Word Count:
Abstract: 230
Main text: 2148
Tables: 4
Figures: 1
Short title: Coagulopathy and endothelial dysfunction in
paediatric venous malformationKeywords: Coagulopathy, venous malformation, intralesional,
ROTEM®, syndecan-1, glycocalyx.Abbreviations: Venous malformations (VM), syndecan-1 (SDC-1),
localised intralesional coagulopathy (LIC), disseminated intravascular
coagulopathy (DIC), clotting time (CT), clot formation time (CFT),
maximum clot firmness (MCF), clot amplitude at 5 and 10 minutes after CT
(A5 and A10), recombinant tissue plasminogen activator (tPA)
Objective (69)
The occurrence of unpredictable pain crises are the principal
determinant of the quality of life for patients with venous
malformations (VM). A definite coagulation phenomenon, characterized by
an increase in D-dimer levels and the presence of phleboliths within the
malformation, has been previously reported. By applying Virchow’s triad
and evaluating intralesional samples, our objective is to delineate the
coagulation profile and the extent of endothelial dysfunction within the
malformation.
Methods (42)
With the authorization of the Ethics Committee, a research project was
undertaken on intralesional and extralesional blood samples from 30
pediatric patients afflicted with spongiform VM. Thromboelastometry
analyses were performed using ROTEM® Sigma, and the
concentration of syndecan-1 was determined by ELISA.
Results (80)
In the ROTEM® analyses, the A5, A10, and MCF values
were below the established reference ranges in the intralesional samples
in both the EXTEM and INTEM assays indicating that intralesional clots
had significant instability. Furthermore, during the investigation of
the delayed fibrinolysis phase using recombinant tissue plasminogen
activator (rtPA) in EXTEM analysis, widespread hyperfibrinolysis was
observed intralesional. Additionally, analysis of syndecan-1 showed
significant differences between extralesional and intralesional levels
(p<0.026) and controls (p<0.03), suggesting
differences in the state of endothelium.
Conclusions (39)
For the first time, we developed a comprehensive understanding of the
coagulopathic profile of VM and the role of endothelial dysfunction in
its pathogenesis. These findings will enable the implementation of
targeted therapies based on the individual coagulation profiles.
Introduction (352)
Venous malformations (VM) are vascular anomalies, affecting 1% of the
general population, characterized by venous dilatations of dysplastic
veins, leading to an increased risk of thrombosis. This condition can
result in elevated D-dimer levels in extralesional blood, known as
localised intralesional coagulopathy (LIC) .In some cases, a decrease in
fibrinogen levels may precede the development of disseminated
intravascular coagulopathy (DIC) , although very few cases have been
described in the literature. Asymptomatic lesions are common, but they
may cause unpredictable pain crises, mostly due to exacerbation of LIC.
The emotional distress caused by these episodes can lead to a lower
quality of life for patients affected by VM compared with the general
population .
To date the most significant discoveries for advancing treatment of
patients affected by VM was the identification of a collection of
mutated genes and their clinical impact in cellular models .These
advances have enabled the application of targeted therapies that inhibit
hyperfunctioning signalling pathways, such as sirolimus and mTOR
proteins , alpelisib and PIK3CA proteins , and rebastinib and TIE
receptors . Despite the identification of the initial genetic error,
thrombosis phenomena are still based on Virchow’s classical triad. In
this regard, different research groups have analysed conventional
coagulation parameters using extralesional blood samples although the
use of new tools for a more complete analysis of the clot-formation
process has recently been reported .Viscoelastic tests allow us to
quickly identify the function of different elements involved in
coagulation and fibrinolysis processes, which has popularised their use
in situations that require rapid response .
Recently, glycocalyx impairment has been linked to several diseases with
significant social impacts involving endothelial dysfunction .This
structure, which contains glycosaminoglycans and glycoproteins, mediates
various physiological processes, such as angiogenesis , vascular
permeability , and coagulation .
To investigate coagulopathic phenomena and endothelial dysfunction in
paediatric patients with venous malformations, we conducted
thromboelastometry studies using ROTEM® technology
(Tem GmBH; Munich, Bavaria, Germany). Additionally, we analysed the
intralesional coagulation system and investigated the degree of
endothelial dysfunction as a function of syndecan-1 glycoprotein levels.
Methods (547)