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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 17  |  Issue : 3  |  Page : 222-226

Plasma D-dimer as a biomarker of chronic urticaria treatment


1 Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission08-Mar-2018
Date of Decision16-Oct-2018
Date of Acceptance02-Jun-2019
Date of Web Publication26-Nov-2019

Correspondence Address:
Fathia Khattab
Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Zagazig University, 44511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_9_18

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  Abstract 


Background Under the appropriated stimulus, it has been demonstrated that neutrophils, eosinophils, and monocytes may express tissue factor and therefore activate the extrinsic pathway of coagulation.
Objective To assess the plasma d-dimer (DD) level in patients with chronic urticaria during exacerbation and remission and correlate this level with the severity of the disease.
Patients and methods This case–control study included 30 patients with clinically proved Chronic Urticaria (CU) (group I) and 15 healthy control (group II). The plasma levels of DD were measured by enzyme-linked immunosorbent assay.
Results The level of plasma DD in active patients ranged from 400 to 1950 ng/ml, with median of 1050 ng/ml. The level of DD in the plasma of controls ranged from 210 to 600 ng/ml, with median of 400 ng/ ml. There was a highly statistically significant difference between cases and control in DD level. Patients with active chronic urticaria had the highest plasma levels of DD (P<0.01) when compared with patients with CU under remission and the control group.
Conclusion Plasma DD level could be an indicator of the severity of CU as it positively correlates with it. It is also a good prognostic marker as its level decreases after the treatment or remission.

Keywords: chronic urticaria, D-dimer, omalizumab


How to cite this article:
Metwalli M, Khattab F, Zidan AA. Plasma D-dimer as a biomarker of chronic urticaria treatment. Al-Azhar Assiut Med J 2019;17:222-6

How to cite this URL:
Metwalli M, Khattab F, Zidan AA. Plasma D-dimer as a biomarker of chronic urticaria treatment. Al-Azhar Assiut Med J [serial online] 2019 [cited 2020 Feb 20];17:222-6. Available from: http://www.azmj.eg.net/text.asp?2019/17/3/222/271686




  Introduction Top


D-Dimer (DD) is a specific product of the degradation of fibrin clots that results from the actions of three enzymes: thrombin generated from the activation of the coagulation cascade that converts fibrinogen into fibrin clots, activated factor XIII that cross-links fibrin clots by means of covalent bonds between fibrin monomers, and plasmin, the ultimate enzyme of fibrinolysis that degrades cross-linked fibrin [1]. DD elevations are detected in plasma during the onset of thrombus formation and its elevation usually lasts about a week. For this reason, it is possible to find high levels of DD during increased fibrinolytic activity. It occurs in high concentrations in many clinical conditions, such as deep vein thrombosis and pulmonary embolism [2]. Level of DD was found to be elevated in a patient with exacerbation of chronic urticaria compared with patients in remission. So the measurement of DD can be used for assessing the severity of the disease [3]. Chronic urticaria is a common disorder presenting as cutaneous wheals with or without angioedema for more than 6 weeks, occurring on a continuous or recurring basis over prolonged periods of time and caused by the release of vasoactive mediators from mast cells within the dermis [4]. The pathogenesis of chronic urticaria is poorly understood. Chronic urticaria is associated with autoimmune disorders, most commonly hypothyroidism, but also celiac disease, systemic lupus erythematosus, and type 1 diabetes mellitus. Pseudo-allergens, actual allergens, Helicobacter pylori infection, and other infections/infestations are involved in its pathogenesis [5]. Omalizumab is a humanized anti-immunoglobulin E (IgE) monoclonal antibody licensed in the European Union as an add-on therapy for adults, adolescents, and children (age≥6 years) with inadequately controlled severe allergic (IgE-mediated) asthma, and in the USA for adults and adolescents (age ≥12 years) with moderate-to-severe allergic asthma. Omalizumab was efficacious in patients with Chronic spontaneous urticaria (CSU) nonresponsive to H1-antihistamines [6].


  Patients and methods Top


This case–control study was conducted on 30 patients, with an age range from 6 to 68 years. They had been recruited from the Outpatient Clinics of the Department of Dermatology, Venereology, and Andrology, Zagazig University Hospitals, from November 2017 to May 2018. Patients were divided into two groups: group A, which was analyzed as (a) active patients (30 case with wheal for 6 weeks) with Chronic Urticaria (CU) who underwent treatment and (b) remission patients (same 30 case with no wheal for 6 weeks after treatment), after control of urticaria, and group B, which included ordinary individuals as the control group. The inclusion criteria were patients of any age, each sex, and a diagnostic algorithm based on recommendations of the British Society for Allergy and Clinical Immunology. The diagnosis in each affected person was on the basis of the appearance of wheals anywhere on the body for more than 6 weeks. Exclusion criteria are patients with the immunocompromised condition; patients who took immunomodulating drugs, antihemorrhagic or anticoagulant drugs within 30 days; patients with focal infection, with lesions being suspicious for urticarial vasculitis; and other diseases that would regulate the coagulation cascade like liver diseases and hematological malignancies.

The evaluation of CU is clinical and based on the presence of episodic urticarial lesions found during the physical examination. However, the patient’s history might reveal that the lesions usually appear and resolve within 24 h. On physical examination, patients have urticarial lesions that are circumscribed, raised, and erythematous with a possible central pallor. Three basic laboratory tests were done: Complete blood picture (CBC) count, C-reactive protein (CRP) or Erythrocyte sedimentation rate (ESR), and thyroid-stimulating hormone level.

Disease activity was assessed by the European Academy of Allergology and Clinical Immunology; Global Allergy and Asthma European Network; European Dermatology Forum (EAACI/GA2LEN/EDF) activity score, which is composed of wheals score (none = 0, 1 for 1–20 wheals, 2 for 20–50 wheals, and 3 for >50 lesions in 24 h) and itching score (none = 0, mild = 1, moderate = 2, and intense = 3). The disease activity is scored from 0 to 6 (summation of wheals and itching scores). Zero scores considered as none, score 1–2 as mild, score 3–4 as moderate, and score 5–6 as a severe disease activity [7].

Sample collection and storage

Two milliliter of peripheral blood (9 volume) was collected in citrate anticoagulant (1 vol.), which is achieved by appropriate collection tubes by clean venipuncture. Plasma supernatant was decanted following a 20-min centrifugation at 5000 rpm, then samples were kept cryopreserved at −20°C up to 6 months, and thawed for 15 min at 37°C just before use. Thawed specimen must be tested within 4 h.

D-Dimer assay

This was performed by enzyme-linked immunosorbent assay (Zymutest d-dimer; Hyphen BioMed, Neuville-sur-Oise, France) according to the manufacturer’s instructions. According to this kit, the expected DD concentration in normal human plasma is usually less than 500 ng/ml.


  Results Top


A total of 30 patients with clinically proven CU were enrolled in this study (group I), comprising 16 (53.3%) males and 14 (46.7%) females. Group II includes 15 healthy participants as control, comprising 11 (73.3%) females and four (26.7%) males. Patient’s data are presented in [Table 1].
Table 1 Demographic data of the studied groups

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The level of plasma DD in active patients ranged from 400 to 1950 ng/ml with median 1050 ng/ml, and the level of plasma DD in remission cases ranged from 320 to 700 ng/ml with median 600 ng/ml. The level of DD in the plasma of controls ranged from 210 to 400 ng/ml, with median of 305 ng/ml. There was a highly statistically significant difference between cases and control in DD ([Table 2] and [Figure 1]). Active patients were divided into three groups according to severity as follows: six (20%) patients with mild urticaria, 10 (33.3%) patients with moderate urticaria, and 14 (46.7%) patients with severe urticaria, whereas remission cases were divided into two groups as follows: 12 (40%) patients with no severity and 18 (60%) patients with mild urticaria. There was no statistically significant difference between DD and either age or sex in active cases, but there was a highly statistically significant difference between DD and severity in active cases ([Figure 2]). Active patients were controlled by treatment with nonsedating antihistamines (in mild cases), nonsedating antihistamines with high dose, moderate cases, and combined treatment (severe cases) (previous treatment plus omalizumab 150–300 mg Subcutaneous injections (SC)/4 weeks) ([Table 3]). The plasma level of DD in active patients treated with nonsedating antihistamines (in mild cases) ranged from 400 to 760 ng/ml, with median 520 ng/ml, with nonsedating antihistamines with high dose (moderate cases) ranged from 600 to 1080 ng/ml, with median 830 ng/ml, and combined treatment (severe cases) ranged from 400 to 1950 ng/ml, with median of 1350 ng/ml. There was a statistically significant difference between DD level in mild and moderate cases, and also there was a highly statistically significant difference between DD level in patients with moderate and severe cases. In remission cases, there was a highly statistically significant decrease of DD level in remission cases ([Table 4]).
Table 2 D-Dimer level of studied groups

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Figure 1 Shows d-dimer levels in studied groups.

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Figure 2 Correlation between severity and d-dimer level in active cases.

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Table 3 Relation between d-dimer level among active cases

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Table 4 Relation between d-dimer and severity in remission cases

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  Discussion Top


The level of DD was elevated in patients with exacerbation of chronic urticaria compared with patients in remission. So the measurement of the DD can be used for assessing the severity of the disease [2]. In this study, the mean age of patients was 30.13±17.60 years in active cases and 28.13±17.60 years in remission cases, and this corresponds to the peak age of CU in most studies (20–40 years). Similar results was reported, with mean age of 29.6±8.8 years [8]. The results of our study showed significantly higher plasma level of DD in patients with chronic urticaria, with P value less than 0.001 (median 1050 ng/ml in active cases and 600 ng/ml in remission cases) compared with healthy control. Moreover, it is observed that levels of DD were significantly higher among patients with Chronic spontaneous urticaria (CSU) than among healthy controls, with P value less than 0.001 (median 662.5 ng/ml) [8]. In addition, it was found that the plasma levels of DD increased significantly (P<0.01) in patients with CU compared with healthy controls [9]. Triwong et al. [2] gave the same results, with median level of 476.2 ng/ml. Similar results were reported by Asero et al. [10], as they found that plasma DD levels were significantly higher in patients with CU [median and range 11.20 nmol/l (5.68–86.13 nmol/l)] than in normal patients [1.41 nmol/l (0.96–1.62 nmol/l)] (P<0.01). Elevated plasma DD could be explained by activation of the coagulation cascade via tissue factor pathway with the involvement of inflammatory cells, leading to the formation of thrombin, which might be responsible for generating C5a and increasing vascular permeability owing to the stimulation of endothelium or the release of proinflammatory mediators by mast cells [11]. In this study, there was a highly statistically significance difference between active and remission cases in disease severity, as P 0.000. In this study, there was a highly statistically significant difference between DD and severity in active cases, and there was a highly statistically significant difference between DD and severity in remission cases. So, significantly higher DD levels were detected in more severe grades of urticaria. These results agree with a study that found that DD level before treatment in grade 1 severity was 250.0 (250.0–487.5) ng/ml, in grade 2 severity was 500.0 (475.0–737.5) ng/ml, in grade 3 severity was 875.0 (787.5–1000.0) ng/ml, and in grade 4 severity was 1500 (1475–2000) ng/ml, and there was a significant dramatic drop in levels of DD (median 487.5 ng/ml, P<0.001) [8]. Patients with severe urticaria displayed significantly higher levels of DD than patients with moderate and mild disease and observed a significant reduction of DD levels when the disease severity improved [12]. The same results were recorded as the DD level was elevated in severe cases of CU, with median of 1410.8 ng/ml, and this level decreased after treatment [2]. In this study, plasma DD levels were not significantly related to age (P=0.908) or sex (P=0.153) in patients and controls. This denies the effect of these factors on the generation of plasma DD. In this study, there were statistically significant relations between DD and type of treatment taken by the patients (P=0.005), as rising DD levels were observed in association with increasing modalities of therapy. The plasma level of DD in active patients treated with nonsedating antihistamines (in mild cases) ranged from 400 to 760 ng/ml, with median of 520 ng/ml, in patients treated with nonsedating antihistamines with high dose (in moderate cases) ranging from 600 to 1080 ng/ml, with median of 830 ng/ml, and in patients treated with combined treatment (in severe cases) ranged from 400 to 1950 ng/ml, with median of 1350 ng/ml. These results agree with those reported by Farres et al. [8] as the plasma level of DD in patients treated with nonsedating anti-histamines was 250.0 ng/ml with range of 162.5–437.5 ng/ml, in patients treated with nonsedating antihistamines with high doses was 475.0 ng/ml, with range of 375.0–625.0 ng/ml, and in patients treated with combined treatment was 500.0 ng/ml, with range of 475.0–1037.5 ng/ml. It found that the use of DD levels in the blood of patients with chronic urticaria could be a potential serum marker to withdraw antihistamine treatment, as there is a decrease in their values [11]. The plasma levels of DD are frequently elevated in patients with severe CSU before omalizumab administration and decrease according to the clinical response of the disease to the drug, suggesting a possible effect of omalizumab on coagulation activation and fibrin degradation in a subset of patients with CSU [13].

Our results suggest that CSU associated with elevated DD plasma levels might represent an endotype characterized by the activation of inflammation pathways that makes the patients more responsive to omalizumab treatment. It is apparently contradictory that patients with a CSU are not reported to be at risk for thrombotic events despite an increased activation of the coagulation cascade. A possible explanation is that the activation of coagulation occurs extravascularly and can be efficiently counteracted by fibrinolysis. DD measurement is easily available and thus represents a potentially ideal candidate potential biochemical marker for CU. Patients with CSU are characterized by a severe disease that often does not respond to antihistamines but frequently shows a prompt and complete response to anti-IgE. Clinicians should be aware of the potential utility of DD levels to evaluate disease severity, track patient response to treatment, and assess the need for anticoagulation therapy regarding treatment with heparin and tranexamic acid.


  Conclusion Top


Plasma DD level could be a hallmark of the severity of CU because it undoubtedly correlates with it and is a prognostic marker, as its level decreases after treatment or remission of CU.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Criado PR, Antinori LC, Maruta CW, Reis VM. Evaluation of D-dimer serum levels among patients with chronic urticaria, psoriasis and urticarial vasculitis. An Bras Dermatol 2013; 88:355–360.  Back to cited text no. 1
    
2.
Triwong D, Kulthanan K, Chularojanamontri L, Pinkaew S. Correlation between plasma D-dimer levels and the severity of patients with chronic urticaria. Asia Pac Allergy 2013; 3:100–105.  Back to cited text no. 2
    
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Marzano AV, Tedeschi A, Menicanti C. Chronic spontaneous urticaria: the emerging position of coagulation. Curr Dermatol Rep 2013; 2:18–23.  Back to cited text no. 3
    
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Viegas LP, Ferreira MB, Kaplan AP. The maddening itch: an approach to chronic urticaria. J Investig Allergol Clin Immunol 2014; 24:1–5.  Back to cited text no. 5
    
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Cugno M, Genovese G, Ferrucci S, Casazza G. IgE and D-dimer baseline levels are higher in responders than nonresponders to omalizumab in chronic spontaneous urticarial. Br J Dermatol 2018; 179:776–777.  Back to cited text no. 6
    
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Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy 2018; 73:1393–1414.  Back to cited text no. 7
    
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Farres MN, Refaat M, Melek NA, Ahmed EE, Shamseldine MG, Arafa NA. Activation of coagulation in chronic urticaria in relation to disease severity and activity. Allergol Immunopathol (Madr) 2015; 43:162–167.  Back to cited text no. 8
    
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Zhu H, Liang B, Li R, Li J, Lin L, Ma S, Wang J. Activation of coagulation, anti-coagulation, fibrinolysis and the complement system in patients with urticarial. Asian Pac J Allergy Immunol 2013; 31:43–50.  Back to cited text no. 9
    
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Asero R, Tedeschi A, Riboldi P, Griffini S, Bonanni E, Cugno M. Severe chronic urticaria is associated with elevated plasma levels of D-dimer. Allergy 2008; 63:176–180.  Back to cited text no. 10
    
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Asero R, Tedeschi A, Coppola R, Griffini S, Paparella P, Riboldi P et al. Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria. J Allergy Clin Immunol 2007; 119:705–710.  Back to cited text no. 11
    
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Takahagi S, Mihara S, Iwamoto K, Morioke S, Okabe T, Kameyoshi Y, Hide M. Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy 2010; 65:649–656.  Back to cited text no. 12
    
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Asero R, Marzano AV, Ferrucci S, Cugno M. d-Dimer plasma levels parallel the clinical response to omalizumab in patients with severe chronic spontaneous urticaria. Int Arch Allergy Immunol 2017; 172:40–44.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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