Ariens, Robert A. S.

Bagoly, Zsuzsa

Pieters, Marlien

Rijken, Dingeman C.

Wolberg, Alisa S.

BioMed Research International

University of Debrecen Electronic Archive

Editorial
Clot Structure and Fibrinolysis in Thrombosis and Hemostasis
Zsuzsa Bagoly,1 Robert A. S. Ariëns,2 Dingeman C. Rijken,3
Marlien Pieters,4 and Alisa S. Wolberg5
1Department of Laboratory Medicine, Division of Clinical Laboratory Sciences and MTA-DE Cerebrovascular and
Neurodegenerative Research Group, University of Debrecen, Debrecen, Hungary
2Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
3Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
4Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom, South Africa
5Department of Pathology and Laboratory Medicine and McAllister Heart Institute, University of North Carolina, Chapel Hill,
NC, USA
Correspondence should be addressed to Zsuzsa Bagoly; bagoly@med.unideb.hu
Received 25 October 2017; Accepted 26 October 2017; Published 15 November 2017
Copyright © 2017 Zsuzsa Bagoly et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
“Inimicum quamvis humilem metuendum est” (“An enemy,
however small, is to be feared”).
Today, thrombotic disorders aremajor contributors to the
global burden of disease [1]. The formation of a thrombus,
however small, is the common pathology underlying dev-
astating illnesses including ischemic heart disease, ischemic
stroke, and venous thromboembolism. Due to the high
rates of mortality and morbidity associated with arterial and
venous thromboembolism, great efforts have been made in
the past years to expand our knowledge on the biological,
physical, and chemical features of the blood clot. In this spe-
cial issue, original research articles and reviews focus onmost
recent advances on fibrin clot characteristics, mechanisms of
clot formation/dissolution, and related clinical conditions.
Fibrin fibers constitute one of the major structural
components of the blood clot, providing the clot with a
three-dimensional polymeric protein network that imparts
considerable elastic strength, with the mechanical and struc-
tural properties thereof influencing morbidity and mortality
rates associated with thrombotic events. Surprisingly, the
process of lateral association of protofibrils into fibrin fibers
is still poorly understood. In the research paper by W. Li
et al., the authors aim to gain insights into the relatively
less studied internal structure of fibrin fibers and describe a
novel fiber model. Based on experiments using fluorescence
intensity and force (modulus) measurements, they propose
that protofibrils are densely packed at the fiber center, but
are sparse and loosely connected towards the fiber periphery.
The clinical implications of abnormal fibrin clot properties
are described in a review article by A. Undas. It has been
known for some time that fibrin clots that are composed
of thinner, highly branched fibers are less permeable, more
rigid, and less susceptible to dissolution by fibrinolytic pro-
teins. A. Undas provides a timely update on the so-called
prothrombotic fibrin clot phenotype and its relevance to
venous thromboembolism. Listing experimental and clinical
studies, the author describes a number of clot structure
modifiers implicated in the occurrence of the prothrombotic
fibrin clot phenotype and the resulting clot characteristics
accounting for a potential risk for thromboembolism.
Not only the formation, but also the dissolution of the
fibrin clot is dependent on biochemical and biophysical
processes. The review article by N. E. Hudson highlights the
importance of understanding fibrinolysis in the light of fibrin
biophysical characteristics. The review considers the impact
of several structural and mechanical parameters on lytic
rates. The author summarizes the newest findings with the
expectation that improved understanding of the connection
between the biophysical aspects of fibrin and fibrinolytic rates
could lead to novel strategies in the development of future
fibrinolytic therapies. As an example, the original research
by A. Tanka-Salamon et al. describes a novel thrombolytic
Hindawi
BioMed Research International
Volume 2017, Article ID 4645137, 2 pages
https://doi.org/10.1155/2017/4645137
2 BioMed Research International
approach. The purpose of the work was to prepare a
phospholipid-based thermosensitive nanocarrier, in which
trypsin is attached to the inner leaflet of the bilayer shell of
the liposome, and to characterize this new tool in terms of
structure and proteolytic efficiency.The authors show that the
lytic efficiency of trypsin depends on heat-dependent release
from thermosensitive liposomes.Thefibrinolytic efficiency of
these liposomes was found to be improved in the dynamic
fibrinolytic assay under conditions of permeation-driven
fibrinolysis. Because intravascular thrombi are exposed to
permeation forces, these properties of the construct suggest
that it could be a successful candidate as a therapeutic tool,
the utility of which deserves further investigation.
A key player in the inhibition of fibrinolysis is activated
factor XIII (FXIIIa). An interesting review by D. C. Rijken
and S. Uitte de Willige focuses on the impact of this transg-
lutaminase on fibrinolysis. The inhibitory effects of FXIIIa-
mediated cross-links on fibrinolysis are summarized and
differences in the crosslinking of purified fibrin, plasma, or
whole blood clots are highlighted. The potential effect of clot
compaction and clot retraction on the inhibition of lysis by
FXIIIa and the pathophysiologic aspects of FXIIIa-mediated
cross-links are also explained. The catalytic A subunit of
FXIII (FXIII-A) is present not only in plasma but also
intracellularly in several human cells, suggesting effects of
this protein are not restricted to hemostasis. Understanding
the roles of FXIII-A outside of the coagulation system is an
intriguing area of researchwith implications formany clinical
conditions and pathophysiologic processes including wound
healing, angiogenesis, atherosclerosis, and malignancies. In
their review paper, L. Paragh andD. To¨ro˝csik summarize cur-
rent knowledge on intracellular FXIII-A in wound healing,
angiogenesis, and various dermatopathologic conditions.
The pathophysiology of increased thrombotic risk in
various clinical conditions was studied in two original papers
in this issue. N. K. To´th et al. examined local, intracardiac
hemostasis and fibrinolysis abnormalities that are associ-
ated with atrial fibrillation (AF) and increase the risk of
thromboembolism. After measuring a comprehensive set
of fibrinolytic and hemostasis proteins in intracardiac and
peripheral blood samples from AF patients and non-AF con-
trols, the authors concluded that AF patients have elevated
factor VIII and von Willebrand factor levels, present in the
intracardiac and peripheral environment as well, possibly
contributing to the increased thrombotic risk associated with
this disorder. S. C. Meyer et al. investigated whether anti-
platelet factor 4 (PF4)/heparin antibodies contribute to the
increased thrombotic risk observed in myeloproliferative
neoplasms. They conclude that thrombotic risk increases in
anti-PF4/heparin IgG-positive polycythemia vera, reflecting
potential clinical implications and calling for larger, confir-
matory cohorts.
Clot formation in vivo occurs in a complex environment.
Whole blood clots contain cells and cell-derived components
that greatly influence thrombus size, composition, and stabil-
ity. In their timely and comprehensive review, J. Kappelmayer
and B. Nagy Jr. summarize central function of selectins and
their ligands and their roles as key mediators in cellular
events during the development of thrombotic and malignant
conditions. The role of platelets in clot formation, includ-
ing thrombin generation and clot contraction/retraction, is
another major focus in hemostasis and thrombosis research.
R.Huda´k et al. describe the effect of the phosphatase inhibitor
calyculin-A on various platelet activation mechanisms con-
tributing to clot formation, clot retraction, and thrombin
generation and conclude that this inhibitor could serve as a
useful tool in experimental studies.
We are confident that papers in this special issue will be
of interest and relevance to those involved in experimental
and clinical fields related to thrombosis and hemostasis. We
hope that the published articles will provide ideas and inspi-
ration to those dedicated to understand the pathophysiologic
mechanisms of clot formation and lysis, and will inspire
new ideas for diagnosing, treating, and ultimately preventing
thrombotic disorders in the future.
Acknowledgments
We would like to thank all authors who submitted their work
for this special issue. Z. Bagoly is the recipient of U´NKP-
17-4-III-DE-381 New National Excellence Program of the
Ministry ofHumanCapacities, NKFI PD111929, and the Ja´nos
Bo´lyai Fellowship of the Hungarian Academy of Sciences. A.
S. Wolberg receives funding from the National Institutes of
Health (R01HL126974). R. A. S. Arie¨ns is supported by the
British Heart Foundation (RG/08/004/25292).
Zsuzsa Bagoly
Robert A. S. Arie¨ns
Dingeman C. Rijken
Marlien Pieters
Alisa S. Wolberg
References
[1] G. E. Raskob, P. Angchaisuksiri, A. N. Blanco et al., “Thrombo-
sis: a major contributor to global disease burden,” Arterioscle-
rosis, Thrombosis, and Vascular Biology, vol. 12, pp. 1580–1590,
2014.
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