Urticaria is a clinical reaction pattern triggered by many factors causing the liberation of vasoactive substances such as histamine, prostaglandins and kinins. Clinically, uritcaria is classified as acute urticaria when the wheals are lasting for <6 weeks. On the other hand, wheals and/or angioedema lasting for a period of longer than 6 weeks is classified as chronic urticaria leading to significant psychological morbidity and poor quality of life.Females are affected more commonly than males [1-4].

Recently, higher positivity of autologus plasma skin testing (APST) than autologous serum skin testing (ASST) i.e. 80% versus 50% suggests involvement of coagulation pathway in the pathogenesis of chronic urticaria.In chronic urticaria, activation of coagulation cascade occurs that corresponds to the severity of disease.Tissue factor expressed by eosinophils, one of the inflammatory infiltrate, is related to the activation of coagulation cascade. The elevated levels of activated factor VII, prothrombin fragments (PF1+2), and plasma D-dimer in comparison to normal levels of factor XII reported in chronic urticaria suggest activated extrinsic pathway involvement In case of extensive activation of coagulation cascade, plasma levels of plasma D-dimer, a marker of fibrinolysis, are elevated.Since plasma D-dimer is not detectable in the absence of thrombosis, negative plasma D-dimer assays almost exclude diagnosis of coagulation [5-9].

There is scarce information on the variation in coagulation profile and other inflammatory markers among patients sufferingfromChronic Spontaneous Urticaria in Himachal Pradesh. Therefore present study was done to evaluate the variation in coagulation profile and other inflammatory markers among patients with Chronic Spontaneous Urticaria

Aims and Objectives

To evaluate the variation in coagulation profile and other inflammatory markers among patients with Chronic Spontaneous Urticaria

• Research Approach: Descriptive

• Research Design: Hospital based  Cross-sectional survey design

• Study Area: OPD of Dermatology, Venereology and Leprosy clinic of Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh

• Study Duration: between April 2016 and March 2017

• Study Population:  Patients of Chronic Spontaneous Urticaria

• Sample Size: All 100 consecutive patients of chronic Spontaneousurticaria aged 18 years and above attending the outpatient Dermatology, Venereology and Leprosy clinic of Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh between April 2016 and March 2017 were enrolled for the study

• Inclusive Criteria: Who were willing to participate in the study

Exclusion Criteria

Patients suffering from physical urticaria, urticarial vasculitis, or acute urticarial.

• Patients younger than 18 years of age

• Pregnant and lactating women

• Patients taking medications that can influence the coagulation/fibrinolysis pathway (asprin, clopidogrel, warfarin, heparin)

• Study tool: A self designed, semi structured questionnaires consisting of socio-demography, symptoms, duration, previous medical history, values of coagulation profile and other inflammatory markers etc. was created.

• Validity of Tool: By the experts in this field

• Data Collection: Data was collected under the guidance of supervisors. The demographic profile, age, sex, occupation, place of residence, duration and evolution of urticaria, personal and family history, detailed medical history and clinical details of urticaria were recorded on a pre-designed proforma. Physical urticaria was excluded on the basis of thorough clinical history/examination and provocation tests. A clinical examination and investigations were performed to exclude systemic diseases/infections known to cause urticaria

• Data Analysis: Data was collected and entered in Microsoft excel spread sheet, cleaned for errors and analyzed with Epi Info V7 Software with appropriate statistical test in terms of frequencies, percentage, mean standard deviation etc

• Ethical Considerations: The study was conducted after approval from Institutional Protocol Review Board and Institutional Ethics Committee. The patients were enrolled only after informed consent and after clarifying their queries regarding the study. Participant’s confidentiality and anonymity was maintained

The study comprised 100 consecutive patients with chronic Spontaneousurticaria and had 25 males and 75 females (M:F = 1:3) aged between 18 and 69 (mean±SD = 36.12±10.88) years. Thirty seven (37%) patients were aged less than or equal to 30 years and 9 patients were more than 50 years of age. The majority, 68(68%) patients were aged between 18-40 years followed by 23(23%) patients in the age group of 41-50 years. (Table 1)

Table 1:  Age and Gender distribution of Patients

The mean prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), thrombin time (TT) and Absolute Eosinophilscount were 14.99±2.9, 33.1±5.2, 1.08±0.3, 17.01±0.798 and 205.9±142.3 respectively. (Table 2)

Table 2:  Mean Value of Coagulation and Inflammatory Markers in Patients

Twenty-three patients had elevated plasma D-dimer levels of ≥0.3 mg/L whereas 77 had normal levels (≤0.2 mg/l). Only 3 patients had  Serum C-reactive protein>3.0 mg/L while 97 patients had Normal value  below 3.0 mg/L. 69 patients had  Prothrombin Time>13.7 seconds while 31 patients had Normal value between  11.4-13.7 Seconds. 6 patients had  Activated partial thromboplastin time (aPTT)>41.8seconds while 94 patients had Normal value between 27.8-41.8 Seconds. 3 patients had Thrombin time ( TT)> 18seconds while 97 patients had Normal value between 15-18 Seconds. 8 patients had International normalized ratio (INR)> 1.4while 92 patients had Normal value of <1.4.  Four patients had Absolute eosnionphilcount>-500 cells/mm³while 96 patients had Normal value between 20-500 cells/mm³. (Table 3).

Table 3:  Variation in Coagulation and Inflammatory markers in patients

Several etiopathogenetic factors have been proposed for chronic urticaria, but its exact etiopathogenesis remains poorly understood in more than 80% of cases. An etiopathogenetic link between chronic urticaria and activation of extrinsic followed by intrinsic coagulation cascades has been suggested by some researchers [1012]. Activation of the extrinsic coagulation cascade with elevated levels of activated factor VII (VIIa) and normal levels of activated factor XII  has been demonstrated [6,11].

Present study comprised 100 consecutive patients with chronic Spontaneousurticaria and had 25 males and 75 females (M:F = 1:3) aged between 18 and 69 (Mean±SD = 36.12±10.88) years. Similar to our study, in the study done by Maria Regina Cavariani Silvares et al. [13], chronic urticaria-angioedema occurred mainly in females (mean age: 35 years), but also in men (mean age: 32 years).

In our study, the mean prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), thrombin time (TT) and Absolute Eosinophilscount were 14.99±2.9, 33.1±5.2, 1.08±0.3, 17.01±0.798 and 205.9±142.3 respectively. Twenty three patients had elevated plasma D-dimer levels of ≥0.3 mg/L whereas 77 had normal levels (≤0.2 mg/l). Only 3 patients had  Serum C-reactive protein>3.0 mg/L while 97 patients had Normal value  below 3.0 mg/L. 69 patients had  Prothrombin Time(PT)>13.7 seconds while 31 patients had Normal value between  11.4-13.7 Seconds. 6 patients had Activated partial thromboplastin time (aPTT)>41.8seconds while 94 patients had Normal value between 27.8-41.8 Seconds. 3 patients had Thrombin time ( TT)> 18seconds while 97 patients had Normal value between 15-18 Seconds. 8 patients had International normalized ratio (INR)> 1.4while 92 patients had Normal value of <1.4.  Four patients had Absolute eosnionphilcount>-500 cells/mm³while 96 patients had Normal value between 20-500 cells/mm³.

Plasma D-dimeris a break down product of fibrin, a  small protein fragment present in the blood after degradation of  blood clot by fibrinolysis mediated by plasmin due to any etiology. Whenever coagulation and thrombosis is activated plasma D-dimer levels are elevated (normal <221-227 µg/L) and its plasma levels increase during the onset of thrombus formation and remain elevated for about a week. Therefore, it is possible to find high levels of plasma D-dimer during increased fibrinolytic activity.Since plasma D-dimer is not detectable in the absence of thrombosis, negative plasma D-dimer assays almost exclude diagnosis of coagulation. In vitro studies have confirmed that plasma of urticaria patients has significantly higher levels of prothrombin fragment (PF₁₊₂), a polypeptide of 34 kDa, that is released into circulation during the activation of prothrombin to thrombin by factor X.High serum levels of plasma D-dimer have been reported infrequently in patients with chronic urticaria during severe exacerbation correlating with severity and activity of chronic urticarial [14-19].

Takahagi et al. [20] reported disease severity correlating with fibrin degradation productsand plasma D-dimer levels after observing above normal levels of plasma D-dimer in 35% patients with chronic urticaria. Triwongwarant et al. [21] showed elevated plasma D-dimer levels in 48.3% of Thai patients with a positive correlation between disease severity and elevated levels of plasma D-dimer which decreased with reduced disease severity in three patients under follow-up. These observations strongly suggest a positive correlation between disease severity and elevated plasma D-dimer levels [22].

Present study results might support the possible involvement of both coagulation and fibrinolysis pathway in the urticariapathomechanism. Our study in some measure suggest that an increased D-dimer level in patients with Chronic Spontaneousurticaria should be considered as an indicator of its activity and may be regarded as a useful biomarker. Further prospective studies in larger populations conducted at multiple centres are required to expand further our findings.

Limitations

Small number of patients, lack of treatment outcome measures, and unavailability of specific parameters to determine coagulation pathway activation, and a cross-sectional nature of study are some of the limitations of this study.

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