key: cord-0253973-ik4asrue
authors: Kapoor, M.; Panda, P. K.; Saini, L. K.; Bahurupi, Y. A.
title: A Retrospective analysis of DIC score and SIC score in prediction of COVID-19 severity
date: 2021-07-02
journal: nan
DOI: 10.1101/2021.06.26.21259369
sha: bffca46034f7e5d457b6f960f49ca49ec170b12d
doc_id: 253973
cord_uid: ik4asrue

Background: The novel Disseminated Intravascular Coagulation (DIC) score [platelet count, prolonged prothrombin time, D-dimer, and fibrinogen] and Sepsis Induced Coagulopathy (SIC) score [platelet count, International normalized ratio, and Sequential organ failure assessment score] are markers of coagulopathy, which, for the first time, are explored in line with the COVID-19 disease outcomes. The correlation of D-dimer with these findings is also studied. Patients and methods: A retrospective analysis of hospital-based records of 168 COVID-19 patients. Data including D-dimer, routine investigations, DIC and SIC scorings (all within three days of admission) were collected and correlated with the outcomes. The study was conducted in a tertiary care center catering to population of North India. Results: Higher DIC score (1{middle dot}59 {+/-} 1{middle dot}18 v/s 0{middle dot}96 {+/-} 1{middle dot}18), SIC score (1{middle dot}60 {+/-} 0{middle dot}89 v/s 0{middle dot}63 {+/-} 0{middle dot}99), and D-dimer titers (1321{middle dot}33 {+/-} 1627{middle dot}89 v/s 583{middle dot}66 {+/-} 777{middle dot}71 ng/ml) were significantly associated with severe COVID-19 disease (P<0{middle dot}05). DIC score and SIC score [≥] 1, and D-dimer [≥] 1315 ng/ml for severe disease; DIC score [≥] 1, SIC score [≥] 2, and D-dimer [≥] 600 ng/ml for Pulmonary Embolism (PE); and DIC score and SIC score [≥] 1, and D-dimer level [≥] 990 ng/ml for mortality were the respective cut-off values we found from our study. Conclusion: Higher DIC scores, SIC scores, and D-dimer values are associated with severe COVID-19 disease, in-hospital mortality, and PE risk. They can serve as easily accessible early markers of severe disease and prioritize hospital admissions in the presently overburdened scenario, and may be used to develop prognostic prediction models.

Results: Higher DIC score (1·59 ± 1·18 v/s 0·96 ± 1·18), SIC score (1·60 ± 0·89 v/s 0·63 ± 0·99), and D-dimer titers (1321·33 ± 1627·89 v/s 583·66 ± 777·71 ng/ml) were significantly associated with severe COVID-19 disease (P<0·05). DIC score and SIC score ≥ 1, and D-dimer ≥ 1315 ng/ml for severe disease; DIC score ≥ 1, SIC score ≥ 2, and D-dimer ≥ 600 ng/ml for Pulmonary Embolism (PE); and DIC score and SIC score ≥ 1, and D-dimer level ≥ 990 ng/ml for mortality were the respective cut-off values we found from our study.

Higher DIC scores, SIC scores, and D-dimer values are associated with severe COVID-19 disease, inhospital mortality, and PE risk. They can serve as easily accessible early markers of severe disease and prioritize hospital admissions in the presently overburdened scenario, and may be used to develop prognostic prediction models.

The Coronavirus disease 2019 (COVID- 19) pandemic has taken the whole world by storm. Despite the falling number of cases in few areas, it has re-emerged in many countries, raising concerns. Various prognostic markers are proposed to recognize severe disease so that priority is given to those patients first for hospitalization given the overburdened healthcare infrastructure.

Hemostasis (ISTH) proposed it as a DIC scoring system. The presence of a disease associated with DIC (malignancy, severe infection, or sepsis) is a prerequisite for using this scoring system. Increasing scores highly correlate with higher mortality rates. The coagulation profile [platelet count, prolonged prothrombin time (PT), D-dimer, and fibrinogen) is a marker of DIC's dynamic nature (Table 1 ). These must be repeated serially. (Table 1) and has a high predictive value for 28-days mortality. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. D-dimer from the very beginning has been shown to correlate with the severity and mortality in the ongoing COVID-19 pandemic.(5-7) D-dimer forms as a by-product of the clotting mechanism in the body. When a blood All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint clot breaks, D-dimer gets released into the bloodstream. The average D-dimer value is less than 500 ng/ml; any value greater than 500 ng/ml is considered high. (8) (9) (10) (11) (12) As is well known, a patient with COVID infection is predisposed to venous thromboembolism, (13) and this is one of the factors responsible for the worse outcomes. Hence, we explore these new scoring systems, the DIC score and the SIC score, along with the D-dimer values, all of which are markers of coagulopathy, in line with the COVID-19 disease severity, mortality, and the risk of Pulmonary Embolism (PE) development.

The study was carried out at All India Institute of Medical Sciences, Rishikesh (AIIMS Rishikesh), a tertiary care center catering to North India's population.

We retrospectively analyzed all the case records of lab-confirmed COVID-19 patients at least 18 years of age from March 2020 till December 2020. COVID-19 positivity was defined as a positive result on reverse transcriptasepolymerase chain reaction (RT-PCR) SARS-CoV-2 assay of nasopharyngeal or oropharyngeal swab specimens. SD Biosensor standard M nCoV real-time detection kit was used for PCR. Biorad CFX 96 real-time thermocycler, and a Thermo flex 96 extractor machine was used for RNA extraction. All laboratory tests were performed in the institutional laboratory, according to the institutional standards. All patients received routine care as per hospital protocol. The D-dimer levels (calculated by immune-turbidometric assay) and routine blood investigations within three days of hospital admission were collected. DIC scores and SIC scores were calculated according to the respective guidelines.(1) , (3) Patients having active thromboembolic disease before symptom onset or before testing for COVID-19 and pregnant females were excluded from the analysis. CT pulmonary angiogram (CTPA) was done based on the clinical judgment of the physician. We categorized the patients during hospitalization into various severity categories according to the Ministry of Health and Family Welfare (MoHFW), India guidelines ( Table   2 ).(14) All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint We determined the correlation of DIC score, SIC score, and D-dimer levels at admission with the clinical outcome and severity in COVID-19 patients and estimated the cut-offs of these parameters in predicting the severity, mortality, and PE risk.

Continuous data following normal distribution and homogeneity of variance was expressed as mean ± SD.

Comparison done by independent samples t-test or expressed as median (25- Logistic regression of a binary response variable (Y) on a binary independent variable (X) with a sample size of 127 observations achieved 80% power. Considering a 20 % drop rate, we took a sample size of 168.

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint clinical staging. ROC curves were plotted to derive the cut-offs for various outcomes. Statistical analyses were performed with the SPSS software version 25. P-value < 0·05 was considered statistically significant.

The Institutional Ethical committee of All India Institute of Medical Sciences Rishikesh approved the study prior to data collection. >>>>>>>> Insert Figure 1 here <<<<<<<<<<<

A total of 168 subjects were recruited in our study ( Figure 1 ). 67·3% (113) of the total patients were males, whereas 32.7% (55) were females. The baseline characteristics of the patients are presented in Table 3 . 39·9% (67) of the patients had mild disease, whereas 22·6% (38) had moderate, and 37·5% (63) had severe disease at presentation. The mortality rate was 19·6% (33), while 80·3% (135) patients were discharged from the hospital. Based on the clinician's recommendation, CTPA was done for 82 subjects. It was reported as normal for 70 (85·3%) patients, whereas PE was detected in 12 (14·6%). Association of the variables with the severity of COVID disease is presented in Table 4 . The correlation of DIC scores, SIC scores, and D-dimer values with the various outcomes is presented in Tables 5 and 6 . Higher DIC score (1·59 ± 1·18 v/s 0·96 ± 1·18), SIC score (1·60 ± 0·89 v/s 0·63 ± 0·99), and D-dimer titers (1321·33 ± 1627·89 v/s 583·66 ± 777·71 ng/ml) showed a significant correlation with severe COVID-19 disease (P<0·05). Non-survivors also had higher DIC score (2·10 ± 1·22 v/s 1·10 ± 1·29), SIC score (2·00 ± 0·90 v/s 0·89 ± 1·06), and D-dimer levels (2239·16 ± 1825·84 v/s 672·91 ± 972·87 ng/ml) (P<0·05).

Similarly, patients with PE demonstrated raised DIC score (2·00 ± 1·59 v/s 1·19 ± 1·27; P=0·05), SIC score (1·92 ± 0·99 v/s 1·26 ± 0·95), and D-dimer titers (2025·80 ± 1814·02 v/s 904·34 ± 1285·98 ng/ml) (P<0·05). 41 patients (24·4%) were hypertensive, whereas 49 (29·16%) were diabetic. Both diabetes mellitus and hypertension were significantly associated with severe disease (Table 7) . We analyzed the receiver-operating curve (ROC) cut-All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint 1 0 offs for the various outcomes. D-dimer showed the highest likelihood ratio (LR+) for all the outcomes followed by SIC score. [Figures 2 (a),(b) ,(c); Table 8 ] All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint 1 1 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint 1 2 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint 1 4 >>>>>>>> Insert Figure 2 (a),(b) ,(c) here <<<<<<<<<<<

The COVID-19 pandemic, although contained in some parts of the world, is still re-emerging in many countries.

This has led to the re-introduction of lockdown in some countries.(15) This shows that still, we are far away from altogether tackling this pandemic. (16) It is essential to find out objective parameters to triage COVID-19 patients by predicting severity and outcome; this study was planned with this aim.

To our knowledge, our study is the first of its kind to evaluate the correlation of DIC and SIC scoring with the (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint 1 5 a significant association with the severity of COVID-19 disease in our study, with higher DIC score (1·59 ± 1·18 v/s 0·96 ± 1·18) and SIC score (1·60 ± 0·89 v/s 0·63 ± 0·99) being significantly associated with severe COVID-19 disease (P< 0·05). We propose DIC and SIC score ≥ 1 as the cut-off for predicting severe disease (sensitivity 76%/91%). DIC is a strong predictor of mortality, with studies showing up to 71·4% of the expired patients fulfilling the criteria for DIC compared to 0·6% of the survivors. (19) In our study too, higher DIC (2·1 ± 1·22 v/s 1·1 ± 1·29) and SIC (2·00 ± 0·90 v/s 0·89 ± 1·06) scores demonstrated significant association with mortality (P< 0·05). We found DIC (sensitivity 91%) and SIC (sensitivity 100%) score ≥ 1 as the cut-off for predicting mortality in this study. As is well known, the pro-thrombotic state can lead to events of venous thromboembolism, particularly PE. PE occurs whenever a clot forms within the pulmonary vasculature.(20) SIC scoring showed a significant association with PE probability, whereas DIC scores, although elevated in the PE patients, were not statistically significant. We found DIC (sensitivity 100%) score v/s 904·34 ± 1285·98 ng/ml, P=0·01) as compared to those with normal CTPA findings, and propose a D-dimer cutoff of 600 ng/ml as a threshold (sensitivity 83%) for PE , although further studies are required. Even though All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. previous studies have labeled the cut-off as >2000 ng/ml or even more,(31) our D-dimer value cut-off for PE is lower. One explanation is that we have assessed the D-dimer values within three days of admission and not at the time of PE occurrence, as we are studying D-dimer as a prognostic marker. As is seen with any test, false-negative and false-positive results may be seen. Many physiologic states can lead to elevated D-Dimer levels, including pregnancy, malignancy, smoking, trauma, infections, or sepsis. In addition to these, elderly patients, chronic immobilization, autoimmune diseases, and patients with recent surgeries can also present with high D-Dimer values.

An age-adjusted cut-off for D-Dimer is being proposed due to the increase in D-Dimer values as age progresses. (32, 33) We can calculate D-dimer values easily, and hence utilizing D-dimer values we can quickly determine patients requiring aggressive care and intensive care unit admissions well in advance. (34) As most of the patients have diabetes mellitus or hypertension as their significant comorbidities, we evaluated their correlation with the various parameters. Both of these correlated reasonably well with the disease severity. We found the D-dimer levels to be significantly higher amongst the hypertensive (1551·19 ± 1686·63 v/s 783·60 ± 1132·86 ng/ml, P=0·001) as shown in previous studies also.(35) It is well known that people with diabetes are at a higher risk for thrombotic events due to the imbalance between clotting factors and fibrinolysis.(36) Diabetic subgroup has higher D-dimer titers amongst the COVID positive patients.(37) Our study also demonstrated higher D-dimer levels in the diabetics (1281·08 ± 1508·30 v/s 843·22 ± 1227·86 ng/ml, P=0·05). DIC score was high in the hypertensive patients (1·85 ± 1·37 v/s 1·14 ± 1·22), whereas the SIC score was significantly higher in both the hypertensives (1·56 ± 0·95 v/s 0·97 ± 1·06) and the diabetics (1·39 ± 0·97 v/s 1·00 ± 1·08) (For all P<0·05). This again strengthens the fact that both these groups have a higher probability of thromboembolic events, hence demand more focused treatment in the ongoing COVID pandemic.

Our study has limitations. First, owing to our study design we could analyze only the hospitalized patients which allowed us to include fewer mild severity disease cases in comparison to high prevalence of mild COVID 19 cases in the population. So, the results of mild cases cannot be extrapolated to the population as a whole. Hence, larger population studies are needed to confirm our finding. Second, the decision to perform CTPA was purely at the discretion of the treating physician. Hence, CTPA could not be done for all the 168 subjects. As a result, we could have missed some sub-clinical PE cases. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint 1 7

The novel DIC score, SIC score, and D-dimer levels correlate with the COVID-19 disease severity, in-hospital mortality, and PE probability. Hence, they serve as excellent and easily accessible objective parameters to triage COVID-19 patients by predicting severity and outcome. This can help identify the severe cases early in the disease and decide the bed allocations in the presently overburdened hospitals. We propose the following cut-offs: DIC score and SIC score ≥ 1, and D-dimer ≥ 1315 ng/ml for severe disease; DIC score ≥ 1, SIC score ≥ 2, and D-dimer ≥ 600 ng/ml for PE; and DIC score and SIC score ≥ 1, and D-dimer level ≥ 990 ng/ml for mortality prediction, although further studies are required to strengthen these claims.

Statistical Relationship with PT, APTT, and Simplified Scoring Systems with Combinations of PT and APTT. ISRN Hematol

Towards Definition, Clinical and Laboratory Criteria, and a Scoring System for Disseminated Intravascular Coagulation

New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: A retrospective analysis of a nationwide survey

The third international consensus definitions for sepsis and septic shock (sepsis-3)

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Why COVID-19 Makes Some People Sicker Than Others -The Atlantic

Mild versus severe COVID-19: Laboratory markers

Biomarkers for the detection of apparent and subclinical cancer therapyrelated cardiotoxicity

Diagnostic significance of fibrin degradation products and d-dimer in patients with breast cancer-related lymphedema. Ann Rehabil Med

Biosensing of D-dimer, making the transition from the central hospital laboratory to bedside determination

D-dimer: Preanalytical, analytical, 1 9 postanalytical variables, and clinical applications

Incidence of thromboembolism in patients with COVID-19: a systematic review and meta-analysis

A look into Possible New Treatment Modality for COVID-19: ACE 2

SARS-CoV-2: A storm is raging

Coagulopathy as a Prodrome of Cytokine Storm in COVID-19-Infected Patients

Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia

Dimer Concentrations and COVID-19 Severity: A Systematic Review and Meta-Analysis. Front Public Heal

D-dimer level is associated with the severity of COVID-19

D-Dimer as a potential biomarker for disease severity in COVID-19

Elevated D-dimer levels on admission are associated with severity and increased risk of mortality in COVID-19: A systematic review and metaanalysis

Zhonghua Jie He He Hu Xi Za Zhi

E026. Available from

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: A case control study

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

D-dimer level is a useful predictor for mortality in patients with COVID-19: Analysis of 483 cases

Pulmonary embolism in COVID-19: Clinical characteristics and cardiac implications

A higher D-dimer threshold for predicting pulmonary embolism in patients with COVID-19: a retrospective study

What makes D-dimer assays suspicious-heterophilic antibodies?

Diagnostic accuracy of biomarker D-dimer in patients after stroke suspected from venous thromboembolism: A diagnostic meta-analysis

Hematological findings and complications of COVID-19

Relation of endothelium, thrombogenesis, and hemorheology in systemic hypertension to ethnicity and left ventricular hypertrophy

Funding: None

All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint 2 0 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.26.21259369 doi: medRxiv preprint