Morphological Changes in Blood Cells as Indicators for Disease Progression in COVID 19

A novel highly pathogenic human corona virus (COVID19) has been recently recognised in Wuhan, China as the cause of corona disease outbreak. It has rapidly spread from China to various countries across the world evolving as a pandemic. In our study we have categorized the covid positive patients into mild, moderate and severe based on the clinical criteria suggested by WHO. The coagulation parameters of the patients were analysed and documented. A peripheral smear was made for every patient and the morphological changes in blood cells were documented. The peripheral smear findings were then correlated with the disease stage and coagulation parameters. There were significant differences in the total WBC count and the differential WBC count between stages 1 &2 and stages 1 & 3 (p<0.005). Leucocytosis, neutrophilia and toxic changes in neutrophils were seen in severe stage of the disease and in covid coagulopathy suggesting these are important indicators of disease severity. Schistocytes an important finding in any other coagulopathy was not present in covid associated coagulopathy. Activated lymphocytes was found to be the most common morphological presentation seen in all covid patients irrespective of the disease stage whereas plasmacytoid lymphocytes was an important finding in severe stage disease. Monocyte cytoplasmic vacuoles, large/giant platelets were other morphological findings observed but these findings did not have any significant correlation with disease stage. Since follow up smears of the same patient were not analysed during disease progression and also post recovery, additional research in this field will provide further insights.

Simple Coagulation Profile as Predictor of Mortality in Adults Admitted with COVID-19: A Meta-Analysis

Context: COVID-19 severe manifestations must be detected as soon as possible. One of the essential poor characteristics is the involvement of coagulopathy. Simple coagulation parameters, including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and platelet, are widely accessible in many health centers. Objectives: This meta-analysis aimed to determine the association between simple coagulation profiles and COVID-19 in-hospital mortality. Method: We systematically searched five databases for studies measuring simple coagulation parameters in COVID-19 on admission. The random-effects and inverse-variance weighting were used in the study, which used a standardized-mean difference of coagulation profile values. The odds ratios were computed using the Mantel-Haenszel formula for dichotomous variables. Results: This meta-analysis comprised a total of 30 studies (9,175 patients). In our meta-analysis, we found that non-survivors had a lower platelet count [SMD = -0.56 (95% CI: -0.79 to -0.33), P < 0.01; OR = 3.00 (95% CI: 1.66 to 5.41), P < 0.01], prolonged PT [SMD = 1.22 (95%CI: 0.71 to 1.72), P < 0.01; OR = 1.86 (95%CI: 1.43 to 2.43), P < 0.01], prolonged aPTT [SMD = 0.24 (95%CI: -0.04 to 0.52), P = 0.99], and increased INR [SMD = 2.21 (95%CI: 0.10 to 4.31), P = 0.04] than survivors. Conclusions: In COVID-19 patients, abnormal simple coagulation parameters on admission, such as platelet, PT, and INR, were associated with mortality outcomes.

A Composite study of Coagulation Milieu in Covid-19: Experience from a Tertiary Care Centre from India

Background:: The understanding of pathogenesis is necessary for the development of effective treatment for COVID-19. Various studies have postulated that there is a complex interplay of mediators of coagulation and inflammation responsible for the pathogenesis of COVID-19. We did this study on coagulation parameters and inflammatory markers and their effect on outcome in patients with COVID-19. Methods: This was a single centre observational cross-sectional study. Procoagulants [Prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, lupus anticoagulant (LA), fibrinogen, factor-VIII (F-VIII)]; anticoagulants [protein-C (PC), protein-S (PS), antithrombin] and inflammatory markers [interleukin-6 (IL-6) and highly sensitive – C-reactive protein (hs-CRP)] were measured at the time of hospitalization and correlated with the severity of the disease. Results: A total of 230 patients were enrolled, of which 61.3%, 20.0%, and 18.7% had asymptomatic/ mild, moderate, or severe disease, respectively. COVID-19 disease severity was associated with rising trends with coagulation parameters (PT, APTT, D-Dimer; p value 0.01, <0.0001, <0.0001, respectively). Falling trends of anticoagulant (PC, Antithrombin; p value <0.0001, 0.003 respectively) and rising trends of procoagulant (fibrinogen, F-VIII; p value 0.004, <0.0001 respectively) were observed with increasing COVID-19 disease severity. Multivariate logistic regression analysis found that advanced age, D-Dimer, and hs-CRP (p value 0.035, 0.018, <0.0001 respectively) were independent predictors of mortality in COVID-19. Procoagulant parameters (D-dimer, APTT, Factor VIII) were positively correlated with anticoagulant parameters (PC and PS) and inflammatory parameters (hs-CRP). Conclusions: This study revealed increased levels of coagulation and inflammatory parameters, which correlated with the severity of COVID-19. Age, D-dimer, IL-6, hs-CRP, APTT, fibrinogen, and Factor VIII were significantly higher in patients with moderate and severe disease as compared to asymptomatic/mild disease. Advanced age, D dimer, and hs-CRP were significantly associated with poor outcomes.

Novel Coronavirus Infection (COVID-19) Related Thrombotic and Bleeding Complications in Critically Ill Patients: Experience from an Academic Medical Center

Introduction: Thrombosis and bleeding are recognized complications of the novel coronavirus infection (COVID-19), with a higher incidence described particularly in the critically ill. Methods: A retrospective review of COVID-19 patients admitted to our intensive care units (ICU) between 1 January 2020 and 31 December 2020 was performed. Primary outcomes included clinically significant thrombotic and bleeding events (according to the ISTH definition) in the ICU. Secondary outcomes included mortality vis-a-vis the type of anticoagulation. Results: The cohort included 144 consecutive COVID-19 patients with a median age of 64 years (IQR 54.5–75). The majority were male (85 (59.0%)) and Caucasian (90 (62.5%)) with a median BMI of 30.5 kg/m2 (IQR 25.7–36.1). The median APACHE score at admission to the ICU was 12.5 (IQR 9.5–22). The coagulation parameters at admission were a d-dimer level of 109.2 mg/mL, a platelet count of 217.5 k/mcl, and an INR of 1.4. The anticoagulation strategy at admission included prophylactic anticoagulation for 97 (67.4%) patients and therapeutic anticoagulation for 35 (24.3%) patients, while 12 (8.3%) patients received no anticoagulation. A total of 29 patients (20.1%) suffered from thrombotic or major bleeding complications. These included 17 thrombus events (11.8%)—8 while on prophylactic anticoagulation (7 regular dose and 1 intermediate dose) and 9 while on therapeutic anticoagulation (p-value = 0.02)—and 19 major bleeding events (13.2%) (4 on no anticoagulation, 7 on prophylactic (6 regular dose and 1 intermediate dose), and 8 on therapeutic anticoagulation (p-value = 0.02)). A higher thrombosis risk among patients who received remdesivir (18.8% vs. 5.3% (p-value = 0.01)) and convalescent serum (17.3% vs. 5.8% (p-value = 0.03%)) was noted, but no association with baseline characteristics (age, sex, race, comorbidity), coagulation parameters, or treatments (steroids, mechanical ventilation) could be identified. There were 10 pulmonary embolism cases (6.9%). A total of 99 (68.8%) patients were intubated, and 66 patients (45.8%) died. Mortality was higher, but not statistically significant, in patients with thrombotic or bleeding complications—58.6% vs. 42.6% (p-value = 0.12)—and higher in the bleeding (21.2%) vs. thrombus group (12.1%), p-value = 0.06. It did not significantly differ according to the type of anticoagulation used or the coagulation parameters. Conclusions: This study describes a high incidence of thrombotic and bleeding complications among critically ill COVID-19 patients. The findings of thrombotic events in patients on anticoagulation and major bleeding events in patients on no or prophylactic anticoagulation pose a challenging clinical dilemma in the issue of anticoagulation for COVID-19 patients. The questions raised by this study and previous literature on this subject demonstrate that the role of anticoagulation in COVID-19 patients is worthy of further investigation.

Hematologic and coagulopathy parameter as a survival predictor among moderate to severe COVID-19 patients in non- ICU ward: a single-center study at the main referral hospital in Surabaya, East Java, Indonesia

Background : This research aimed to examine and analyze risk factors for death, hematologic parameters and coagulation in COVID-19 patients at RSUD Dr. Soetomo Surabaya, one of the referral centers for probable COVID-19 patient cases in East Java. Method : This was a retrospective analytical study by taking secondary data on patients with probable COVID-19 cases who were treated in hospital isolation rooms from May to September, 2020. Result : Of 538 probable COVID-19 patients, 217 were tested positive, with an average age of 52.11±13.12 years, and there were 38 death cases. Hematologic parameters, such as white blood cell, neutrophil and lymphocyte counts, showed significantly different result in the deceased group. On the other hand, coagulation parameters, consisting of D-dimer, CRP, PT, and aPTT showed significantly similar value in the deceased group. Univariate analysis concluded that chronic kidney disease, diabetes mellitus, coronary heart disease, WBC, NLR, and PPT counts could predict the mortality, while multivariate analysis revealed that coronary heart disease was the only significant independent predictor of mortality. Conclusion : This research shows that hematologic and coagulation parameters increased in the majority of COVID-19 patients and the deceased group. While the number of neutrophils and WBC increases, the number of lymphocytes decreases significantly as the disease gets more severe.. Coronary heart disease is an independent predictor of mortality.

Coagulation parameters in the newborn and infant – the Copenhagen Baby Heart and COMPARE studies

Objectives The coagulation system is not fully developed at birth and matures during the first months of infancy, complicating clinical decision making within hemostasis. This study evaluates coagulation parameters at birth and two months after birth, and tests whether cord blood can be used as a proxy for neonatal venous blood measurements. Methods The Copenhagen Baby Heart Study (CBHS) and the COMPARE study comprise 13,237 cord blood samples and 444 parallel neonatal venous blood samples, with a two month follow-up in 362 children. Results Because coagulation parameters differed according to gestational age (GA), all analyses were stratified by GA. For neonatal venous blood, reference intervals for activated partial thromboplastin time (APTT) and prothrombin time (PT) were 28–43 s and 33–61% for GA 37–39 and 24–38 s and 30–65% for GA 40–42. Reference intervals for international normalized ratio (INR) and thrombocyte count were 1.1–1.7 and 194–409 × 109/L for GA 37–39 and 1.2–1.8 and 188–433 × 109/L for GA 40–42. Correlation coefficients between umbilical cord and neonatal venous blood for APTT, PT, INR, and thrombocyte count were 0.68, 0.72, 0.69, and 0.77 respectively, and the distributions of the parameters did not differ between the two types of blood (all p-values>0.05). Conclusions This study describes new GA dependent reference intervals for common coagulation parameters in newborns and suggests that cord blood may serve as a proxy for neonatal venous blood for these traits. Such data will likely improve clinical decision making within hemostasis among newborn and infant children.

Geographic Remoteness Is Associated with Increased Blood Product Utilization and Higher Rates of Hospitalization and Deaths in Adults with Immune Thrombocytopenia

INTRODUCTION Immune thrombocytopenia (ITP) is a hematological disease characterized by immune-mediated destruction of platelets. Prior to starting therapy for ITP it is critical to determine whether it is idiopathic or related to a secondary underlying condition as this informs treatment. There is significant use of blood products and components in patients with chronic ITP for management of thrombocytopenia and bleeding, including intravenous immune globulin (IVIg). Platelet transfusions are generally reserved for life-threatening bleeding or may be used in the preoperative setting in patients unresponsive to other therapies. The aims of this study are to identify gaps in process of care and to examine the impact of geographical remoteness on health service utilization and outcomes in adults with chronic ITP in Alberta. METHODS Adults who received rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA) as second-line therapy for ITP during 2012-2019 in the province of Alberta, Canada were identified via the provincial special drug access database. Diagnostic workup including bone marrow biopsy results, abdominal imaging (ultrasound or CT scan), coagulation parameters, viral serologies for hepatitis, human immunodeficiency virus (HIV), serum protein electrophoresis (SPEP), and quantitative immunoglobulins were recorded and rates of completed tests were calculated. Utilization of IVIg, platelets, and packed red blood cells was assessed. Rates of hospitalization, mortality, and ITP-related deaths were calculated and compared according to geographic region. RESULTS Of the 204 patients identified for analysis 106 were female (52%). Most patients (123; 60%) lived within a major centre, whereas 21 (10%) lived over 250 km from a major centre. Review of diagnostic laboratory parameters revealed incomplete coagulation parameters in 117 patients (58%), and no coagulation parameters checked in 16%. Eighty-nine patients (44%) did not have quantitative immunoglobulins tested, and 57 (28%) did not have an SPEP performed. Fifty-three (26%) did not have any abdominal imaging performed to assess for splenomegaly or liver disease. Thirty-five (17%) did not have any viral serologies for hepatitis B, C, or HIV completed. Bone marrow aspirate and biopsy was performed in 110 patients (54%). Eighty-six (77%) of these biopsies yielded a normal result. Eight biopsies (7%) displayed a lymphoproliferative disorder or plasma cell disorder which was suspected or known prior to completing the test. There was significant geographic discrepancy in utilization of blood products and hospitalizations. During 527 patient years of follow up, 83 patients received a total of 343 doses of platelets. Eleven patients (13%) received platelet transfusions for inappropriate indications, and eight (9%) for unclear indications. One hundred twenty-seven patients received IVIg (mean 1290 g) with comparable usage across geographic regions. Compared to patients within 250 km from a major centre, those with geographic remoteness (&gt;250 km from a major centre) utilized more platelets (mean 5.2 vs 1.2 doses; Figure 1) and packed red blood cells (mean 4.3 vs 1.2 units; Figure 2). Those with geographic remoteness also experienced a higher rate of ITP-related hospitalizations (mean 1.5 vs 1.1) and deaths (24% versus 9%). At a median follow-up of 3.42 years from ITP diagnosis, 27 patients (13%) were deceased. Fourteen of these deaths were ITP-related due to bleeding or infection (52%). There appears to be a gradient of rates of both all-cause and ITP-related deaths by distance from a major centre (Figures 3 and 4). DISCUSSION This study highlights gaps in quality of care in patients with chronic ITP in Alberta, Canada. A significant number of patients have an incomplete workup for ITP at the time of diagnosis with the most forgotten tests being coagulation studies, SPEP, quantitative immunoglobulins, viral serologies, and abdominal imaging. Additionally, we identified an unexpectedly high rate of bone marrow biopsies performed in our population. Most of these bone marrow examinations did not result in any change in management. Finally, this study identified that geographic remoteness is associated with increased health services utilization and ITP-related deaths. These data can be used to inform further quality improvement initiatives in chronic ITP and help address geographic inequities in healthcare outcomes. Figure 1 Figure 1. Disclosures Sun: Bayer: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Shire: Consultancy; Octapharma: Consultancy, Research Funding.

Ethnic Variation in Hospitalized COVID-19 Patients and Correlation with Coagulopathy, Thrombosis, Prognosis and 30 Day Mortality Outcomes in California's Central Valley

Background: The COVID-19 pandemic has brought a spotlight on the high incidence of thrombosis and abnormal coagulation parameters in patients with the 2019 novel coronavirus. We evaluated 30 day mortality and thrombotic events relative to anticoagulation therapy and coagulation parameters in Hispanic and non-Hispanic patients in California's central valley. Methods: We identified 886 non-pregnant adults hospitalized at Community Medical Centers in the Central Valley of California with SARS-CoV2 infections from 3/1/20 to 9/1/20. We conducted manual chart review and excluded patients on long term anticoagulation prior to admission. We collected data on ethnicity, coagulation labs, thrombotic events and 30 day all-cause mortality outcomes. The distributions of variables were reviewed to detect illogical and out of range values. Differences in means of continuous variables were evaluated via the t-test. Differences in categorical variables were evaluated with chi square tests. All tests are two-sided and a p-value &lt; 0.05 was considered statistically significant. Results: Among the 866 COVID positive patients, 568 (64%) were Hispanic and 318 (36%) were non-Hispanic. The gender distribution was equivalent with 57% males and 43% females. Hispanic patients were younger with a mean age of 56.1 years vs 63.2 years in non-Hispanics. Mean BMI was 32.7 for Hispanics and 30.5 for non-Hispanics (p&lt;0.05). The risk factor assessment for severe COVID-19 infection revealed a history of thrombosis or thrombophilia, bleeding tendency, obesity, active cancer, diabetes, cardiovascular disease, end stage renal disease, liver cirrhosis and immunosuppression, all of which were not statistically significant between Hispanics and non-Hispanics. However, chronic lung disease (p&lt;0.05) and residing in a skilled nursing or long-term care facility (p&lt;0.001) were statistically significant (Table 1). 16% of non-Hispanics had chronic lung disease vs 10.9% of Hispanics. Likewise, 10.4% of non-Hispanics inhabited care facilities compared to 3.9% of Hispanics. Review of initial CRP values exhibited statistical significance (p=0.017) amidst Hispanics at 145.3 and non-Hispanics at 124.8. Other labs including PT, INR, PTT, d-dimer, fibrinogen, platelets, ferritin and ESR were not statistically significant between ethnic groups. Mean hospital stay for Hispanics and non-Hispanics were analogous at 12.8 days and 12.9 days respectively. Intensive care unit admission rates were higher for Hispanics at 32.7% (186/568) in contrast to non-Hispanics at 28.3% (90/318) (p=0.171). Evaluation of 30 day mortality revealed that 14.2% (81/568) of Hispanic patients died compared to 17.9% (57/317) of non-Hispanic patients. (p=0.147). The bleeding rate was 4.8% in Hispanics and 3.8% in non-Hispanics. 59 (6.6%) patients experienced some form of thrombosis, which was dichotomized to show that 39 (6.8%) Hispanics and 20 (6.2%) non-Hispanics incurred thrombosis during hospitalization. 19.4% (18/93) of patients on therapeutic anticoagulation and 5.1% (34/657) of patients on prophylactic low dose anticoagulation developed thrombosis (P=0.00001). 30 day mortality was higher in patients receiving therapeutic vs low dose standard anticoagulation prophylaxis (20.4% Vs 14.5%. p=0.006). Thrombotic events transpired at 4.7% (22/464) in patients with initial d-dimer &lt;2500 in comparison to 15.8% (19/120) of patients with values ≥2500 (p&lt;0.001). Additionally, 30 day mortality was lower for patients with d-dimer &lt; 2500 at 13.4% (62/464) than for patients with d-dimer ≥ 2500 at 30.8% (37/120) (p&lt;0.001). Prothrombin time (PT) &gt; 16 correlated with a higher incidence of thrombosis (17% vs 6.7%. p&lt;0.001) and 30-day mortality (36% vs 15.9%. p &lt;0.001). Similarly, 30 day mortality was increased in patients with ferritin &gt; 1000 (22.7% vs 12.1%. p= 0.002). However, the same was not observed for ferritin levels and thrombosis. Conclusions: This study illuminates ethnic variances with respect to COVID-19 hospital outcomes. Hispanic patients were younger and had less risk factors for severe COVID-19 infections. Regardless of ethnic differences, incidence of thrombosis and 30 day mortality were similar. Despite sicker patients receiving therapeutic anticoagulation, the 30 day mortality and rate of thrombotic events remain higher among these patients. D-dimer ≥ 2500 and elevated PT were associated with higher rate of thrombosis and death. Figure 1 Figure 1. Disclosures Abdulhaq: BMS, Alexion, Oncopeptides, Morphosys, Pfizer, Norvartis: Honoraria; Oncopeptides, Alexion, Amgen: Speakers Bureau; Morphosys, BMS, Amgen: Membership on an entity's Board of Directors or advisory committees.