JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2018, 69, 4

www.jpp.krakow.pl | DOI: 10.26402/jpp.2018.4.02

Review article

A. UNDAS, M. ZABCZYK

ANTITHROMBOTIC MEDICATIONS AND THEIR IMPACT

ON FIBRIN CLOT STRUCTURE AND FUNCTION

Institute of Cardiology, Jagiellonian University Medical College, and the John Paul II Hospital, Cracow, Poland

Fibrin constitutes a major protein component of intravascular thrombi in all locations. Fibrin formation and its functions
are essential for physiological hemostasis and the pathologic thrombosis. Formation of dense fibrin networks which are
relatively resistant to lysis is observed in patients with venous or arterial thromboembolism, including myocardial
infarction, ischemic stroke and venous thromboembolism. Measures of clot characteristics, in particular clot
permeability and clot lysis time, may predict arterial and venous recurrent thromboembolic events. Medications,
including vitamin K antagonists (VKA), direct oral anticoagulants (DOAC), and parenteral direct or indirect thrombin
or activated factor X inhibitors increase clot permeability, reflecting fibrin network density, in association with enhanced
efficiency of fibrinolysis. These effects are only in part related to decreased thrombin generation. There is evidence that
aspirin can also favorably alter fibrin clot properties probably through acetylation of fibrinogen. No such effects were
observed for P2Y12 inhibitors. Of note, plasma fibrin clot permeability has been shown to predict adverse clinical
outcomes in patients receiving oral anticoagulants, which might have practical implications. The current review
summarizes data on effects of antithrombotic agents on fibrin clot phenotype in cardiovascular disease.

K e y w o r d s : direct oral anticoagulants, fibrin clot, antiplatelet, anticoagulant, fibrinolysis, thromboembolism, aspirin,
coagulation factors

INTRODUCTION composed of thousands of protofibrils arranged side-by-side (5).

Fibrin formation is the final step of blood coagulation (1).
Fibrinogen, the soluble fibrin precursor, is a multifunctional
340-kDa glycoprotein that consists of two sets of three
polypeptides: Aa, Bb, and g, linked in a dimeric structure by 29
disulfide bonds. The central E region contains the N termini of
all 6 chains. The chains in the form of 2 coiled-coils composed
of 3 chains represent two symmetrical globular D domains
containing the b-nodules and g-nodules formed by the carboxy
termini of the Bb and g-chains, respectively. The C-terminal
segment of the Aa chain goes through the D region and folds
back to join the coiled-coil for several residues (Aa residues 213
to 610). About 10% of fibrinogen molecules contain g’chains, in
which the 4 C-terminal residues are replaced with a 20-residue
sequence with a large negative charge (1-3).
Fibrin formation initiates thrombin that splits off two pairs of
fibrinopeptides A and B from the N termini of the Aa and Bb
chains, respectively, in the central nodule, leading to the exposure
of binding sites ‘A’ and ‘B’. Polymerization of fibrin monomers
involves formation of half-staggered and double-stranded
protofibrils through binding of knobs ‘A’ and ‘B’ in the central
nodule of fibrin monomer to complementary holes ‘a’ and ‘b’ in
the g- and b-nodules, respectively, of another monomer, which is
followed by the assembly of protofibrils into fibers through lateral
aggregation promoted mainly by intermolecular aC:aC
interactions between protofibrils and probably also by interactions
between both a- and g-chains (3, 4). Fibrin fibers are on average
Fibrin fibers are known to display the largest extensibility among
protein fibers because they can be strained 180% (2.8-fold
extension) without sustaining permanent lengthening, and to
525% (average 330%) before rupturing (6).
When bound to fibrin, thrombin activates factor (F)XIII
which enhances the formation of e-(g-glutamyl)lysyl covalent
bonds between g-g, g-a and a-a chains of adjacent fibrin
molecules, along with binding several proteins, including a2-
plasmin inhibitor, into a fibrin clot (7). Fibrin(ogen) binds a
variety of proteins related to coagulation, inflammation, platelet
activation and many others as shown in our recent report that
provided evidence for the presence of almost 500 proteins within
plasma clots in humans (8).
Fibrinolysis induced by plasmin that is responsible for
thrombus removal and maintaining blood flow leads to digestion
of fibrin at specific lysine residues. Fibrin enhances the activation
of plasminogen by tissue plasminogen activator (tPA). Plasmin
cleaves a number of Lys-X and Arg-X bonds in the fibrin
molecule, thereby breaking down the structure of the fiber. Fibrin
clot properties affect the rate of clot lysis in part due to their
impact on the distribution of lytic enzymes, which results in
faster lysis of less compact fibrin meshworks (9). Fiber thickness
has a strong impact on the rate of fibrinolysis induced by tPA,
with its increase in regions composed of thicker fibers (10).
Since in vivo fibrin structure and function can be modified by
blood flow, cellular blood components, endothelial cells,
circulating proteins and other molecules, as well as
2
posttranslational modifications e.g. oxidation, or glycation (11),
plasma fibrin clots and those made from purified fibrinogen may
have different characteristics and extrapolation of in vitro findings
could be challenging. To evaluate clot characteristics in vitro, the
permeability assay measuring the volume of percolating buffer
through a clot under different hydrostatic pressure is commonly
used and attempts to standardize it have been made (12). Other
measures of clot structure in plasma-based and purified fibrinogen-
based systems involve the fiber diameter and the size of the pores
in the fiber network on scanning electron microscopy (SEM) or
confocal microscopic images. Efficiency of fibrinolysis is assessed
using a variety of assays with various final concentrations of tPA
added to plasma samples together with thrombin or tissue factor
(TF) and phospholipids. Recently an assay that concomitantly
measures fibrin clot formation and lysis has been introduced and
supported by the International Society on Thrombosis and
Haemostasis Scientific Standarization Subcommittee (13).
Growing evidence indicates that patients with a history of
arterial and venous thrombotic events have altered fibrin clot
phenotype, involving the formation of more compact fibrin
meshworks displaying impaired permeability and lysability (14-
16). Fibrin formation during blood coagulation is influenced by
genetic and to a larger extent, environmental factors, which
explain a substantial interindividual variability of clot properties,
regardless of the methodology used. Pharmaceutical agents
affecting blood coagulation have been postulated to act in part
through modification of clot features.
This review is focused on the effects of antithrombotic
agents used in cardiovascular patients on fibrin clot formation,
structure and degradation. Potential clinical implications of
modified fibrin properties will be highlighted.
FIBRIN CLOTS AND THROMBOSIS
AT VARIOUS LOCATIONS
The pathogenesis of venous thromboembolism (VTE)
encompassing deep-vein thrombosis (DVT) and pulmonary
embolism (PE), that occurs in 1 – 2 per 1000 adult individuals in
Europe, is complex and multifactorial (17). Analysis of
pulmonary thromboemboli in acute PE shows the predominance
of fibrin (up to 80%) over cellular components (18, 19). It has
been reported that clots prepared in vitro after addition of 1 U/ml
human thrombin to platelet-poor plasma (PPP) obtained from
patients with a history of first-ever idiopathic DVT assessed at
4 – 20 months of anticoagulant therapy displayed 34% lower clot
permeability, 40% longer lysis time and 8% lower rates of the D-
dimer release from fibrin clots compared with controls (20).
Scanning electron microscopy of intracoronary thrombi
from patients with ST-segment elevation myocardial infarction
(STEMI) demonstrated that fibrin content within thrombi
increases with time up to 66.9% at six hours since the chest pain
onset (21). A 2-fold increase in fibrin content per each ischemic
hour has been estimated in STEMI patients (21). Compared to
stable coronary artery disease (CAD), in acute coronary events
(ACS) the in vitro formation of less permeable and lysable PPP
clots (1 U/ml human thrombin was used as a clotting activator)
in association with oxidative stress and inflammation has been
shown within the first 12 hours from the onset of chest pain (22).
The histological analysis of thromboemboli retrieved during
thrombectomy from the middle cerebral artery and intracranial
carotid artery of patients with acute ischemic stroke showed
random fibrin fibers mixed with platelet deposits with a large
heterogeneity (23). It is estimated that fibrin constitutes about
60% of the retrieved thrombi obtained from stroke patients and
the most common type of the thrombi (44%) is fibrin-dominant
(24). Acute ischemic stroke within the first 72 hours of symptom
onset has been found to be associated with 30% lower in vitro
PPP clot permeability and prolonged lysis time by 11%, coupled
with faster fibrin formation by 8% (1 U/ml human thrombin was
used as the clotting activator in all assays) compared with
healthy controls (25). Fibrin clot compaction correlated with
neurological deficit both on admission and at discharge of
patients admitted for acute ischemic stroke (25). More compact
plasma clots resistant to lysis were shown when clots were
generated from plasma samples of patients with cryptogenic
stroke at 3 to 19 months (26).
Atrial fibrillation (AF), the most common cardiac
arrhythmia, causes about 15% of ischemic strokes with poor
clinical outcomes, including 25% mortality within 30 days. It
has been shown that patients with chronic AF and previous
stroke have prolonged clot lysis time (CLT) assessed in PPP in
vitro in the presence of 0.6 pM human TF, combined with higher
thrombin-activatable fibrinolysis inhibitor (TAFI) antigen than
those free of stroke (27). Of note, CLT, plasminogen activator
inhibitor (PAI-1), TAFI activity and soluble thrombomodulin
were positively correlated with CHA2DS2-VASc scores,
reflecting stroke risk in AF (27). Experimental studies in a swine
model demonstrated that cerebral arteries occluded by fibrin-
rich clots have a lower recanalization rate and a longer mean
recanalization time than did arteries occluded by erythrocyte-
rich clots, suggesting that the histology of the occluding
thromboembolus may affect the angiographic outcome of
mechanical thrombectomy (28).
Antithrombotic drugs include antiplatelet agents and
anticoagulants, both oral and parenteral.
ASPIRIN
The strongest evidence from several groups shows favorable
alterations in clot structure following administration of aspirin.
Aspirin acts by irreversible inhibition of platelet
cyclooxygenase-1 (COX-1) due to acetylation of serine 529
residue, which inhibits the synthesis of the pro-aggregatory
thromboxane A2 (29). In large primary prevention trials aspirin
use was associated with reduced by 12% occurrence of serious
vascular events, including 20% lower incidence of MI (30).
Acetyl salicylic acid is the mainstay of the secondary prevention
of cardiovascular disease (30, 31), however, non-adherence is
still a major problem (32).
In ACS patients, low dose of aspirin (75 – 100 mg per day)
has not been less effective than doses of 300 – 325 mg/day (33).
Beyond inhibition of platelet activation by aspirin, which is a
main mechanism related to reduced risk of arterial thrombotic
events, aspirin may provide many additional antithrombotic
effects, including reduced thrombin generation, attenuation of
FXIII activation or acetylation of fibrinogen or antithrombin (34,
35). Administration of low-dose aspirin was shown to be
associated with improved clot properties probably through
fibrinogen acetylation (36, 37). Fibrinogen is acetylated at
several lysine residues, which also are involved in the FXIII-
mediated crosslinking of fibrin (37). Human fibrinogen treated in
vitro with aspirin (0.8 mmol/l for 24 hours) shows using mass
spectrometry 12 acetylation sites (lysines) in all three
polypeptide chains (35). In healthy men the intake of aspirin at a
daily dose of 37.5, 320 and 640 mg increased permeability and
density of clots prepared in vitro from PPP in the presence of 0.4
U/ml thrombin by 44%, 31%, and 21%, respectively, and
treatment with low-dose aspirin led to formation of thicker fibrin
fibers with larger pores (38). Using a cell model with transfection
with fibrinogen and the analysis of clots made in vitro from
purified fibrinogen after addition of 0.5 U/ml thrombin, aspirin
has been demonstrated to render fibrin networks looser and their

fibers thicker, leading to lower clot rigidity by 30% and enhanced
clot lysis (36). In healthy subjects treated with aspirin for 1 week,
final turbidity of clots prepared in vitro from purified fibrinogen
(clotting mixture as above) increased by 18% in response to
aspirin 50 mg daily for 7 days, with two-fold increase in fiber
thickness (36). Improved properties of plasma clots in response
to low-dose aspirin have been observed in CAD patients as well
as patients with VTE (39). Taken together, aspirin-induced
alterations to clot characteristics might be additional
antithrombotic action of this drug.
P2Y12 INHIBITORS
Inhibitors of platelet P2Y12 receptor (i.e. ticlopidine,
clopidogrel, prasugrel or ticagrelor), with preference to the two
latter agents are recommended in patients after coronary
intervention or MI, usually in combination with aspirin (40).
P2Y12 is a chemoreceptor for adenosine diphosphate (ADP)
mainly found on platelets surface and involved in platelet
aggregation. Binding of ADP to P2Y12 receptor activates the
glycoprotein (GP)IIb/IIIa receptor resulting in enhanced platelet
degranulation, thromboxane production and aggregation. The
thienopyridines (ticlopidine, clopidogrel and prasugrel) are
indirect platelet inhibitors, which metabolites covalently and
irreversibly bind to the P2Y12 receptor. Direct P2Y12 receptor
inhibitors (ticagrelor and cangrelor) can change P2Y12 receptor
conformation, resulting in its reversible inhibition (40).
Available data show no effect of clopidogrel on plasma clot
properties. In subanalysis of the PLATO trial comparing
ticagrelor with standard therapy in acute MI, in vitro fibrin clot
formation and lysis (PPP mixed with 0.03 U/ml thrombin)
assessed few days since the symptom onset were unaffected by
P2Y12 inhibitors, however clot lysis time predicted clinical
outcomes (41). Precisely, after adjusting for cardiovascular risk
factors, each 50% increase in lysis time was associated with
cardiovascular death or spontaneous MI (hazard ratio [HR] 1.17,
P < 0.01) and cardiovascular death alone (HR 1.36; P < 0.001).
There was no effect of randomized antiplatelet treatment or
bleeding events on clot characteristics (41).
GPIIB/IIIA INHIBITORS
The aIIbb3 (GPIIb/IIIa) is an integrin family receptor on the
platelet surface, which plays a critical role in thrombosis and
hemostasis and interacts with many ligands, including
fibrinogen. GPIIb/IIIa antagonists inhibit platelet aggregation
independently of the type of platelet agonist. Currently, among
GPIIb/IIIa antagonists abciximab, eptifibatide and tirofiban are
available. In contrast to platelet studies, in the fibroblast model
neither avb3, aIIbb3, nor other tripeptide Arg-Gly-Asp (RGD)-
binding integrins caused the spatially-dependent morphology
seen in clots formed during in situ thrombin generation (42).
This suggests that a major mechanism causing the spatially
heterogeneous fibrin clot morphology is likely attributable to
differential rates of thrombin generation at and above the cell
surface (42). Moreover, aIIbb3 determines fibrin structure in
platelet-rich clots, whereas integrin interactions play a minor to
no role in clots formed by fibroblasts, smooth muscle cells and
human umbilical vein endothelial cells (HUVECs) (42). In this
model, extravascular cells and tumor necrosis factor (TNF)-a-
stimulated HUVECs produce stable fibrin networks resistant to
lysis (43). Analysis of fibrin clots formed at increasing red blood
cell counts shows a decrease in fiber diameter, with its increase
following inhibition of GPIIb/IIIa, while red blood cells impair
clot lysis, with no effect of aggregation inhibition (44).
3
VITAMIN K ANTAGONISTS (VKA)
Vitamin K antagonists (VKA), including warfarin,
acenocoumarol and phenprocoumon, have been the standard of
care in anticoagulated patients regardless of indication, for many
years. Until now this class of drugs is often used in patients with
AF for stroke prevention (45, 46). VKAs still play the important
role in acute and extended management of VTE. The molecular
target of VKAs is vitamin K epoxide reductase complex subunit
1 (VKORC1) and their effects are governed by genetic and
environmental factors strongly modifying anticoagulant actions.
Mutations in the genes encoding VKORC1 and cytochrome
P450 2C9 (CYP2C9) largely contribute to the interindividual
variations in VKAs dose requirements. VKA-induced
impairment of gamma-carboxylation of FII, FVII, FIX and FX
results in reduced thrombin generation (47).
Warfarin at a concentration adjusted to obtain the therapeutic
range (international normalized ratio 2 – 3) in a commercially
available PPP resulted in higher in vitro clot permeability by about
35% (in a model with 5 pM recombinant human TF used as the
clotting activator) (48). Warfarin and acenocoumarol have been
shown to increase plasma clot porosity in patients with AF as early
as after 3 days of treatment, reaching the plateau value after 7 days
(Fig. 1 left panel, Fig. 2A) (49). Improvements in plasma clot
properties have been found to be related to lower activities of
vitamin K-dependent clotting factors and lower protein C activity
(49). Importantly, activated coagulation factor concentrate can
completely reverse the changes in fibrin clot properties following
warfarin (48). Drabik et al. have reported that low permeability of
a fibrin clot prepared in vitro after addition of 1 U/ml human
thrombin to PPP, is an independent predictor of both
thromboembolic events and major bleedings in AF patients
anticoagulated with VKA for at least 3 months and observed for
about 4 years (50). Patients with lower clot permeability (< 6.8 ×
10–9 cm2) had increased risk of ischemic stroke or transient
ischemic attack (HR, 6.55; 95% confidence interval [CI], 2.17-
19.82) and major bleeds (HR, 10.65; 95% CI, 3.52 – 32.22), while
those with elevated clot porosity (³ 6.8 ×10–9 cm2) had an
increased rate of minor bleeding compared with the remainder
(11.63% versus 3.55% per year) (50). Increased clot permeability
predisposed to minor bleedings in the same patients receiving
VKA, which appears to agree with findings in several bleeding
disorders because less compact clots are more prone to lysis and
they disintegrate before mucosal or skin rupture is fully healed.
DIRECT ORAL ANTICOAGULANTS (DOACS)
Non-vitamin K antagonist oral anticoagulants (NOACs) or
direct oral anticoagulants (DOACs), including dabigatran,
rivaroxaban, apixaban or edoxaban, have demonstrated
favorable efficacy and safety compared with VKAs. Large
randomized controlled trials in VTE patients indicate that the
NOACs were at least as effective as the conventional treatment
in preventing recurrent VTE (51). Recurrent VTE occurred in a
similar proportion of AF patients (2.0% on NOACs versus 2.2%
on VKA) whereas use of NOACs is associated with a 40%
reduction in the risk of major bleeding (51). Similar results have
been reported for patients with nonvalvular AF. Compared with
warfarin, there was a 19% reduction in the occurrence of stroke
or systemic embolism, 10% reduction in all-cause mortality and
50% reduction in both hemorrhagic stroke and intracranial
bleeding in NOAC users with AF (52).
Dabigatran, a direct thrombin inhibitor, has been shown to
enhance clot lysability and this effect was in part mediated by
TAFI (53). Reduced thrombin formation and suppressed
thrombin-mediated reactions during NOAC treatment appear to
4

Fig. 1. Scanning electron microscopic (SEM) images showing representative plasma clots from patients with: atrial fibrillation before
and during warfarin treatment (left) and venous thromboembolism before and after rivaroxaban intake (right). INR, International
Normalized Ratio. Plasma fibrinogen concentrations about 2.5 g/l. Magnification × 5000.

account for the formation of less compact and more lysable
fibrin clots.
The strongest evidence shows that rivaroxaban, a direct
activated FX (FXa) inhibitor, favorably alters fibrin clot
properties (Fig. 1 right panel, Fig. 2B) (54, 55). Formation of
fibrin networks composed of thicker fibers forming larger pores
associated with a 2-fold increased clot permeability and 3-fold
faster lysis has been observed compared with the control clots
generated in the absence of rivaroxaban (Fig. 3) (54). Similar
improvement in the presence of rivaroxaban has been reported in
whole blood clots (54). Plasma clots formed in the presence of
rivaroxaban solution were made of thicker fibrin fibres, had
larger pores and were more permeable (54). Increased clot
permeability has been shown at therapeutic plasma
concentrations of apixaban by 36 – 53% (Fig. 3) (48). Of note,
activated coagulation factor concentrate can only partly reverse
changes in clot properties induced by DOACs (48). We have
shown recently that in patients with a history of VTE,
rivaroxaban treatment increases clot permeability by 40% (55).
Rivaroxaban treatment improved fibrin clot properties also in
carriers of the G20210A prothrombin mutation (3% of the
European population) associated with 30% higher prothrombin
levels, but anticoagulant therapy with rivaroxaban cannot lead to
return normal fibrin clot phenotype (55).
Very recently, Carter et al. (56) have shown that rivaroxaban
and apixaban as FXa-specific DOACs can enhance fibrinolysis
in plasma by a modulation of fibrinolytic effects of FXa.
Moreover, a direct correlation between accelerated fibrinolysis
and FXa conversion from FXaa to FXab has been shown (56).
Although DOACs, including dabigatran, in different models of
in vitro clot formation have reduced thrombin generation and/or
promoted fibrin degradation, the direct influence of these
anticoagulants on fibrin structure using clotting activators
containing thrombin or TF needs to be elucidated.
It is unclear whether drug-induced changes in fibrin clot
properties may contribute to bleeding risk in anticoagulated
patients. Our preliminary data from a cohort study performed in
AF patients suggest that low clot permeability measured off
 5

Fig. 2. Changes in fibrin clot permeability (Ks) and clot lysis time (CLT) in patients with atrial fibrillation (panel A) and venous
thromboembolism (panel B) during vitamin K antagonist and rivaroxaban treatment, respectively. Boxes represent mean ± standard
deviation or median and interquartile range. OAT, oral anticoagulant therapy; INR, International Normalized Ratio. * P < 0.05.

anticoagulation independently predicts an increased risk of both OTHER MEDICATIONS OF POTENTIAL

stroke and clinically relevant bleeding events in rivaroxaban
treated patients who were followed for a median 40 months (A.
Undas, unpublished data). It is unknown whether clot
permeability has a comparable prognostic potential in patients
on dabigatran and apixaban.
OTHER ANTICOAGULANTS
Unfractionated and low-molecular-weight heparins have
been shown to improve clot properties as evidenced by analysis
of nanostructure of fibrin clots in the presence of antithrombin
(57). Parenteral direct thrombin inhibitors, argatroban,
bivalirudin and danaparoid, have been shown to increase fibrin
clot permeability at therapeutic concentrations in in vitro
models to a similar extent (Fig. 3) (58). Increased clot
permeability has been reported at therapeutic plasma
concentrations of a parenteral indirect FXa inhibitor,
fondaparinux by 58 – 76% (48).
ANTITHROMBOTIC ACTIVITY
Statins, potent cholesterol-lowering drugs, are
recommended in subjects at high-risk of CAD (59). Statins have
been reported in various models to produce several
antithrombotic effects, including down-regulation of TF
expression, resulting in suppressed thrombin generation and
thrombin-mediated reactions, such as fibrinogen cleavage, FV
and FXIII activation and increase in thrombomodulin
expression in endothelial cells, resulting in increased protein C
activation (60). Additional antithrombotic effect of statin use
represent favorable alterations in fibrin clot phenotype (60). A
3-month simvastatin treatment can result in increased clot
permeability in patients free of cardiovascular events and low-
density lipoprotein cholesterol < 3.4 mmol/l (61). Increased clot
permeability (+16%) has been reported in patients receiving
simvastatin with no association with low-density lipoprotein
cholesterol reduction (62). It has been reported that a 3-day use
of atorvastatin reduces plasma clot density by 23% (63).
6
Fig. 3. Influence of oral and parenteral anticoagulants added to plasma at given final amounts encountered in vivo on fibrin clot
permeability coefficient (Ks) relative to baseline values. Boxes represent mean ± standard deviation or median and interquartile range.
Properties of fibrin clots prepared in vitro from PPP obtained
from advanced CAD patients taking simvastatin or atorvastatin
correlated with a post-treatment decrease in thrombin-
antithrombin complex levels, most likely induced by down-
regulation of TF expression (64). It might be speculated that
changes in fibrin clot structure observed in patients treated with
statins are involved in clinical benefits of this class of drugs, as
evidenced by reduced risk of thrombosis in individuals taking
statins in primary and secondary prevention (60).
Regarding anti-hypertensive agents, data on fibrin-
modulating effects of angiotensin-converting enzyme inhibitors
(ACEIs) are most consistent. As shown for quinapril, ACEI
administered in patients with CAD can improve in vitro assessed
plasma fibrin clot properties (64). Depressed thrombin formation
observed after treatment with ACEIs in CAD patients has been
shown to be associated with improved clot permeability (64).
Newer data on various classes of drugs indicates that most
antihypertensive drugs may slightly improve clot properties
measured in plasma-based assays (65).
Treatment with insulin has been shown to make fibrin more
permeable despite no improvement in the control of glycaemia
(66). In vitro experiments showed that metformin, the most
commonly used antidiabetic agent in prevention and therapy of
type 2 diabetes (67), interferes with the polymerization process
of fibrin monomers and reduces FXIII-mediated cross-linking of
fibers that show increased lysability (68). Metformin can
increase clot permeability also in obese, nondiabetic individuals
(69). In diabetic patients better glycaemia control render fibrin
clots more permeable and lysable and the key mechanism altered
by these interventions is glycation of fibrinogen and other
proteins like plasminogen (37, 70). Limited data suggest that
administration of omega-3 polyunsaturated fatty acids (71)
might also increase permeability and susceptibility to lysis of
clots prepared in vitro using 1 U/ml human thrombin and PPP
obtained from patients with stable cardiovascular disease.
Conclusions
Venous or arterial thromboembolic events are associated
with the so-called prothrombotic fibrin clot phenotype, reflected
by denser networks that are formed quickly and are relatively
resistant to lysis. Clot properties in thrombotic disease can be
modulated by some antithrombotic drugs, in particular
anticoagulants and aspirin. Therapies targeting fibrin clot
properties might be a new class of agents able to improve
outcomes in patients with arterial and venous thromboembolism.
Acknowledgments: The study was supported by a grant of
Jagiellonian University Medical College (K/ZDS/007717,
to A.U.).
Conflict of interests: None declared.
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R e c e i v e d : August 6, 2018
A c c e p t e d : August 30, 2018
Author’s address: Prof. Anetta Undas, Institute of Cardiology,
Jagiellonian University Medical College, 80 Pradnicka Street,
31-202 Cracow, Poland.
E-mail: mmundas@cyf-kr.edu.pl