specific immune complex (IC)-mediated reaction. Platelet activation was independent of heparin, but inhibitable by both therapeutic and high dose heparin. All 6 samples were positive for IgG-specific antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS-CoV-2 virus. These samples were additionally characterized by significant endothelial activation, shown by increased von Willebrand factor antigen and activity. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, ruling out thrombotic thrombocytopenic purpura. Our study thus identifies platelet-activating ICs as a mechanism that contributes to CAC thrombosis. Scientific CategoryThrombosis and Hemostasis Key PointsO_LIPatients with COVID-19 thrombosis have immune complexes that activate platelets through Fc{gamma}RIIA signalling C_LIO_LIPatients with COVID-19 thrombosis demonstrate increased VWF antigen and activity that is not related to severe ADAMTS13 reduction C_LI

20: Interactive web application for plotting personalized prognosis prediction curves in allogeneic hematopoietic cell transplantation using machine learning
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Posted 18 Dec 2019

Interactive web application for plotting personalized prognosis prediction curves in allogeneic hematopoietic cell transplantation using machine learning
678 downloads medRxiv hematology

Hiroshi Okamura, Mika Nakamae, Shiro Koh, Satoru Nanno, Yasuhiro Nakashima, Hideo Koh, Takahiko Nakane, Asao Hirose, Masayuki Hino, Hirohisa Nakamae

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for malignant hematological disorders. Transplant clinicians estimate patient-specific prognosis empirically in clinical practice based on previous studies on similar patients. However, this approach does not provide objective data. The present study primarily aimed to develop a tool capable of providing accurate personalized prognosis prediction after allo-HCT in an objective manner. We succeeded in generating personalized prognosis prediction curves of 1-year overall survival (OS), progression-free survival (PFS), relapse/progression, and non-relapse mortality (NRM) adjusted for new allo-HCT candidates by eight pre-transplant factors using our interactive web application (https://predicted-os-after-transplantation.shinyapps.io/RSF_model/). A random survival forest model using the data of patients who underwent allo-HCT at our institution was applied to develop this application. To assess its predictive performance, the entire cohort (363 cases) was split into a training cohort (70%) to develop the predictive model and test cohort (30%) to confirm its performance time-sequentially. The areas under the receiver-operating characteristic curves for 1-year OS, PFS, relapse/progression, and NRM in test cohort were 0.70, 0.72, 0.73, and 0.77, respectively. In conclusion, the new web application could allow transplant clinicians to inform a new allo-HCT candidate of the objective personalized prognosis prediction and facilitate decision-making.

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