Abstract

Background

Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) are specific drug hypersensitivity reactions initiated by cytotoxic T-lymphocytes. Augmentation of T-cell activation by positive co-stimulation and Major Histocompatibility Complex-restricted presentation of the culprit drug triggers T-cell activation following interaction with T-cell receptors. This T-cell activation results in expression of cytokines including TNF-α, interferon-γ, granzyme B and granulysin from NK cells. Besides their role in causing SJS/TEN, these cytokines cause coagulation activation.

Materials & Methods

Following an Institutional Review Board approved protocol blood samples were obtained from subjects suspected of SJS/TEN and normal healthy volunteers (n=2). Confirmatory biopsies were performed in all SJS/TEN subjects which confirmed SJS/TEN in 4 subjects and were negative in 7 subjects. Cytokine levels were measured using the cerebral II array biochip from Randox Laboratories Limited (Crumlin, UK). Besides cerebral array II, other parameters such as thrombin-antithrombin (TAT) complexes (Dade®, Marburg, Germany), fibrinopeptide A (F1.2, Dade®), plasminogen activator inhibitor-1 (PAI-1, Diagnostica Stago® and STACHROME antithrombin (Stago®), ZYMUPHEN platelet microparticles activity (Hyphen® Biomed (Neuville-sur-Oise, France), and HEMOCLOT protein C (Stago®) were measured using ELISA kits as per manufacturers’ instructions.

Results

Compared to the Normal Human Plasma, the IL-4, IL-6, TNF-α, and MCP-1 levels were increased significantly in biopsy-confirmed SJS/TEN patients (see table). Other parameters measured including IL-2, IL-8, IL-10, VEGF, INF-γ, IL-1α, IL1-β and EGF were not significantly increased. A marked increase in the TAT complexes (6.3±5.9 µg/ml), F1.2 (430.4±202.4 pmol/L), platelet microparticles (13.1±9.3 nM) and protein C levels (90.5±63.4%) with a corresponding decrease in PAI-1 (53.3±18.8ng/ml) and antithrombin levels (80.7±42.4%) compared to normal human plasma were also observed. Biopsy-negative SJS/TEN subjects with less pronounced inflammatory stimulus, demonstrated mild elevation in cytokine levels of IL-4 (1.95±0.59 pg/ml), IL-6 (29.81±25.18 pg/ml), TNF-α (7.20±5.04 pg/ml) and MCP-1 (265.10±159.09 pg/ml)).

Table

Inflammatory biomarkers in SJS/TEN patients compared to control plasma

BiomarkerIL-4 (pg/ml)IL-6 (pg/ml)TNF-α (pg/ml)MCP-1 (pg/ml)
SJS/TEN-Mean 1.69 50.5 3.20 222.74 
Control Plasma 1.42 0.45 0.77 25.28 
p-value 0.0094 0.0276 0.0138 0.0025 
BiomarkerIL-4 (pg/ml)IL-6 (pg/ml)TNF-α (pg/ml)MCP-1 (pg/ml)
SJS/TEN-Mean 1.69 50.5 3.20 222.74 
Control Plasma 1.42 0.45 0.77 25.28 
p-value 0.0094 0.0276 0.0138 0.0025 
Conclusions

T-cell activation and release of cytokines especially TNF-α and granzyme B causes immune-mediated activation of coagulation with increase in TAT, MCP-1, F1.2 and platelet microparticles and corresponding decrease of protein C, antithrombin, and PAI-1. These alterations in coagulation may progress to sepsis associated coagulopathy and overt disseminated intravascular coagulation.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.