Comparison of D-dimer levels using coagulometer and immuno-nephelometer in Covid-19

Comparação dos níveis de dímero D usando coagulômetro e imuno-nefelômetro na Covid-19

Abstract

Covid is one of the most lethal viruses in the human respiratory system. Previous outbreaks of Covid19 include a severe respiratory problem (SARS) Cov2 and the Middle East (MERS) respiratory syndrome has recently been identified as one of the most serious health risks. D-dimer is a result of fibrin depletion which increases during a large thrombotic dose attributed to the selective activation of fibrinolytic structure. Measuring D-dimer levels is important in identifying and assessing risk of blood clots and related conditions such as deep vein thrombosis (DVT), pulmonary embolism (PE), and disseminated intravascular coagulation (DIC). This research is of great help to scientists working with new and high standard methods such as Immuno-nephelometer and Coagulometer and the diagnostics machines. Plasma D-dimer levels have demonstrated potential as a prognostic indicator for outcomes in COVID-19 patients. This research aimed to compare D-dimer levels among Covid-19 infected patients at Dr. Soetomo General Academic Hospital using a Coagulometer with an Immuno-Nephelometer. Chest X-rays were performed to confirm active Covid-19 infections and blood samples were collected and centrifuged at 1000 rpm for 15 minutes to get plasma. The plasmas were analyzed using immune-nephelometer and coagulometer diagnostic analyzers. The table showed high levels of D-Dimer which were obtained through analyzers which show the mean and median. The examination and the inflammation were worst, and the chest X-ray showed that shortness of breath became severe. This Study is to make a comparison between CS2500 and Architecti1000 by using immune-nephelometer and coagulometer because the data was statistically analyzed by using KAPPA KOHEN analysis. The confidence interval of 95% (α =0.05) was employed and the results were considered statistically significant. The correlation between CS2500 and Architecti1000 were tested by Mann-Whitney Test correlation and correlation coefficient (r) equals to 0.5 was considered as a threshold to decide the degree of correlation between variables. The findings showed a significant difference between in the D- dimers obtained by CS2500 and Architect i1000 (p=0.019). The compared levels of D-dimer obtained by using coagulometer with an immuno-nephelometer in Covid-19 patients were higher D-Dimer Levels as compared to the normal patients. There is also a difference between CS2500 and Architect i1000 by using immuno-nephelometer and coagulometer because Coagulometer is the more accurate method than the Immuno-nephelometer.

Keywords:
coagulometer; Covid-19; D-dimer; nephelometer

Resumo

A Covid é um dos vírus mais letais no sistema respiratório humano. Surtos anteriores de Covid-19 incluem a Síndrome Respiratória Grave (SARS) Cov2 e a Síndrome Respiratória do Oriente Médio (MERS), recentemente identificada como um dos riscos mais sérios à saúde. O dímero D é resultado da depleção de fibrina, que aumenta durante uma grande dose trombótica, atribuída à ativação seletiva da estrutura fibrinolítica. A medição dos níveis de dímero D é importante para identificar e avaliar o risco de coágulos sanguíneos e condições relacionadas, como trombose venosa profunda (TVP), embolia pulmonar (EP) e coagulação intravascular disseminada (CID). Esta pesquisa é de grande ajuda para cientistas que trabalham com métodos novos e de alto padrão, como o Imuno-Nefelômetro e o Coagulômetro, e com as máquinas de diagnóstico. Os níveis plasmáticos de dímero D demonstraram potencial como indicador prognóstico para desfechos em pacientes com COVID-19. Esta pesquisa teve como objetivo comparar os níveis de dímero D entre pacientes infectados por Covid-19 no Hospital Acadêmico Geral Dr. Soetomo, utilizando um coagulômetro com um imunonefelômetro. Radiografias de tórax foram realizadas para confirmar infecções ativas por Covid-19 e amostras de sangue foram coletadas e centrifugadas a 1000 rpm por 15 minutos para obtenção do plasma. Os plasmas foram analisados ​​utilizando analisadores diagnósticos de imunonefelômetro e coagulômetro. A tabela mostrou níveis elevados de dímero D, obtidos por meio de analisadores que mostram a média e a mediana. O exame e a inflamação pioraram, e a radiografia de tórax mostrou que a falta de ar se tornou grave. Este estudo visa comparar o CS2500 com o Architecti1000, utilizando imunonefelômetro e coagulômetro, pois os dados foram analisados ​​estatisticamente pela análise KAPPA-KOHEN. O intervalo de confiança de 95% (α = 0,05) foi utilizado e os resultados foram considerados estatisticamente significativos. A correlação entre o CS2500 e o Architecti1000 foi testada pelo teste de correlação de Mann-Whitney, e o coeficiente de correlação (r) igual a 0,5 foi considerado um limiar para determinar o grau de correlação entre as variáveis. Os resultados mostraram uma diferença significativa entre os dímeros D obtidos pelo CS2500 e pelo Architect i1000 (p = 0,019). Os níveis comparados de dímero D obtidos pelo uso do coagulômetro com um imunonefelômetro em pacientes com Covid-19 apresentaram níveis de dímero D mais elevados em comparação aos de pacientes normais. Há também uma diferença entre o CS2500 e o Architect i1000 ao usar o imunonefelômetro e o coagulômetro, pois o coagulômetro é um método mais preciso do que o imunonefelômetro.

Palavras-chave:
coagulômetro; Covid-19; dímero D; nefelômetro

1. Introduction

D-dimer, the result of fibrin depletion, is increased during a large thrombotic dose due to the selective activation of the fibrinolytic structure (Lippi et al., 2014). D-dimer measurement is important to measure the progression of D-dimer levels (Van der Pol et al., 2017). Examination of the results obtained by various techniques is unthinkable because the concentration of the D-dimer is less than the metal. The test changes due to the lack of a definite structure in the D-dimer with the same synthesis (Szecsi et al., 2010). A limited level of D-dimers in clinical confirmation anticipates the risk of venous thromboembolism, while other common risk factors, for example, age or weight list did not. D-dimer dose of venous thromboembolism was clinically effective when the level was <1.0 μg/ml while patients with significant levels (≥ 3.0 μg/ml) had a higher risk of venous thromboembolism. Our data also suggests that the detection of D-dimers may improve the risk gauge. The need for migration to the emergency unit and / or intrusive ventilation mechanical continued in patients who developed venous thromboembolism, although the general clinical qualifications did not differ from patients who did not grow up at that time.

This has reliable reliability for predicting levels of D-dimer levels in Coronavirus pneumonia, very high levels of validation related to primary presentation, and high mortality (Tang et al., 2020; Zhou et al., 2020). Increasing plasma D-Dimer was found to be a predictor of harmful effects in respiratory disorders in a few investigations (Fruchter et al., 2015). The purpose of our research was to see how effective the predictive dynamic D-Dimer variant was the primary trial in confirming and elevating the cause during sleep, in patients with Coronavirus. D-Dimer is a magnetic field that is transported by the hydrolysis of fibrin (Gorjipour et al., 2019). It could reveal the effects of pollution on coagulation in disorders that aren't yet diagnosed. Several studies have linked elevated D-dimer levels to hypercoagulable blood pressure and the prevalence of apoplexy in patients with pneumonia (Arita et al., 2016; Guo et al., 2020). D-Dimer of patients with primary coronary artery disease was completely expanded, with severe complications of stiffness and minor thrombotic development in the arteries (Jin et al., 2020). In this review study, we examined the single-dimensional D-Dimer but further examined the dynamic changes of the D-Dimer, especially the intensity of the visual stimulus. D-Dimer measurements are often used to show vein apoplexy (DVT) and aspiratory embolism (PE) in unwell individuals who were referred to the disaster office after a venous thromboembolism event (VTE). D-Dimer testing should be used in conjunction with a comprehensive, sequential symptomatic approach that includes both test and clinical approaches (Doppler ultrasonography, scintigraphy, and registered tomography)

A D-dimer test that is negative, together with its high sensitivity and negative predictive value (NPV), can safely avoid a VTE event in outpatients with low-dose PTP without the need for imaging studies (Bates et al., 2003; Perrier et al., 1999; Schutgens et al., 2003). Also, the demonstration of all D-dimer tests should be evaluated in close proven outcomes that focus on the patient's eligibility before clinical use by considering the need to perform these tests, variance in combination of limited analyzes, differences in antibodies and measurements used in test units, and a variety of measurements. Alternatively, given the exceptional number of techniques available these days, given the various procedures and flexible clinical practice, the D-dimer's decision to evaluate VTE rejection should consider the variance of variance (CV) in the cutting area and the implications for exposure and clarity (Righini et al., 2008).

Covid is one of the most important microbes in the human respiratory system. Previous outbreaks of Covid-19 include a severe respiratory problem (SARS) Cov2 and the Middle East (MERS) respiratory syndrome has recently been identified as one of the most serious health risks. A large number of patients were admitted to the hospital near the end of December 2019 emergency clinics with a pneumonia diagnosis of unknown etiology. As indicated by the latest information, as of walk 1, 2020, the total In China, there were 79,968 confirmed cases, with 2,873 of them being fatal, and 41,681 were released. Except for In China, there were 7,041 confirmed instances in similar countries, with 105 people killed and 459 reinstated. On January 31, 2020, the World Health Organization (WHO) reported that Coronavirus was listed meaning it could pose a threat to various nations and required a systematic global response. The study attempts to elucidate sub-atomic invulnerable pathogenesis and analysis of Coronavirus and provide guidance on the antagonism and SARS medication development -Cov2 contaminants, based on the ongoing SARS-Cov2 testing and information from SARS-Cov2 investigators and MERS-Cov.

2. Materials and Methods

2.1. Research type and design

This is an experimental research design where the study Covid19 patients were completely randomized in order to try and distribute the underlying variables. This study was a laboratory true experimental study design, to identify the D-Dimer levels. For this study, the experimental Covid19 positive patients were chosen for blood collection by randomization where those samples were collected by following the WHO proper protocols. Concentrated Plasma was preserved in refrigerator at -20 °C or -70 °C for further laboratory processing.

A number of reagents were employed from the beginning until the completion of this research. SARS-CoV-2 IgG Reagent Kit 6R86 was used specifically for this research because the patients were infected with corona virus.

Syringe was used for the collection of blood from the positive infected Covid19 patients. The Gloves was used to help and prevent direct contact with pathogens, either from contact with body fluids by surface contamination or by needle-stick for the safety of the health workers. The tourniquet was used by the phlebotomist to assess and determine the location of a suitable vein for venipuncture. Dry gauze was being used for dressing after the blood collection. The suitable tubes were used because the collected blood samples were taken in the tubes for further laboratory experiments and procedures. Alcohol was applied after removing the tourniquet for the cleaning of patient arms. Centrifuge was used for the separation of blood samples into different layers which was serum, liquid and solid. The obtained results of the D-Dimer tests were collected through Sysmex CS2500 and Architecti1000 these were the two machines which was used for this research.

2.2. Inclusion criteria

• Confirmed covid-19 patients;

• D-dimer test was prescribed by the doctor;

• The level of D-dimer varied from low to very high levels;

• Confirmed covid-19 patients were admitted in Dr. Soetomo General Academic Hospital because the inform consent from the participated patients have been done due to their approval and permission and by the approval of ethical clearance.

2.3. Exclusion criteria

• The samples are really lipemic, Icteric, heamolytic so it was not measured by the turbidometery;

• Quantity was not sufficient;

• Patients who were not agreed to be involve in the project.

This study has been approved by the local medical research ethics committee at Dr. Soetomo General Academic Hospital, Surabaya, Indonesia with an approval No: 070/1013/CRU/IX/2020.

3. Results

3.1. Immunoturbidimetry

Immunoturbidimetry to detect the quantity of an analyte, immunoturbidimetry measured the turbidity of a specimen. When the assay reagent is added, antibodies and antigen combine to make immunological complex that occurs, raising the sample's turbidity. Some light was dispersed some of the sample was absorbed by the solution, and the remainder passed through the sample when light was sent through the reaction solution. The absorption of light by the sample was also measured, whereas nephelometry detects light dispersed at a specific. The level of analyte is determined by comparing it to a known concentration calibrator.

3.2. Immunological aspect with a clinical condition

The chest X-rays were performed during the process through which it was confirmed that on 26th of march, 2021 the D-Dimer level of a patient was 7580 ng/ml while on the 31st of march the D-Dimer level comes down to 3500 ng/ml. In the below figured the chest X-rays showed the trend of increasing infiltrate until 2nd of April and then it got decreased on 4th April. The D-Dimer level was increased on 26th of March due to Covid-19, so the increased D-Dimer could be caused by inflammation, but on 31st march was not as high as it was at first time. Examination and the inflammation were worst showed which was showed by chest X-ray and the shortness of the breath was also became more severe which was showed by the blood gas analysis, so the decrement of D-Dimer from initial value did not correlate with the grade of inflammation (Figure 1 The above Chest X-rays shows that the D-Dimer levels were of high level due to the shortness of the breathing of Covid19 patients and then these chest x-rays were performed during their stay at the hospital to evaluate and examine their progress.)

Figure 1
The above Chest X-rays shows that the D-Dimer levels were of high level due to the shortness of the breathing of Covid19 patients and then these chest x-rays were performed during their stay at the hospital to evaluate and examine their progress.

The above Chest X-rays shows that the D-Dimer levels were of high level due to the shortness of the breathing of Covid19 patients and then these chest x-rays were performed during their stay at the hospital to evaluate and examine their progress.

(Figure 2. Temporal trends in chest X-ray findings, D-dimer levels, and clinical severity in a COVID-19 patient. Chest X-ray demonstrated progressive pulmonary infiltrates until 2 April, followed by partial resolution by 4 April. D-dimer, markedly elevated on 26 March, decreased by 31 March but without correlation to radiographic progression or clinical worsening. Peak respiratory compromise, indicated by arterial blood gas analysis and increased dyspnea, coincided with maximal radiographic involvement rather than with D-dimer levels. Measurements were obtained several days following the onset of infection. At this stage, the patient’s D-dimer concentration demonstrated a notable increase relative to the initial assessment, whereas respiratory parameters remained largely unchanged. These findings were consistent with the presence of metabolic acidosis, which subsequently showed partial resolution within a few days (Figure 3).

Figure 2
Temporal trends in chest X-ray findings, D-dimer levels, and clinical severity in a COVID-19 patient.

Figure 3
These were performed after few days of the infection in which it can be observed that the patients was an increased from the initial stage and the respiration conditions were not having any difference which was caused by the metabolic acidosis and this acidosis got decreased after a couple of days.

A separate case involved a patient diagnosed with coronavirus disease 2019 (COVID-19) who exhibited elevated D-dimer levels attributable to the infection. Laboratory testing, conducted in May, revealed an increase in D-dimer from the baseline value, with no appreciable alterations in respiratory function. The observed reduction in acidosis was considered to reflect compensatory physiological mechanisms in response to metabolic acidosis. Nevertheless, the patient’s clinical condition deteriorated again after several days, accompanied by a further rise in D-dimer levels compared with the preceding measurement, although the values did not exceed those recorded during the initial evaluation.

As the main goal of this research is to make a comparison between CS2500 and Architecti1000 by using two methods i-e immunonephelometer and coagulometer so according to the result of the statistical test, there is a difference between CS2500 and Architecti1000 (p=.019) (Figure 4. The Mann–Whitney U test was employed to compare the two analyzers. Mean and range values were reported, as the distribution of data for both groups was non-normal. This deviation from normality was likely attributable to the fact that all patients were confirmed positive for SARS-CoV-2 infection. While a standard parametric test would yield a p-value < 0.05 under normal distribution assumptions, the presence of non-normal data necessitated the use of a non-parametric approach. The assumption of equal variances was not met, as confirmed by the Mann–Whitney U test. Figure 5 illustrates these findings and is cited here in sequential order for clarity. Comparison of D-dimer levels using coagulometer with immuno-nephelometer

Figure 4
Normal Plot Architect i1000.

Figure 5
Detrended Normal Q-Q Plot of Architect i1000.

Immuno-nephelometric techniques have proven particularly suitable for automation, with advancements in this field relying heavily on the development of dispersed light detection sensors. Early instruments measured light scattering at a fixed angle of 90°, while subsequent systems demonstrated increased sensitivity by utilizing improved light scattering detection at lower angles of 31° or less (Figure 6). These designs facilitated the generation of high-intensity light at a relatively low cost. Moreover, the technique of rate nephelometry has evolved considerably. In this approach, light dispersion is measured at two or more distinct time points, enabling quantification of the rate of increase in light scatter over the defined measurement interval.This method is based on the notion that dispersion is proportional to the size of immune complexes, which is proportional to the antigen-antibody reaction time.

Figure 6
Normal Q-Q Plot of CS2500.

Immuno-nephelometric techniques have proven to be well-suited for automation, with advancements in this field being largely dependent on the development of dispersed light detection sensors. Early instruments measured light scattering at a fixed angle of 90°, whereas subsequent systems demonstrated enhanced sensitivity to the incident light beam by employing lower detection angles of 31° or less, thereby improving light scattering measurement efficiency (Figure 7). These devices are capable of generating high-intensity light at a relatively low cost. Significant progress has also been achieved in the refinement of rate nephelometry. In this modified approach, light dispersion is measured at two or more distinct time points, enabling quantification of the incremental increase in light scattering over the specified interval. This methodology is predicated on the principle that light dispersion is directly proportional to the size of immune complexes, which, in turn, correlates with the progression of the antigen–antibody reaction over time.

Figure 7
Detrended Normal Q-Q Plot of CS2500.

4. Discussion

4.1. Comparison of D-dimer levels in previous Covid-19 patients

The hospitalized patients Covid-19 and a D-dimer level that has been validated in the lab measured at least 3 D-dimer values within 3 days of the onset (for entrance D-dimer analysis) measured before to the result of interest (for D-dimer trend analysis) were retrospectively analysed. in RSUD. Dr. SOETOMO hospital, Surabaya between February 1, 2021, and May 31st, 2021. The electronic medical record of a patient admitted with a diagnosis of COVID-19 was used to identify them. A positive reaction between reverse transcriptase and polymerase chain (RT-PCR) SARS-CoV-2 screening a sample of a sinonasal swab defined confirmed Covid-19. The accessibility and findings of D-dimer levels were assessed and extracted using the clinical laboratory's health system. The relevance of VTE in the pathophysiology of COVID-19, as well as the possible role of D-dimer levels as COVID-19 markers and prognosis predictors, has piqued interest. Higher entry D-dimer was linked to a higher in this retrospective study, the risk of the all-death rates, the necessity for mechanical ventilation (intubation), and VTE were all examined research of 30 COVID-19 patients. However, the admitted D-dimer did not appear to be a reliable predictive test for COVID-19 patients' outcomes when used alone. Following admission, specific D-dimer patterns were closely linked to the same outcomes. However, as a stand-alone metric, D-dimer trend/trajectory a valid prospective test for these consequences did not appear to be beneficial.

The compared D-dimer assays were the facts that effected assay comparability which was not international standard and for D-dimer. There were different reporting units which was D-dimer Unit (DDU) and fibrinogen equivalent unit (FEU). The antibodies had different affinity to D-dimer compounds, and it had different reagents and assay methodologies which resulted in different interferences and signals. It is concluded that each manufacturer established its own standardization method. Various assays have different performance characteristics. It had different standardizations typically result in different quantitative results on the same patient.

4.2. Incidence of asymptomatic deep vein thrombosis in patients with Covid-19 pneumonia and elevated D-dimer levels

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the main manifestations of venous thromboembolism (VTE). DVT and PE is almost always an outcome of DVT and carries common risk factors. D-dimer is a result of fibrin breakdown which functions fibrinolysis as a potential marker. It is commonly raised during thrombotic episodes. Since December 2019, when the coronavirus disease 2019 (COVID-19) first appeared in Wuhan province and quickly spread throughout China and the world, biological and clinical-epidemiological characteristics of the infection have been published.

Although majority of these research were limited by sample size and/or problematic methodology, and they all only looked at static D-dimer levels, some recent research has suggested that D-dimer levels may be a good predictor of outcomes in COVID-19 patients (with none examining D-dimer trends). In a study of 343 inpatients with COVID-19 from Wuhan Asia General Hospital, an AUC of 0.89 for a ROC of admission D-dimer as a predictor of in-hospital death was observed. They also claimed that their proposed D-dimer limit of 2 g/ml had a sensitivity and specificity of 92 and 93 percent for mortality prediction, respectively. However, these conclusions were based on only 13 deaths events in the sample, which is insufficient to build a thorough and trustworthy ROC. A D-dimer level more than 1 g/ml was reported as a predictor of poor prognosis in a retrospective study of 191 patients from two different hospitals in Wuhan, China. Again, this conclusion was reached based on a small number of death events (n = 54). More importantly, this conclusion was reached after comparing small groups of patients with D-dimer levels that were arbitrarily set. Patients who needed to be admitted to the intensive care unit (ICU) had greater d-D-dimer readings than those who did not, according 41 COVID-19 patients were admitted to a single centre in Wuhan, China, for prospective research. However, this comparison included only 13 ICU it was based on a restricted single analysis of patients. The fact that individuals with COVID-19 usually have considerably high D-dimer values has been used to support the theory that thromboembolic processes play a significant role in the pathophysiology of this condition.

4.3. Clinical characteristics of corona virus disease 2019 in China

When the pandemic began, there were more than 20,000 individuals returning from Wuhan to Taizhou, according to statistics. As a result, Taizhou has become one of the primary hotspots for imported cases. Given the fast spread of SARS-CoV-2 in Taizhou, a bigger sample size analysis is urgently needed. It aimed to give an up-to-date definition of the clinical characteristics of COVID-19 patients in Taizhou by collecting data from 145 laboratory confirmed cases. The goal of this case study was to characterize the clinical characteristics of 145 COVID-19 patients who were hospitalized and to compare them to seriously unwell patients with non-severely ill patients (Chen et al., 2020). The data collected from 1099 patients from 552 hospital in 30 provinces in China.

In terms of prognostic laboratory data, which may be even more important for the timely identification of patients at higher risk of adverse outcome, Wang et al. published an interesting study in which they looked at the behavior of six laboratory parameters over the course of 19 days in 138 patients with COVID-19 infection (33 with severe disease), five of whom died during their hospital stay (Table 1. There were a few notable distinctions between patients who needed to be admitted to the intensive care unit and those who did not (ICU) Higher values of LDH (2.1-fold), alanine aminotransferase (ALT) (1.5-fold), aspartate aminotransferase (AST) (1.8-fold), total bilirubin (1.2-fold), creatinine (1.1-fold), cardiac troponin I (2.2-fold), D-dimer (2.5-fold), and procalcitonin (0.9-fold) were seen in those who did not (1.2-fold) (Lippi and Plebani, 2020). The former test does not appear to have changed significantly in COVID-19 patients at admission, but the steady increase in its value appears to reflect a worse prognosis. This is not surprising, given that serum procalcitonin levels are normally normal in patients with viral infections (or viral sepsis), but gradually rise with bacterial superinfection, potentially contributing to the clinical course's adverse progression. Measurement of additional novel sepsis biomarkers, such as presepsin, for example, would almost certainly aid in improving the accuracy of COVID-19 case detection.)

Table 1
Laboratory Parameters.

Parameter	Non severe	Severe	Survival	Non Survivals
D dimer ≥ 0.5 ug/mL	43.2%	59.6%	44.2%	69.4%
CRP ≥ 10 mg/L	56.4%	81.5%	58.8%	91.1%
PCT≥ 0.5 ng/mL	3.7%	13.7%	3.9%	24.0%

5. Conclusion

Based on the findings of this research, it is concluded that the compared levels of D-dimer obtained by using coagulometer with an immuno-nephelometer in Covid-19 patients were higher D-Dimer Levels as compared to the normal patients. Besides that, there is also a difference between CS2500 and Architect i1000 by using immuno-nephelometer and coagulometer because Coagulometer is the more accurate method than the Immuno-nephelometer.

Data Availability Statement

The research data are only available upon request to the corresponding author. (SciELO recommends this option only in cases where there are ethical, security or financial restrictions).

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Edited by

• Editor:
  Marcelo A.M. Esquisatto

Publication Dates

• Publication in this collection
  22 Sept 2025
• Date of issue
  2025

History

• Received
  22 Oct 2024
• Accepted
  27 Mar 2025