To the Editor,
We read with much interest the review article recently published by
Mostmans et al. (1). The work is an excellent compilation of studies on
alterations of vascular endothelial cell-associated molecules and
coagulation factors in urticaria. We want to congratulate the authors
for the completion of this comprehensive review. However, despite
mounting evidence, we were surprised that the authors commented in the
discussion section that the “implication of a prothrombotic state in
chronic urticaria patients is still under debate since both depressed
coagulation activity and normal plasma coagulation factors have also
been reported.” A comparative look at the coagulation profile used in
all studies described in Table 5 of the article shows that researchers
describing upregulation of coagulation parameters used well-recognized
markers of coagulation activation, whereas researchers reporting
“normal plasma coagulation factors” used less sensitive assay or
non-canonical markers of clotting activation (1). In addition, the fact
that one or two markers among a set of coagulation parameters remain
normal or low in urticaria patients compared to a control group does not
necessarily mean there is no activation of coagulation. For example,
there was no significant change in the plasma levels of activated factor
VII but there were increased plasma levels of D-dimer or
thrombin-antithrombin complex in the same urticaria patients compared to
controls (2, 3). Another important issue that needs to be considered is
the study design. For example, the study reported by Takahagi et al. had
no control group (4). They considered the plasma levels of D-dimer and
fibrin-degradation products as normal or high merely based on a cut-off
line. Although not all patients showed levels of D-dimer or
fibrin-degradation products higher than the cut-off value, the authors
found significantly increased plasma concentrations of D-dimer and
fibrin degradation products in patients with severe urticaria compared
to patients with moderate/slight disease and, importantly, that the
levels of those markers increased during exacerbations compared with
before or after (4). The material or sample used to measure hemostatic
parameters is also an important source of bias. For example, Zhu et al.
reported lower plasma levels of soluble tissue factor in urticaria
patients than in controls (3). However, most studies have described
significantly increased tissue factor expression on the cell surface of
leukocytes in skin lesions from urticaria patients compared to controls
(5, 6). This is understandable because tissue factor is generally
expressed as a cell membrane-bound protein, at particular sites of
tissue injury, while just a small fraction of it is released as a
soluble factor. Other issues that were not considered that are important
for conclusions about previous studies are the study population size,
the inclusion of historic or concurrent controls, the use of validated
assays and whether the results were confounded by treatment regimens. In
addition to lessons learned from this review by Montmans et al., other
proofs of the involvement of the coagulation cascade in urticaria
include reports showing the beneficial effect of anticoagulants (e.g.,
heparin, warfarin, nadroparin) in patients with refractory urticaria or
unresponsive to antihistamines, and reports showing that the plasma
levels of D-dimer can predict clinical response to therapy with
antihistamines or anti-IgE monoclonal antibody (1, 5). What remains
debatable is whether IgE antibodies against tissue factor with
concomitant dysfunction of the endothelial cell-mediated
thrombomodulin/protein C anticoagulant pathway plays a major role in the
mechanism of coagulation activation in urticaria patients (5). Taken
together, we believe that there is robust evidence in the literature
supporting the role of the coagulation cascade activation and consequent
deposition of fibrin in the affected areas in the pathogenesis of
urticaria.