N Ragab, S Salem, N Hussein
chronic idiopathic urticaria, chronic urticaria of known cause, coagulation, d-dimer, fibrinolysis, thrombin
N Ragab, S Salem, N Hussein. Evaluation of Plasma D-dimer Levels in Chronic Idiopathic Urticaria (CIU). The Internet Journal of Dermatology. 2009 Volume 8 Number 1.
Chronic urticaria (CU) is a common disorder presenting as cutaneous wheals with or without angioedema for more than 6 weeks, occurring on a continuous or recurrent basis over prolonged periods of time and caused by release of vasoactive mediators from mast cells within the dermis 
It has been reported that mast cells may show profibrinolytic activity . The supernatants of cultured mast cells are capable of inducing the conversion of plasminogen to plasmin and of lysing a fibrin clot 
D-dimer is a breakdown product produced by the degradation of cross linked fibrin by the plasmin due to any etiology 
This case control study included thirty CU patients (16 females and 14 males) recruited from the outpatient clinics of Dermatology; and Allergy and Immunology, Faculty of Medicine, AinShams University. Their ages ranged from 19 to 48 years. Ten patients were suffering from CU of known cause and twenty patients were suffering from CIU, with various degrees of severity. The diagnosis was made on clinical grounds. Doubtful cases were not included in the study. Urticarial severity was estimated according to the number of wheals as follows :
1–10 small (<3 cm in diameter) wheals: grade 1 (slight).
10–50 small wheals (<3 cm in diameter) or 1–10 large wheals (>3 cm in diameter): grade 2 (moderate).
>50 small wheals or >10 large wheals (>3 cm in diameter): grade 3 (severe).
Virtually all the body covered with wheals with angioedma: grade 4 (very severe).
Patients and controls were subjected to full history taking, general examination, dermatological examination and other investigations as required to exclude possible causes of CU such as prick test, neutrophil phagocytosis inhibition test (PIT), erythrocyte sedimentation rate (ESR), complete blood count (CBC) and thyroid function tests. Two millilitres of blood were obtained from patients (before and after remission) and from controls to measure plasma D-dimer levels by ELISA (Zymutest D-dimer; Hyphen BioMed, France). Statistical analysis of the results was performed using SPSS program version 14.
There was no statistically significant difference as regards gender and age between cases and controls. Also, there was no statistically significant difference as regards gender, age and duration of the disease between CIU patients and patients with CU of a known cause and between patients with different severity grades. There was no significant correlation between plasma D-dimer level and age of studied patients,)r=-0.021, p>0.05) or between it and duration of the disease (r=0.22, p>0.05).
The levels of plasma D-dimer in all patients, CIU patients, CU patients of known cause and controls are shown in
The levels of plasma D-dimer regarding different severity grades in CIU patients and CU patients of known cause are shown in
The levels of plasma D-dimer after treatment ranged from 31 to 311 ng/ml with a mean of 132.47 ng/ml (±79.61) and a median of 103 ng/ml. The levels of plasma D-dimer was statistically significantly higher in all patients before treatment compared to after treatment levels (p<0.001). In each severity group, there was a statistically significant decrease as regards the plasma D-dimer levels after than before treatment (p<0.05)
The sequence of etiologic and pathogenic activation of the coagulation cascade in chronic idiopathic urticaria is still insufficiently defined. If autoantibodies, complement, and mast cell–derived factors such as histamine, tryptase, and/or different cytokines are responsible for the activation of endothelial cells causing tissue factor expression, then the observed activation of the extrinsic coagulation pathway would be a secondary consequence of urticaria, and thrombin might act as the final actor amplifying the increase in vascular permeability observed in this disease .
Results of our study showed a significantly higher elevation in the plasma level of D-dimer in all CIU patients compared to healthy controls. Similar results were reported by
In our study higher levels of D-dimer were detected in relation to the severity of CIU that a highly significant difference (p>0.001) was detected between severe and mild cases. Similar results were reported by
Plasma D-dimer levels were elevated in all CU patients with no significant difference between patients with CIU and patients with CU of a known cause (p>0.05). This favors elevated D-dimer levels as an aggravating factor not a cause in CU. In fact, there are several pieces of evidence denoting the activation of the extrinsic pathway of coagulation cascade leading to fibrinolysis, which is indicated by elevated plasma D-dimer levels in CU.
Studies on animal models showed that thrombin increases vascular permeability both directly, acting on endothelial cells  and indirectly by inducing release of proinflammatory mediators by mast cells  and generates C5a in the absence of C3, thus bypassing the whole first part of the complement cascade.
we followed up all 30 patients after complete remission of symptoms by treatment which included steroids, antihistamines and desensitization therapy. There was a significant dramatic drop of plasma D-dimer levels compared to those during the acute exacerbation of the disease (p<0.001). Similarly,
In conclusion, the present work provides further evidence for the elevation of D-dimer, as a clue of activated coagulation cascade, in the circulation of CU patients. Its concentration increases with increased disease severity reverting the lower levels after complete remission of symptoms. Activated tissue coagulation pathway may be an aggravating or pathogenic factor in any type in CU not a specific cause in CIU. The possible role of anticoagulant therapy in decreasing severity of the disease and preventing worsening of symptoms is suggested and need further controlled studies to evaluate its efficacy.