European Journal of Cardiovascular Medicine

SCA is a hereditary blood condition that causes the creation of aberrant hemoglobin S, which results in the development of stiff, sickle-shaped red blood cells. Due to ischemia and infarction, these malformed cells can impede blood flow, producing volatile organic compounds (VOCs) that cause excruciating pain and organ damage. Because of their severity and unpredictability, volatile organic compounds (VOCs) are a hallmark of SCA and present substantial clinical management issues [1].

Recent advancements in understanding the pathophysiology of SCA have highlighted the role of inflammation and hypercoagulability as pivotal factors in the initiation and propagation of VOCs. During these crises, the sickled cells, along with other cellular elements such as leukocytes and platelets, contribute to a pro-thrombotic state, enhancing the risk of thromboembolic events [2]. D-dimer, a fibrin degradation product, is commonly elevated during episodes of acute thrombosis and has been studied as a biomarker for the severity of VOCs. Elevated levels of D-dimer in SCA patients suggest an ongoing activation of the coagulation cascade, which correlates with the severity of the crisis and could potentially guide therapeutic strategies [3].

Chest complications, including acute chest syndrome (ACS), which is defined by a new infiltrate on chest X-ray accompanied by symptoms such as fever, chest pain, and respiratory distress, represent one of the most severe manifestations of VOCs. ACS is the leading cause of mortality in SCA patients and often necessitates aggressive treatment including transfusion therapy [4]. Radiographic studies play a crucial role in diagnosing such complications early, allowing for timely and appropriate management.

Given the significance of timely diagnosis and the potential for D-dimer levels to serve as a prognostic tool, there has been an increasing interest in exploring the correlation between radiographic findings and serum D-dimer levels in patients with SCA during VOCs. Studies have suggested that high D-dimer levels are associated with more severe clinical outcomes and could predict the occurrence of complications like ACS [5]. This study aims to investigate the correlation between chest X-ray findings and serum D-dimer levels in patients with SCA during VOCs, to better predict complications and guide treatment.

Study Design

This study is a retrospective observational study.

Study Setting

The study will be conducted at VSS Institute of Medical Sciences and Research (VIMSAR), Burla, Sambalpur, Odisha. The institution is a tertiary care center that caters to a significant population of patients with sickle cell anemia, making it an ideal setting for this research.

Study Duration

The study will cover medical records from January 1, 2024, to December 31, 2024. Data collection and analysis will take place within this period.

Participants

A total of 100 patients diagnosed with sickle cell anemia and admitted with vaso-occlusive crises during the study period will be included. The patient data will be retrieved from hospital records, including laboratory reports and imaging findings.

Inclusion Criteria

1. Patients diagnosed with sickle cell anemia based on clinical and laboratory findings.
2. Patients aged ≥ 18 years at the time of admission.
3. Patients with documented vaso-occlusive crisis as per clinical criteria.
4. Patients who underwent both chest X-ray and serum D-dimer testing during the crisis episode.

Exclusion Criteria

1. Patients with incomplete or missing medical records.
2. Patients diagnosed with other hemoglobinopathies or co-existing respiratory infections (e.g., pneumonia, tuberculosis).
3. Patients with a history of thromboembolic disorders unrelated to sickle cell disease.
4. Pregnant women and pediatric patients (<18 years).

Bias

To minimize bias, patient selection will be conducted randomly from available hospital records while ensuring adherence to inclusion and exclusion criteria. Data extraction will be performed by independent researchers to reduce selection and observer bias. Additionally, all radiological and laboratory reports will be analyzed blinded to clinical outcomes.

Data Collection

Data will be collected retrospectively from hospital medical records, including:

• Demographic details (age, sex, history of sickle cell anemia).
• Clinical presentation (symptoms of vaso-occlusive crisis, duration of crisis).
• Laboratory data (serum D-dimer levels at admission).
• Radiological findings (chest X-ray reports documenting pulmonary abnormalities).

The extracted data will be entered into a structured database for statistical analysis.

Procedure

The collected data will be analyzed to determine the relationship between chest X-ray abnormalities (e.g., pulmonary infiltrates, consolidation, effusions) and serum D-dimer levels in patients experiencing VOCs. A comparative analysis will be performed to assess the significance of elevated D-dimer levels in patients with and without radiological abnormalities.

Statistical Analysis

SPSS software, version 23.0, will be used for all statistical analyses. The independent t-test or Mann-Whitney U test, as applicable, will be used to compare continuous variables, such as D-dimer levels, which will be reported as mean ± standard deviation (SD). Chi-square or Fisher's exact test will be used to assess categorical variables (such as the existence of pulmonary infiltrates). The Pearson's or Spearman's correlation coefficient will be used to evaluate the relationship between serum D-dimer levels and chest X-ray results. Statistical significance is defined as a p-value < 0.05.

The study included 100 participants with sickle cell anemia experiencing VOCs. The participants had a mean age of 38.5 years with a standard deviation of 10.2 years, ranging from 18 to 59 years. The sample consisted of 60% males and 40% females. The average oxygen saturation at presentation was 92.4% with a standard deviation of 4.2%, and the mean duration of hospital stay was 6.8 days with a standard deviation of 3.1 days.

Distribution of Chest X-ray Findings

The findings from chest X-rays varied among the participants, indicating different levels of pulmonary complications:

• Normal findings: Observed in 50 patients (50%)
• Pulmonary infiltrates: Noted in 30 patients (30%)
• Consolidation: Found in 15 patients (15%)
• Pleural effusion: Present in 5 patients (5%)

Table 1: Distribution of Chest X-ray Findings

D-dimer Levels and Chest X-ray Findings

The study analyzed the relationship between D-dimer levels and chest X-ray findings, demonstrating varying levels of D-dimers associated with different pulmonary findings.

Table 2: D-dimer Levels by Chest X-ray Findings

Correlation Between D-dimer Levels and Oxygen Saturation

A significant negative correlation was found between D-dimer levels and oxygen saturation, indicating that higher D-dimer levels are associated with lower oxygen saturation levels.

Table 3: Correlation Coefficient between D-dimer Levels and Oxygen Saturation

Hospital Stay Duration Based on X-ray Findings

The length of hospital stays was also correlated with the severity of chest X-ray findings.

Table 4: Hospital Stay Duration by Chest X-ray Findings

The retrospective study conducted on 100 sickle cell anemia patients. The demographic profile of the cohort revealed an average age of 38.5 years with a predominance of male patients (60%). The average oxygen saturation at presentation was moderately high at 92.4%, yet the variation in D-dimer levels and X-ray findings underscored differing degrees of crisis severity.

The analysis of chest X-ray findings indicated that half of the patients exhibited normal X-rays, while the remainder displayed signs of pulmonary complications, ranging from infiltrates and consolidation to pleural effusion. Notably, D-dimer levels varied significantly with these radiographic findings. Patients with normal X-rays had the lowest mean D-dimer levels at 0.97 mg/L, suggesting minimal systemic coagulation activity. In contrast, those with more severe pulmonary findings such as consolidations and pleural effusions exhibited higher D-dimer levels, peaking at 2.78 mg/L for those with pleural effusions. This gradation in D-dimer levels aligns with the increasing severity of pulmonary damage and implies a possible role of D-dimer as a marker for pulmonary complications in sickle cell crises.

Further, the study established a negative correlation between D-dimer levels and oxygen saturation, where higher D-dimer levels corresponded to lower oxygen saturation percentages, affirming the clinical impact of increased coagulation activity on pulmonary function. The correlation coefficient of -0.42 with a significance level of p=0.001 strongly supports this association.

Hospital stay durations were also reflective of the severity of the findings on chest X-rays. Patients with normal radiographic findings had the shortest average hospital stays of approximately 4.8 days, whereas those with pleural effusion, the most severe complication noted, stayed the longest at nearly 11.8 days. This variation in hospitalization duration further emphasizes the burden of pulmonary complications on healthcare utilization and patient morbidity in vaso-occlusive crises. In summary, the study highlights the utility of serum D-dimer levels as a biomarker for detecting and assessing the severity of pulmonary complications in sickle cell anemia patients during vaso-occlusive crises. The direct correlations between increased D-dimer levels, severity of chest X-ray findings, decreased oxygen saturation, and prolonged hospital stays elucidate the interconnected dynamics of coagulation, pulmonary health, and clinical outcomes in this patient population.

Several studies have investigated the correlation between coagulation markers, including D-dimer levels, and the occurrence of vaso-occlusive crises (VOC) in sickle cell anemia (SCA) patients.

A study by Ebele et al. assessed serpin A5 levels and coagulation parameters in SCA patients during vaso-occlusive crises and in steady-state. The findings indicated that D-dimer levels were elevated during crises compared to steady-state, but the difference was not statistically significant (p = 0.11). The study confirmed that hypercoagulability is a key factor in vaso-occlusive crises, with increased levels of prothrombotic substances such as serpin A5 and prolonged prothrombin time during crises [6]. Similarly, Adebola et al. conducted a study on children with SCA and reported significantly higher mean D-dimer levels (7358 ± 4354.33 ng/ml) during painful crises compared to steady-state (5509 ± 3506.2 ng/ml). These results support the presence of an exaggerated hypercoagulable state in pediatric SCA patients during crises [7].

Effiong et al. investigated capillary blood flow and D-dimer activity in SCA patients and found significantly elevated D-dimer levels in steady-state patients compared to controls. The study also revealed that patients experiencing crises had lower capillary blood flow, highlighting the link between microvascular impairment and coagulation abnormalities in SCA [8]. Mohamed et al. further examined hypercoagulability changes in Sudanese SCA patients and observed a significant increase in D-dimer levels during vaso-occlusive crises compared to the steady state (p = 0.006). This study confirmed that VOC is associated with fibrinolysis activation, which contributes to vascular complications in SCA patients [9].

Fadelmula and Abdalla evaluated the effect of hydroxyurea treatment on D-dimer levels in SCA patients and found that treated individuals had significantly lower levels (0.93 ± 0.52 ng/ml) compared to untreated patients (4.61 ± 1.76 ng/ml, p < 0.0001). Additionally, patients receiving hydroxyurea treatment showed improved clinical outcomes with a lower frequency of vaso-occlusive crises, reinforcing the beneficial role of hydroxyurea in mitigating coagulation abnormalities in SCA [10]. These findings collectively demonstrate that D-dimer levels are consistently elevated during vaso-occlusive crises, supporting their potential role as biomarkers for hypercoagulability in sickle cell anemia.

The study's findings demonstrate the relationship between sickle cell anemia patients' blood D-dimer levels and chest X-ray findings during vaso-occlusive crises. Lower oxygen saturation levels and more severe pulmonary abnormalities were linked to higher D-dimer levels, indicating that D-dimer may be a helpful biomarker for determining the degree of pulmonary problems in these patients. Furthermore, the degree of chest X-ray abnormalities is associated with longer hospital admissions, highlighting the influence of pulmonary problems on sickle cell disease clinical outcomes.

1. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148(2):94-101.
2. Ataga KI, Orringer EP. Hypercoagulability in sickle cell disease: a curious paradox. Am J Med. 2003;115(9):721-8.
3. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
4. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med. 2000;342(25):1855-65.
5. Fasano RM, Booth GS, Miles M, et al. Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. Blood. 2016;127(7):1014-21.
6. Ebele U, Aderonke H, Akinsegun A, Fafatu B, Nda I, Augustine B, et al. Assessment of serpin A5 levels and coagulation parameters of sickle cell anemia patients during bone pain vaso-occlusive crisis and steady state. Egypt J Haematol. 2022;47(3):152-157.
7. Adebola MB, Olanrewaju D, Ogundeyi MM, Shonde-Adebola KB. Coagulation changes in children with sickle cell anaemia during painful crises and steady state at Federal Medical Centre Abeokuta, Nigeria. Open Access Library J. 2018;5(12):1-17.
8. Effiong OL, Aneke J, Okafor I, Soronnadi C, Abasibom IE. Speed of capillary blood flow and D-dimer levels in sickle cell anaemia patients in Calabar, Cross River State. Int J Res Med Sci. 2021;9(12):3725-3731.
9. Mohamed EA, Elgari MM, Babker AM, Waggiallah H. Comparative study of hypercoagulability change in steady state and during vaso-occlusive crisis among Sudanese patients living with sickle cell disease. Afr Health Sci. 2020;20(1):392-396.

10. Fadelmula EA, Abdalla MA. Determination of D-dimer level in sickle cell anemia patients under hydroxyurea treatment in Sinnar state, Sudan. GSC Biol Pharm Sci. 2020;10(2):106-110.