Plasma D-Dimer Level in Vietnamese Patients with Chronic Urticaria.

BACKGROUND: Chronic Urticaria (CU) is one of the most common skin diseases, affecting 2-3% of the population. Many studies have demonstrated that plasma D-dimer levels could be considered as a biomarker for disease activity and treatment response in patients with CU. AIM: To evaluate plasma D-dimer levels in patients with CU and their correlation with disease severity.
METHODS: The present study was a case-controlled study conducted in 97 patients with CU and 40 healthy subjects. Plasma D-dimer levels were measured using the enzyme-linked immunosorbent assay.
RESULTS: The mean plasma D-dimer level in patients with CU (807.76 ng/mL) was significantly higher than that in normal subjects (424.63 ng/mL) (P < 0.001). A significant correlation was observed between plasma D-dimer levels and the urticaria active score (P = 0.005, r = 0.28). Our study also suggested a significant difference in plasma D-dimer levels between patients with CU with and without angioedema.
CONCLUSIONS: Patients with CU had higher plasma D-dimer levels than the control group. A positive statistical correlation was observed between plasma D-dimer levels and severity of CU. Copyright:

Introduction

Chronic Urticaria (CU) is one of the most common reasons for patients to visit primary care practitioners, dermatologists, and hospitals[1] affecting at least 2–3% of the population.[2]

CU is characterized by the development of wheals (hives), angioedema, or both, and persistance for at least 6 weeks or more.[3] The quality of life in patients with CU is highly affected,[4] and nearly half of the patients suffer from CU even after 3 years of diagnosis.[5]

The pathogenesis of the disease has been investigated for decades. Urticaria is a mast cell-driven disease in which histamine and other mediators released from activated skin mast cells result in sensory nerve activation, vasodilation, plasma extravasation, and cell recruitment to urticarial lesions.[3]

Besides autoimmunity, in some patients with CU, the coagulation cascade is activated through the extrinsic pathway, and this activation could increase the plasma levels of D-dimer.[678]

Recent studies have demonstrated that plasma D-dimer levels could be considered as a biomarker for disease activity and treatment response in patients with CU.[910111213] However, no data concerning plasma D-dimer levels in Vietnamese patients with CU have yet been presented. We conducted this study to investigate the relationship between plasma D-dimer levels and disease activity in Vietnamese population.

Materials and Methods

Patients

After receiving institutional ethics clearance, the study was conducted in 97 patients with CU (at least twice a week for more than 6 weeks) who visited the outpatient department of Ho Chi Minh City Hospital of Dermato-Venereology, Vietnam, from October 2018 to June 2019. Adult patients (aged ≥18 years) clinically diagnosed with CU were included in the study. Patients diagnosed with other diseases that could alter the coagulation cascade and those on anticoagulant therapy were excluded from the study.

A total of 40 age- and sex-matched healthy subjects undergoing a routine check-up were recruited as the control group.

All patients and controls agreed to participate in this study and signed a written consent form. The demographic data, and the personal, family, and medical histories of the patients were recorded.

Assessment of disease activity

At the time of blood sampling, all patients were interviewed by an investigator to determine the urticaria activity score (UAS). Disease activity was assessed on the basis of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU -founded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF) EAACI/GA2LEN/EDF activity score,[3] which is composed of the wheal score and the pruritis score. The disease activity was scored from 0 to 6, where 0 is considered as none, 1–2 as mild, 3–4 as moderate, and 5–6 as severe. The UAS7, the sum of scores of 7 consecutive days, was also used in our study to determine disease activity and response to treatment among patients with CU.

Methods

Plasma D-dimer levels were measured using the enzyme-linked immunosorbent assay (ELISA) in accordance with the manufacturer's instructions (Instrumentation Laboratory Company – Bedford, MA 01730-2443 (USA)). Levels below 500 ng/mL were considered normal.

Statistical analysis

The data were analyzed using Stata version 14.2. Descriptive statistics and percentages were used to describe demographic data, clinical features, and plasma D-dimer levels. The differences between groups were evaluated using the Chi-square, Mann–Whitney and Kruskal–Wallis nonparametric tests. Correlation was evaluated using Spearman's rank test and logistic regression analysis. The significance level was set at P < 0.05.

Results

Demographic and clinical characteristics of patients

Of the 97 patients, 26 were males (26.8%) and 71 were females (73.2%) with a mean age of 35.80 ± 13.22 years. The average age of onset was 33.67 ± 13.64 years. Most of the patients (72%) had a disease duration of less than 1 year with a mean duration of 19.61 months. Of the 97 patients, 19 (20%) also had angioedema, whereas 20 patients (21%) had a family history of atopy (allergic rhinitis, asthma, atopic dermatitis, or urticaria). Most of the patients (79.4%) had moderate (39.2%) to severe (40.2%) disease severity. Only 15 patients had mild disease (15.5%) and five patients had controlled symptoms.

Correlation between plasma D-dimer levels and disease severity

D-dimer levels in patients who had longer disease duration were significantly higher (P < 0.05) when compared among three groups: less than 1 year, 1–5 years, and more than 5 years.

The difference between the proportion of abnormal plasma D-dimer levels in patients with CU and the control group was statistically significant (58.8% vs. 35%, P= 0.01) (Chi-square test). Plasma D-dimer levels were significantly higher in patients with CU than in the control group (807.76 ng/mL vs. 424.63 ng/mL, P < 0.001). Disease severity and plasma D-dimer levels among the groups are mentioned in Table 1.

Table 1

Plasma D-dimer levels and proportion of abnormal plasma D-dimer levels in patients with CU

Disease activity groups	No. of patients (%)	Plasma D-dimer levels (ng/mL) (Mean)	Proportion of abnormal D-dimer levels in each group n (%)
None	5 (5.1)	510.40	2 (40)
Mild	15 (15.5)	516.40	7 (46.7)
Moderate	38 (39.2)	713.21	22 (57.9)
Severe	39 (40.2)	1050.08	26 (66.7)
Total patients	97	807.76	57 (58.8)

Moreover, patients with CU having angioedema had significantly higher D-dimer levels than patients without angioedema (1205.74 ± 758.90 ng/mL vs. 710.82 ± 593.54 ng/mL, P = 0.002) [Figure 1].

Figure 1

Plasma D-dimer levels and angioedema

A positive statistical correlation was observed between plasma D-dimer levels and the UAS (P = 0.005, r = 0.28) [Figure 2], and UAS7 (P = 0.01, r = 0.25) [Figure 3].

Figure 2

Correlation between plasma D-dimer levels and the UAS

Figure 3

Correlation between plasma D-dimer levels and the UAS7

Discussion

It is essential to investigate reliable biomarkers to assess disease severity when determining the correlation between disease severity and treatment response. In a systemic review, Rafael et al.[11] found that disease severity might also predict the duration of chronic spontaneous urticaria (CSU).

Several studies have shown that the coagulation cascade might be involved in the pathogenesis of CU.[781214] Once extrinsic coagulation cascade has been activated, it leads to formation of thrombin and mast cell activation. Large amount of histamine release from mast cell is crucial for edema formation in urticaria.[8] D-dimer, a fibrin degradation product formed during the lysis of a thrombus, lasts approximately 1 week after the coagulation cascade is activated.[12] In patients with severe disease activity, this activation can increase D-dimer levels. Evidence also suggests that the plasma levels of prothrombin fragment 1 + 2 (F1 + 2), D-dimer, and C-reactive protein (CRP) may function as markers of CSU severity.[11]

In our study, we observed higher plasma D-dimer levels in patients with CU than in the control group. This result is similar to those of studies conducted in Thailand, Korea, Italy, and Brazil.[12131516] The present study provided further evidence of a possible mechanism of activated coagulation in the extrinsic pathway for CU.

The proportion of abnormal plasma D-dimer in our study group was also statistically higher than that in the control group. This proportion was 54.5% in a study by Paulo et al.,[12] whereas it was 59% in a study by Asero et al.[17] Our study demonstrated that patients with CU had higher plasma D-dimer levels and proportion of abnormal plasma D-dimer. This finding is concurrent with that of a literature review by Pavel et al.,[18] which exhibited a strong evidence of significant differences in blood levels or values of D-dimer, CRP, matrix metalloproteinase-9 (MMP-9), and F1 + 2 between patients with CSU and healthy controls.

Angioedema swellings occur deeper in the dermis and in the subcutaneous or submucosal tissue.[1] In urticaria patients, angioedema tends to be painful rather than itchy and often lasts for 2–3 days. This study exhibited a significant difference in D-dimer levels among patients with CU with and without angioedema. Asero et al.[7] suggested that thrombin formation by blood coagulation may induce dermal edema by increasing vascular permeability and lead to mast cell degranulation, which is crucial in urticaria pathogenesis. To the best of our knowledge, an association between plasma D-dimer levels and angioedema has not yet been reported in the literature. Therefore, we hope that these results would contribute to future studies about the correlation between plasma D-dimer levels and angioedema.

A significant positive correlation was found in our study between the disease severity and the plasma levels of D-dimer. Although many potential biomarkers were studied to demonstrate their relationship with disease activity, the D-dimer levels and CRP exhibited strong statistical correlation with CSU activity.[18] According to the results of several studies from different countries, D-dimer plays a vital role as a promising biomarker for CU severity. D-dimer reflects the expression of a tissue factor by eosinophils, coagulation cascade activation, and thrombin generation. The extrinsic pathway of CU is activated, and disease severity is associated with the coagulation cascade.[9]

Moreover, the plasma D-dimer level can be used as a tool to evaluate treatment response in patients with severity; elevated D-dimer levels can be considered as a biomarker for antihistamine-resistant CU, particularly in patients with moderate to severe disease.[19] In this study, D-dimer levels corresponded to UAS7 and were considered as a marker for disease activity and treatment response [Figures 4 and 5]. The UAS7, a unified and simple scoring system, had been validated in the international EAACI/GA2LEN/EDF/WAO urticaria guideline to determine disease activity and treatment response.[3] Until now, the role of the coagulation cascade in the mechanism of urticaria is still debated. It remains unclear whether the increase in coagulation and fibrinolysis is the primary cause of wheal formation or the secondary cause due to histamine release or other reactions of mast cells.[20] However, an association between D-dimer levels and antihistamine-resistant CU has been suggested by many studies,[919] and D-dimer levels has been proposed as a marker for antihistamine-resistant CU. Therefore, when combined with symptom scores, D-dimer could be a predictor for clinical response, especially in refractory cases or antihistamine-resistant CU.

Figure 4

A 22-year-old man with chronic urticaria in 3 months

Figure 5

A 23-year-old man with chronic urticaria in 24 months

Several studies have demonstrated that D-dimer could be used as a promising biomarker in CU. However, larger and more thorough studies are necessary due to lack of strong evidence and specificity of D-dimer in urticaria.

This research, however, was subject to several limitations. The first limitation was that we could not propose a relationship between the D-dimer level and treatment response because of lack of follow-up data. The present study also had a limitation in the subgroup analysis among different urticaria treatments.

Second, this study only focused on finding the correlation between the D-dimer level and disease severity and not on other biomarkers in the coagulation cascade. Future studies can suggest the role of other potential biomarkers in predicting disease activity and treatment response in CU.

Third, although our study demonstrated a relationship between D-dimer levels and angioedema in patients with CU, the number of patients in the angioedema group was relatively small. Therefore, a larger sample size and evidence-based study is needed to strengthen this relationship.

Conclusions

In our study, patients with CU had higher plasma D-dimer levels than normal subjects.

The D-dimer level could be considered as a biomarker for disease severity due to its significant correlation with the UAS.

Although our study was conducted within a limited time, our data also provided evidence toward the vital role of D-dimer in predicting disease severity and treatment response in patients with CU.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.