Journal of

Clinical Medicine

Review
Effects of Hyperglycemia and Diabetes Mellitus on Coagulation
and Hemostasis
Xiaoling Li 1 , Nina C. Weber 1 , Danny M. Cohn 2 , Markus W. Hollmann 1 , J. Hans DeVries 3 ,
Jeroen Hermanides 1 and Benedikt Preckel 1, *

1 Department of Anesthesiology, Amsterdam UMC Location AMC, University of Amsterdam,

1105 AZ Amsterdam, The Netherlands; x.li1@amsterdamumc.nl (X.L.);
n.c.hauck@amsterdamumc.nl (N.C.W.); m.w.hollmann@amsterdamumc.nl (M.W.H.);
j.hermanides@amsterdamumc.nl (J.H.)
2 Department of Vascular Medicine, Amsterdam UMC Location AMC, University of Amsterdam,
1105 AZ Amsterdam, The Netherlands; d.m.cohn@amsterdamumc.nl
3 Department of International Medicine, Amsterdam UMC location AMC, University of Amsterdam,
1105 AZ Amsterdam, The Netherlands; j.h.devries@amsterdamumc.nl
* Correspondence: b.preckel@amsterdamumc.nl; Tel.: +31-20-5669111

Abstract: In patients with diabetes, metabolic disorders disturb the physiological balance of coagu-
lation and fibrinolysis, leading to a prothrombotic state characterized by platelet hypersensitivity,
coagulation disorders and hypofibrinolysis. Hyperglycemia and insulin resistance cause changes in
platelet number and activation, as well as qualitative and/or quantitative modifications of coagula-
tory and fibrinolytic factors, resulting in the formation of fibrinolysis-resistant clots in patients with
diabetes. Other coexisting factors like hypoglycemia, obesity and dyslipidemia also contribute to
coagulation disorders in patients with diabetes. Management of the prothrombotic state includes





 antiplatelet and anticoagulation therapies for diabetes patients with either a history of cardiovascular
Citation: Li, X.; Weber, N.C.; Cohn,
disease or prone to a higher risk of thrombus generation, but current guidelines lack recommen-
D.M.; Hollmann, M.W.; DeVries, J.H.; dations on the optimal antithrombotic treatment for these patients. Metabolic optimizations like
Hermanides, J.; Preckel, B. Effects of glucose control, lipid-lowering, and weight loss also improve coagulation disorders of diabetes
Hyperglycemia and Diabetes Mellitus patients. Intriguing, glucose-lowering drugs, especially cardiovascular beneficial agents, such as
on Coagulation and Hemostasis. J. glucagon-like peptide-1 receptor agonists and sodium glucose co-transporter inhibitors, have been
Clin. Med. 2021, 10, 2419. https:// shown to exert direct anticoagulation effects in patients with diabetes. This review focuses on the
doi.org/10.3390/jcm10112419 most recent progress in the development and management of diabetes related prothrombotic state.

Academic Editor: Tomoaki Morioka Keywords: metabolic disorder; platelets; coagulation factors; hypercoagulation; hypofibrinolysis

Received: 5 May 2021

Accepted: 26 May 2021
Published: 29 May 2021
1. Introduction
Publisher’s Note: MDPI stays neutral
In 2017, the International Diabetes Federation estimated that 451 million adults are
with regard to jurisdictional claims in
diagnosed with diabetes mellitus (DM) worldwide, and the number would increase to
published maps and institutional affil- 693 million by 2045 [1]. Anesthesiologists are increasingly facing high-risk patients with sig-
iations. nificant comorbidities undergoing major surgery, including a significant risk for excessive
bleeding, and hyperglycemia is associated with higher risk of perioperative complica-
tions and poorer outcomes after surgery [2,3]. The hemostatic function of platelets and
coagulation factors sometimes makes it difficult to control the pro-thrombotic state since
Copyright: © 2021 by the authors.
global inhibition of coagulation will impair hemostasis [4]. It is essential to understand
Licensee MDPI, Basel, Switzerland.
the signalling partners and factors involved in platelet hyperresponsiveness or aberrant
This article is an open access article
activation of the coagulation system. This will eventually allow for selective targeting
distributed under the terms and of pro-thrombotic cascades while preserving hemostasis. Metabolic disorders influence
conditions of the Creative Commons coagulation and hemostasis, but the underlying mechanisms have yet to be clarified [5–7].
Attribution (CC BY) license (https:// Besides, the choice and optimal dosage of antithrombotic agents for patients with DM are
creativecommons.org/licenses/by/ still unclear [8]. This review focuses on coagulation dysfunction and prothrombotic states
4.0/). in patients with DM.

J. Clin. Med. 2021, 10, 2419. https://doi.org/10.3390/jcm10112419 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2021, 10, 2419 2 of 14

J. Clin. Med. 2021, 10, 2419 still unclear [8]. This review focuses on coagulation dysfunction and prothrombotic states
2 of 14
in patients with DM.

2. Prothrombotic State Associated with Diabetes Mellitus

2. Prothrombotic State Associated with Diabetes Mellitus
Coagulation and hemostasis involve interactions between tissue and coagulation fac-
Coagulation
tors as andand
well as blood hemostasis involve
endothelial cells,interactions between
finally resulting tissue andofcoagulation
in formation fibrin clots
factors as well as blood and endothelial cells, finally resulting in formation
stopping bleeding [4]. During this process, the fibrinolytic system decomposes of fibrin clots
generated
stopping
clots bleeding
to prohibit [4]. During
widespread this process,
thrombus the fibrinolytic
formation system
and vascular decomposes
occlusion [5]. generated
clotsIn
to patients
prohibithaving
widespread thrombus formation and vascular occlusion [5].
DM, metabolic disorders disturb these physiological mechanisms,
In patients
leading having DM, state
to a prothrombotic metabolic disordersby
characterized disturb these
platelet physiological mechanisms,
hypersensitivity, coagulation
leading to a prothrombotic state characterized
factor disorders and hypofibrinolysis [9] (Figure 1). by platelet hypersensitivity, coagulation
factor disorders and hypofibrinolysis [9] (Figure 1).

Figure 1. Modifications of coagulation and fibrinolysis system in DM. Diabetes disturbs the physiological balance between
coagulation
coagulation and
and fibrinolysis,
fibrinolysis, leading
leading to
to aa prothrombotic
prothrombotic state hallmarked with
state hallmarked platelet hypersensitivity,
with platelet hypersensitivity, coagulation
coagulation factor
factor
disorders and hypofibrinolysis. Hyperglycemia and insulin resistance enhance number and aggregation of
disorders and hypofibrinolysis. Hyperglycemia and insulin resistance enhance number and aggregation of platelets throughplatelets through
increasing von Willebrand factor (vWF) level and inhibiting anti-aggregatory efficiency of nitric oxide and prostaglandin I2.
increasing von Willebrand factor (vWF) level and inhibiting anti-aggregatory efficiency of nitric oxide and prostaglandin I2 .
Hyperglycemia and insulin resistance upregulate level of pro-coagulation mediators like tissue factor (TF), coagulation fac-
Hyperglycemia and insulin resistance upregulate level of pro-coagulation mediators like tissue factor (TF), coagulation
tors (FVII, FXII, FXI and FIX) and thrombin. Diabetes also harasses fibrinolysis by decreasing tissue plasminogen activator
factorsas(FVII,
(tPA) well FXII, FXI and FIX)
as increasing and thrombin.
plasminogen Diabetes
activator also harasses
inhibitor-1 (PAI-1)fibrinolysis by decreasing
and thrombin tissue plasminogen
activator fibrinolysis inhibitoractivator
(TAFI).
(tPA) as well as increasing plasminogen activator inhibitor-1 (PAI-1) and thrombin activator fibrinolysis
Next to hyperglycemia and insulin resistance, co-existing metabolic disorders like hypoglycemia, obesity, dyslipidemia, inhibitor (TAFI).
and
Next to hyperglycemia
non-alcoholic fatty liverand insulin
disease resistance,
(NAFLD) alsoco-existing metabolic
contribute to disorders like
the pro-thrombotic hypoglycemia,
state obesity,
of patients with DM.dyslipidemia, and
non-alcoholic fatty liver disease (NAFLD) also contribute to the pro-thrombotic state of patients with DM.
2.1. Platelet Hypersensitivity
2.1. Platelet Hypersensitivity
In physiological conditions, platelets circulate in the blood for five to seven days and
constantly undergo a lifecycle
In physiological fromplatelets
conditions, megakaryocyte
circulateseparation to phagocytosis
in the blood by macro-
for five to seven days
phages, to maintain
and constantly a normal
undergo platelet
a lifecycle fromcount of 150.000–450.000
megakaryocyte per microliter.
separation After vas-
to phagocytosis by
macrophages,
cular to maintain
injury, platelets a normaltoplatelet
are activated count
aggregate, of 150.000–450.000
forming an occlusiveper microliter.
thrombus andAfter
stop
vascular [10].
bleeding injury, platelets
Both are activated
increased to aggregate,
platelet number formingaggregation
and enhanced an occlusive thrombus
capacity, theand
lat-
stop bleeding [10]. Both increased platelet number and enhanced aggregation capacity,
ter referred to as platelet hypersensitivity, will contribute to a pro-thrombotic state [11]. the
latter
In referred
patients withtoDM,
as platelet hypersensitivity,
over-activation will(mainly
of platelets contribute to a pro-thrombotic
attributed state [11].
to hyperglycemia and
In patients
insulin with DM,
resistance) over-activation
plays a crucial roleofforplatelets (mainly attributed
pro-thrombotic events [12].to hyperglycemia and
insulin resistance) plays a crucial role for pro-thrombotic events [12].

2.1.1. Hyperglycemia
Among patients with type 2 diabetes mellitus (T2DM), mean platelet counts are up to
10% higher in patients with chronic hyperglycemia (glycated hemoglobin, HbA1c > 8%) as
J. Clin. Med. 2021, 10, 2419 3 of 14

compared to euglycemia. Besides, increased mean platelet volume (MPV) is observed in pa-
tients with higher HbA1c and fasting blood glucose (FBG), suggesting that hyperglycemia
also enhances platelet activity [13]. Similarly, positive correlations between higher blood
glucose and increased platelet counts are also found in patients with type 1 diabetes mellitus
(T1DM) [14,15]. Even in patients in a pre-diabetic state, MPV is slightly increased compared
to patients with normal glucose metabolism (10.49 ± 0.96 fL vs. 10.04 ± 1.01 fL) [16]. A
potential underlying mechanism for platelet hyperactivity in hyperglycemia could be an
upregulated expression of pro-aggregatory factors like P-selectin, thromboxane A2 and von
Willebrand factor (vWF) antigen, amplifying the aggregation and adhesion of platelets [17].
In addition, high blood glucose deteriorates the physiologic reaction of platelets on
anti-aggregatory effects of nitric oxide (NO), prostaglandin I2 (PGI2 ) and insulin by inter-
fering with downstream signalling pathways [18]. Both acute and chronic hyperglycemia
upregulate the expression of adhesion molecules on platelet surface (e.g., CD31, CD49b
and CD63), an effect that is reversible after optimizing glucose control [19]. Chronic hy-
perglycemia increases expression of protease-activated receptor 4 in patients with DM,
in turn promoting the release of activated platelet-derived microparticles (PMPs) via
the Ca2+ -calpain pathway. Released PMPs then trigger the secretion of interleukin-6, a
pro-thrombotic and pro-inflammatory mediator in diabetes [20]. Through glycation of
membrane proteins, hyperglycemia also decreases the membrane fluidity of platelets and
results in increased intracellular calcium influx, directly promoting platelet activation and
aggregation [21]. Hyperglycemia also impairs endothelial function by inducing inflamma-
tion and oxidative stress, thereby inhibiting synthesis and release of PGI2 and NO, finally
further promoting platelet aggregation [22].

2.1.2. Insulin Resistance

Patients with T2DM had larger MPV and increased platelet generation compared to
patients having T1DM; MPV correlated with HbA1c only in patients with T1DM [17]. Given
that T1DM is characterized by insulin deficiency and T2DM is hallmarked with insulin
resistance, these data might indicate a potential role of insulin sensitivity and resistance in
coagulation dysfunction [23]. Another study showed a positive correlation between MPV
and homeostasis model assessment insulin resistance index [24]. A possible underlying
mechanism is a modified insulin signalling in platelets associated with insulin resistance:
in healthy individuals, insulin binds with insulin receptors on platelet surfaces, leading to
activation of downstream pathways, e.g., the tyrosine phosphorylation pathway and the
inhibitory G-protein pathway [25]. The latter results in higher cyclic adenosine monophos-
phate (cAMP) generation and lower intracellular calcium inside platelets, thereby inhibiting
their aggregation [18].
However, in patients with insulin resistance, insulin failed to increase cAMP levels
within platelets, thus impairing its anti-aggregational effects [26]. Insulin resistance also
reduces the sensitivity of platelets towards the anti-aggregatory effects of NO and PGI2 ,
which in turn alters calcium influxes and promotes platelet aggregation [27]. Intriguingly,
recent studies linked insulin resistance with an altered composition of gut microbiomes [28],
and the latter contributes to the enhanced thrombosis risk via generation of platelet stim-
ulus metabolites [29]. For instance, trimethylamine N-oxide might directly increase the
aggregation and adhesion capacity of platelet [30], and phenylacetylglycine facilitates
platelet responsiveness and enhances thrombosis tendency [31]. Antidiabetic drugs may
be able to change the microbiome structure and the resulting plasma metabolome. Thus,
pleiotropic effects observed by, e.g., metformin, could at least in part be mediated through
microbiota and their released metabolites and that may include antithrombotic effects of
the drug. This is an active area of research and must show in the near future whether
antidiabetics can play a substantial role in these pathomechanisms [32].
J. Clin. Med. 2021, 10, 2419 4 of 14

2.2. Quantitative and Qualitative Alterations of Coagulation Factors

Coagulants (also known as coagulation factors) are a series of proteins involved in
the coagulation process, working together with platelets to form a firm clot and stop
bleeding [33]. Both, quantitative and qualitative alterations of coagulation and antico-
agulation factors were observed in patients with DM [34], contributing to formation of
lysis-resistant clots.
The extrinsic coagulation or Tissue Factor (TF) pathway is initialized with activation
of tissue factor/Factor VIIa (TF/FVIIa) complexes and plays an essential role in thrombus
generation [35]. In T2DM, hyperglycemia and insulin resistance exert synergistic effects on
the TF pathway, leading to increased pro-coagulatory activity and FVIIa consumption [36].
Several mechanisms are involved: hyperglycemia and hyperinsulinemia both directly
promote the TF transcription in monocytes [37]. Additionally, patients with diabetes are
prone to constant inflammation, and one symptom is increased inflammatory biomarker
levels (e.g., interleukins) in blood [38]. The pathological process directly upregulates TF
expression in endothelial and vascular smooth muscle cells, contributing to the hyper-
coagulation state in DM [39]. Generation of advanced glycation end-products, glycated
lipids or proteins formed during hyperglycemia [40], as well as reactive oxygen species
enhance TF production through activation of the nuclear factor (NF)-κB inflammatory
pathway [41]. Notably, recent studies highlight the role of micro-RNA (miR) in TF expres-
sion and diabetes-related coagulation dysfunction. For instance, miR-126, miR-19a and
miR-181b are negatively associated with both TF protein and TF-mediated thrombogenicity
in patients with diabetes. Further investigations showed that miR-126 and miR-19a both
inhibit the TF expression in endothelial cells, and miR-181b reduced the generation of TF
within monocytes [42–44]. These findings might explain in part the enhanced vascular TF
activity in poorly controlled type 2 diabetes.
The intrinsic coagulation pathway involves sequential activations of FXII, FXI and
FIX, and recent studies have reported dysfunctions of intrinsic coagulation associated with
hyperglycemia and hyperinsulinemia in DM [45,46]. In the Netherlands’ Epidemiology
of Obesity study [46], increases in FVIII (5.33%, 95%CI: 4.00–6.65), FIX (6.19%, 95%CI:
5.15–7.23) and FXI (2.11%, 95%CI: 1.20–3.02) were observed per mmol/L increase in fast-
ing plasma glucose, and these associations remained significant even after adjusting for
confounding factors such as age, sex and body mass index (BMI). Increased synthesis of
FXII, FXI and FIX in hepatocytes along with a shorter activated partial thromboplastin time
(APTT) were observed in patients with impaired insulin sensitivity, probably mediated by
a low-grade inflammatory reaction caused by insulin resistance [47].
Conversion of fibrinogen to fibrin is the last critical step in extrinsic and intrinsic
coagulation pathways, and higher circulating fibrinogen levels are observed in T1DM
and T2DM patients, resulting in a more compacted clot structure along with increased
resistance to fibrinolysis [48]. Hyperfibrinogenemia in DM can be explained by several
factors. Hyperglycemia and insulin resistance enhance hepatic fibrinogen synthesis, and
production of fibrinogen is further increased in obesity, dyslipidemia and non-alcoholic
fatty acid diseases, all of which are common comorbidities in hyperglycemic patients [49].
In addition, low-grade inflammation in DM directly stimulates hepatocytes to synthesize
more fibrinogen [50].
Modified quality of fibrinogen in DM has recently been demonstrated: an increased
glucose level amplifies glycation of fibrinogen and disturbs the fibrinolytic process, and
these alterations could be attenuated by tight glucose control [51]. Enhanced oxidative
stress and sustained inflammatory reactions in patients having DM also alter the structure
of fibrinogen and fibrin, thereby leading to fibrinolysis-resistant clots [52].
Thrombin is derived from prothrombin and is an essential factor that transforms fib-
rinogen into fibrin. In patients with DM, increased thrombin levels lead to enhanced fibrin
generation and clot density, thereby contributing to the pro-thrombotic state [53]. Both
hyperglycemia and hyperinsulinemia stimulate prothrombin synthesis in the liver. Recent
J. Clin. Med. 2021, 10, 2419 5 of 14

studies reported increased thrombin levels in obesity and hyperlipidemia, comorbidities

that can therefore aggravate the hypercoagulable state in patients with DM [54,55].

2.3. Hypofibrinolysis
The hypofibrinolytic state in DM is partly attributed to the formation of fibrinolysis-
resistant clots; however, alterations of the fibrinolytic system have also been observed
among individuals with diabetes [56].
Plasminogen is the precursor of plasmin. During coagulation, generated fibrin binds
with tissue plasminogen activator (tPA), the key catalysator of plasmin generation, which
then initiates fibrinolysis and restrains excessive thrombus formation [57]. In diabetic
patients with DM, tPA is negatively correlated with HbA1c (lower levels of tPA with higher
levels of HbA1c); increased glucose levels inhibit tPA’s pro-fibrinolytic activity, leading to
reduced levels of plasmin in blood with high glucose values [56]. Hyperglycemia enhances
the glycation of plasminogen and thereby inhibits the generation of plasmin, an effect that
is reversible after tight glucose control [58]. The impact of plasminogen on coagulation
disorders in DM is further aggravated as plasminogen is also a pro-inflammatory factor,
thereby promoting insulin resistance and exacerbating a pro-thrombotic state [59].
Plasminogen activator inhibitor-1 (PAI-1) and thrombin-activator fibrinolysis inhibitor
(TAFI) are two crucial inhibitory factors of the fibrinolytic system. PAI-1 forms complexes
with tPA to harass its catalytic capacity, while TAFI prevents plasminogen from binding
to fibrin and terminates the conversion of plasminogen to plasmin [57]. Hyperglycemia
and insulin resistance lead to elevation of these two anti-fibrinolytic factors, resulting in
reduced fibrinolytic factors [60]. The alterations of PAI-1 and TAFI could be reversed by
euglycemia, emphasizing the importance of glucose control in alleviating the fibrinolytic
dysfunction in DM [56]

3. Prothrombotic Effects of Coexisting Metabolic Disorders

DM is a cluster of metabolic disorders, and next to hyperglycemia and insulin resis-
tance, co-existing changes like hypoglycemia, obesity and dyslipidemia also contribute to
the pro-thrombotic state of patients with DM.

3.1. Hypoglycemia
Hypoglycemia is a crucial acute complication of DM treatment and it significantly
increases cardiovascular risk and mortality [61]. Hypoglycemia is also associated with in-
creased thrombus formation based on platelet activation, quantitative and qualitative
alterations of coagulants, as well as impaired fibrinolysis [62,63]. In T2DM patients,
platelet function increased with decreasing blood glucose and increasing epinephrine,
suggesting that hypoglycemia induces platelet activation by sympathetic stimulation [64].
Hypoglycemia also promotes coagulant and fibrinolytic dysfunction by inducing pro-
inflammatory reactions and impairing endothelial function in patients with DM [65]. In-
creased thrombogenicity after hypoglycemia lasted for up to seven days [66], indicating that
hypoglycemia might exert short- to medium-term harmful effects on coagulation function.

3.2. Obesity
Overweight and obesity, according to World Health Organization guidelines defined
as BMI ≥ 25 kg/m2 and 30 kg/m2 , respectively, are common comorbidities of two-thirds of
patients with DM [67]. Obesity is considered a noticeable pro-thrombotic factor: increased
thrombogenicity with higher BMI, and a hazard ratio for thrombosis of 3.4 (95% CI: 2.6–4.6)
was observed in severe obese subjects compared with those of normal-weight [68]. Underly-
ing mechanisms could be the increased number and size of adipocytes in obese individuals,
accompanied by enhanced secretion of TF and PAI-1, finally leading to hyper-coagulation
and hypo-fibrinolysis [69,70]. Additionally, increased body weight causes physical in-
activity and slows down blood flow with stasis, resembling a pro-thrombotic factor by
itself [68].
J. Clin. Med. 2021, 10, 2419 6 of 14

3.3. Dyslipidemia
Dyslipidemia is common among patients with T2DM and is associated with hyper-
coagulation [71]. Individuals with high triglyceride and total cholesterol levels showed
higher fibrinogen levels and shortened APTT, suggesting an enhanced endogenous po-
tential for thrombin generation [72]. Coagulation dysfunction of patients with DM was
partially alleviated by lipid-lowering agents [53]. A potential underlying mechanism could
be increased blood lipids, which directly impair function of hepatic cells (e.g., the origins
of multiple coagulation factors) and in turn disturb coagulation [73]. Oxidized low density
cholesterol also activates scavenger receptors on monocytes, resulting in inflammatory
pathway activation and overproduction of oxidants and coagulation factors [74].

3.4. Nonachoholic Fatty Liver Disease (NAFLD)

Over 50% of patients with T2DM suffer from NAFLD, which may contribute to
coagulation disorders and also a pro-thrombotic state [75]. Given that hepatic cells are the
major producer for multiple coagulants (e.g., VIII, XI, XII), accumulation of liver fat might
correlate with changes in coagulation factor production and prolonged APTT in patients
with NAFLD [76,77]. Contrarily, another study showed that insulin resistance and adipose
tissue inflammation, rather than liver fat content, enhanced the expression and activity of
coagulant factors [47].

4. Management of Pro-Thrombotic State in DM

Due to the prothrombotic state and enhanced cardiovascular risk in diabetic patients,
the necessity of antiplatelet and anticoagulation therapy is well acknowledged, but the
optimal treatment strategies remain controversial [78,79]. In addition, optimized glucose-
lipid control and weight loss further alleviate the pro-thrombotic state in DM [80].

4.1. Antiplatelet Medications

Aspirin is the most widely used antiplatelet agent also in patients with DM [79]. It
binds irreversibly to cyclooxygenase-1 (COX-1) on platelets and prevents the generation of
prostaglandin H2 from arachidonic acid, thus inhibiting thromboxane A2 formation and
platelet activation [81]. Aspirin (75–162 mg per day) is recommended as the first choice for
secondary prevention in patients with a history of cardiovascular disease (grade A) [82], but
the most recent guidelines of the American College of Cardiology and the American Heart
Association do not specifically recommend aspirin as a primary prevention strategy in
diabetes patients [82]. A meta-analysis showed that aspirin reduced the first cardiovascular
event by around 12% in patients without a history of cardiovascular disease, which was less
effective compared to its effects in secondary prevention (22% reduction of cardiovascular
events) [83]. One possible explanation might be that the absolute incidence of a very first
cardiovascular event is low in patients without previous cardiovascular disease, thereby
impairing the efficiency of aspirin in the primary prevention of cardiovascular events [84].
P2Y12 inhibitors like clopidogrel are commonly combined with aspirin for dual antiplatelet
therapy (DAPT), which is recommended (grade A) also for patients suffering from acute
coronary syndrome [82]. Clopidogrel is also considered as a substitute in patients with
contraindications for aspirin [85].
Population-based clinical trials have been carried out to explore the efficacy and
safety of other antiplatelet drugs in patients with DM. Cilostazol, a phosphodiesterase
III inhibitor enhancing cAMP generation and preventing platelet aggregation, decreased
stent thrombosis after stent-implantation in patients having DM when combined with
DAPT [86]. Compared to aspirin, the thromboxane synthase inhibitor picotamide reduced
non-fatal vascular complications in T2DM patients with peripheral vascular disease [87].
However, neither cilostazol nor picotamide were superior to aspirin in preventing overall
mortality [87,88], thus aspirin is still the first-choice antiplatelet treatment in patients with
a history of cardiovascular disease.
J. Clin. Med. 2021, 10, 2419 7 of 14

4.2. Anticoagulation Medications

Currently, anticoagulants such as thrombin-inhibitors or anti-Xa agents are only rec-
ommended in patients with diabetes in case they experience complications, e.g., thrombosis
or high risk for thrombotic tendency (e.g., atrial fibrillation) [82]. Warfarin non-specifically
inhibits the synthesis of several clotting factors by inhibiting the vitamin K epoxide re-
ductase complexes [89]. Direct oral anticoagulants (DOACs) target thrombin or factor
Xa and exert specific anticoagulation activities [90]. Several studies have compared the
effectiveness and safety of DOACs and warfarin in patients at a high risk for thrombotic
diseases. In individuals with and without DM, Rivaroxaban, a specific inhibitor of FXa, is
associated with a lower risk of systemic embolism and major bleeding than warfarin [91,92].
Low-dose rivaroxaban also reduced platelet activation and inflammation via the inhibition
of the binding of FXa towards protease-activated receptors on platelet surfaces [93], possi-
bly ameliorating the pro-thrombotic state in patients with diabetes with no indication for
a full anticoagulant dose. Patients on apixaban, another FXa inhibitor, experienced 30%
less incidents of hemorrhages than those exposed to warfarin [94]. The thrombin inhibitor
dabigatran also leads to more potent reduction in embolic events in individuals with DM
than warfarin, without increasing the risk of hemorrhage [95]. These studies suggest that
DOACs might serve as more potent and safer alternatives to warfarin for anticoagulation
therapy in patients with DM.

4.3. Metabolism Optimization

4.3.1. Glucose Control
Several glucose-lowering agents exert glucose-independent anticoagulation effects in
patients with DM. Alleviation of coagulation dysfunction is mediated by improvement of
insulin resistance, endothelial function, inflammatory reaction and oxidative stress. [96–98].
For instance, metformin, the most widely prescribed anti-diabetes drug, lowers the
activity of coagulation factors and platelets and prevents the formation of fibrinolysis-
resistant clots [99,100]. The attenuation of coagulation function was explained by an
enhancement of insulin sensitivity and a normalization of endothelial function for met-
formin treatment [96]. A recent study revealed that metformin directly lowered expression
and activity of TF in patients with chronic hyperglycemia and poorly controlled glucose,
which was mediated by suppression on endothelial inflammation [97]. Thiazolidinediones
have also been proven to attenuate coagulation dysfunction by reducing fibrinogen and
PAI-1 levels, thereby modulating the balance between clot generation and fibrinolysis [101].
Rosiglitazone inhibited platelet aggregation activity in a dose-dependent manner, medi-
ated by enhanced insulin sensitivity and decreased inflammatory reaction and oxidative
stress [98]. Considering sulphonylureas, glibenclamide dose-dependently inhibited the
expression of TF, producing a potential anticoagulation effect of sulphonylureas [102]. In-
sulin inhibits platelet aggregation by inducing cAMP generation and reducing intracellular
calcium levels [18]. Contrarily, in patients with T2DM, insulin treatment was associated
with higher fibrinogen and PAI-1 levels due to insulin resistance [103].
The anticoagulation potential of glucagon-like peptide-1 receptor agonists (GLP-1
RAs), a group of glucose-lowering agents with cardiovascular protective effects [104],
has been demonstrated; after binding with GLP-1 receptors on platelets, liraglutide in-
creased the sensitivity of platelets towards NO, thereby inhibiting aggregation activity of
platelets [105]. Apart from glucose control, GLP-1 RA also exerts anticoagulation effects by
inhibiting inflammation and promoting NO synthesis of endothelial cells [106].
Sodium glucose co-transporter 2 inhibitors (SGLT-2i’s) are also glucose-lowering drugs
with beneficial cardiovascular effects. These drugs directly alleviate DM-related endothelial
dysfunction, one of the major modulators of coagulation and fibrinolysis [107,108]. A
recent study in human endothelial cells demonstrated that empagliflozin and dapagliflozin
restored NO bioavailability [109], which is an anticoagulation factor inhibiting platelet
aggregation [22]. More recently, empagliflozin has also been shown to decrease the plasma
concentration of PAI-1 in patients with T2DM (by 25%), thereby improving fibrinolysis
J. Clin. Med. 2021, 10, 2419 8 of 14

function [110]. Intriguingly, two clinical trials (NCT04342819 and NCT04400760) are
now performed, recruiting patients with DM to figure out the influence of empagliflozin
and dapagliflozin on platelet functions; these studies will present more insight into the
anticoagulation potential of SGLT-2i’s. The direct anticoagulation effects of mentioned
glucose-lowering agents have been summarized in Table 1.

Table 1. Anticoagulation effects of glucose-lowering agents.

Agent Alterations in Coagulation-Fibrinolysis System

Metformin tPA ↓[83]; platelet aggregation↓[84]; TF ↓[97]
Thiazolidinediones fibrinogen↓; PAI-1↓[101] ; platelet aggregation↓[98]
Sulphonylureas TF↓[102]
Insulin platelet aggregation↓[18]; fibrinogen↑; PAI-1↑[103]
GLP-1RA platelet aggregation↓[105]; NO↑[106]
SGLT-2i’s NO↑[109]; PAI-1↓[110]
GLP-1RA: glucagon-like peptide-1 receptor agonists; SGLT-2i’s: sodium glucose co-transporter 2 inhibitors; tPA:
tissue plasminogen activator; TF: tissue factor; PAI-1: plasminogen activator inhibitor-1; NO: nitric oxide.

4.3.2. Weight Loss

Diet, exercise and bariatric surgery are common weight loss therapies [111], and
their antithrombotic effects have also been explored [112–114]. Gastric bypass surgery
reduced thrombin generation activity by one-third after six months, which is partially
mediated by significant weight loss (27.4 ± 0.7 kg) and improved glucose-lipid metabolism
benefits [112]. The combination of surgery with supervised physical training further
improved coagulation and metabolic benefits [112]. Mild weight reduction (within 5 kg)
induced by leisure exercise and dietary modulation failed to reduce thrombogenic markers
in overweight/obese subjects [113,114], suggesting that the influence of weight loss on
coagulation might be determined by the extent of weight loss. A recent study showed
that lifestyle intervention led to reduced activities of multiple coagulation factors (II, VII,
VIII, IX, XI and XII) and decreased levels of PAI-1 and vWF. These beneficial changes
in the coagulation system were not only mediated through weight loss, but also via the
ameliorated insulin resistance and limited subclinical inflammation [115].

4.3.3. Lipid-Lowering Therapy

The anticoagulation functions of lipid-lowering agents have been described: statin-
lowering therapy led to reductions of thrombotic risk and platelet activity in patients
with DM [53,116]. For instance, fibrates and ezetimibe alleviated hypercoagulability in
patients with impaired glucose metabolism, probably mediated by lipid-lowering and
anti-inflammatory effects[117]. Lipid-lowering agents also directly reduced the expression
levels of several pro-coagulation factors, e.g., TF and P-selectin, thereby inhibiting throm-
bin generation [118]. Moreover, proprotein convertase subtilisin/kexin type-2 (PCSK9)
inhibitors, potent agents against hypercholesterolemia, might enhance the expression of
hepatic low-density lipoprotein receptors and accelerate FVIII degradation within the liver,
thereby lowering circulating FVIII levels [119]. However, at present, there is no direct
proof for the anticoagulation effect of PCSK9 inhibitors and the decreased FVIII in patients
with DM.

5. Conclusions
In summary, patients with T1DM and T2DM are prone to thrombotic events based on a
series of disorders, including platelet hypersensitivity, coagulation factor modifications and
hypofibrinolysis. Studies on the altered coagulation in DM suggest that hyperglycemia, in-
sulin resistance and other comorbidities contribute to the hypercoagulable state (Figure 1).
Thus, management of the enhanced thrombogenicity in DM requires comprehensive treat-
ments of existing prothrombotic factors along with antithrombotic therapy, but current
guidelines lack recommendations on the optimal antithrombotic medications in patients
with DM. Results from clinical studies strongly support the beneficial effects of glucose
J. Clin. Med. 2021, 10, 2419 9 of 14

control, weight loss and lipid-lowering on coagulation dysfunctions, and glucose-lowering

drugs, especially GLP-1 RAs and SGLT-2i’s, tend to ameliorate diabetes related hypercoag-
ulation (Table 1).

Author Contributions: Conceptualisation: X.L., B.P., J.H., N.C.W., J.H.D., M.W.H.; writing–original
draft preparation: X.L., B.P., N.C.W.; writing–review and editing: X.L., N.C.W., D.M.C., M.W.H.,
J.H.D., J.H., B.P.; supervision: B.P., N.C.W., J.H.D. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: X.L. is supported by a Chinese Scholarship Council (CSC) fellowship program.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Cho, N.H.; Shaw, J.E.; Karuranga, S.; Huang, Y.; da Rocha Fernandes, J.D.; Ohlrogge, A.W.; Malanda, B. IDF Diabetes Atlas:
Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 2018, 138, 271–281. [CrossRef]
2. Hulst, A.H.; Visscher, M.J.; Cherpanath, T.G.V.; van de Wouw, L.; Godfried, M.B.; Thiel, B.; Gerritse, B.M.; Scohy, T.V.; Bouwman,
R.A.; Willemsen, M.G.; et al. Effects of Liraglutide on Myocardial Function After Cardiac Surgery: A Secondary Analysis of the
Randomised Controlled GLOBE Trial. J. Clin. Med. 2020, 9, 0673. [CrossRef] [PubMed]
3. Szekely, A.; Levin, J.; Miao, Y.; Tudor, I.C.; Vuylsteke, A.; Ofner, P.; Mangano, D.T. Investigators of the Multicenter Study of
Perioperative Ischemia Research Group. Impact of hyperglycemia on perioperative mortality after coronary artery bypass graft
surgery. J. Thorac. Cardiovasc. Surg. 2011, 142, 430–437e1. [CrossRef] [PubMed]
4. Versteeg, H.H.; Heemskerk, J.W.; Levi, M.; Reitsma, P.H. New fundamentals in hemostasis. Physiol. Rev. 2013, 93, 327–
358. [CrossRef]
5. Chapin, J.C.; Hajjar, K.A. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015, 29, 17–24. [CrossRef] [PubMed]
6. Westein, E.; Hoefer, T.; Calkin, A.C. Thrombosis in diabetes: A shear flow effect? Clin. Sci. 2017, 131, 1245–1260. [CrossRef]
7. Patti, G.; Cerchiara, E.; Bressi, E.; Giannetti, B.; Veneri, A.D.; Di Sciascio, G.; Avvisati, G.; De Caterina, R. Endothelial Dysfunction,
Fibrinolytic Activity, and Coagulation Activity in Patients with Atrial Fibrillation According to Type II Diabetes Mellitus Status.
Am. J. Cardiol. 2020, 125, 751–758. [CrossRef] [PubMed]
8. Sharma, A.N.; Deyell, J.S.; Sharma, S.N.; Barseghian, A. Role of and Recent Evidence for Antiplatelet Therapy in Prevention of
Cardiovascular Disease in Diabetes. Curr. Cardiol. Rep. 2019, 21, 78. [CrossRef]
9. Lemkes, B.A.; Hermanides, J.; Devries, J.H.; Holleman, F.; Meijers, J.C.; Hoekstra, J.B. Hyperglycemia: A prothrombotic factor? J.
Thromb. Haemost. 2010, 8, 1663–1669. [CrossRef]
10. Holinstat, M. Normal platelet function. Cancer Metastasis Rev. 2017, 36, 195–198. [CrossRef] [PubMed]
11. Manzo-Silberman, S.; Nicaise-Roland, P.; Neukirch, C.; Tubach, F.; Huisse, M.G.; Chollet-Martin, S.; Abergel, H.; Driss, F.; Alfaiate,
T.; Ajzenberg, N.; et al. Effect of rapid desensitization on platelet inhibition and basophil activation in patients with aspirin
hypersensitivity and coronary disease. Eur. Heart J. Cardiovasc. Pharmacother. 2017, 3, 77–81. [CrossRef]
12. Santilli, F.; Simeone, P.; Liani, R.; Davi, G. Platelets and diabetes mellitus. Prostaglandins Other Lipid Mediat. 2015, 120, 28–
39. [CrossRef]
13. Saluja, M.; Swami, Y.K.; Meena, S.R. Study of Impact of Glycemic Status (HbA1c) on Platelet Activity measured by Mean Platelet
Volume & Vascular Complications in Diabetics. J. Assoc. Physicians India 2019, 67, 26–29. [PubMed]
14. Malachowska, B.; Tomasik, B.; Szadkowska, A.; Baranowska-Jazwiecka, A.; Wegner, O.; Mlynarski, W.; Fendler, W. Altered
platelets’ morphological parameters in children with type 1 diabetes—A case-control study. BMC Endocr. Disord. 2015, 15, 17.
[CrossRef] [PubMed]
15. Venkatesh, V.; Kumar, R.; Varma, D.K.; Bhatia, P.; Yadav, J.; Dayal, D. Changes in platelet morphology indices in relation to
duration of disease and glycemic control in children with type 1 diabetes mellitus. J. Diabetes Complicat. 2018, 32, 833–838.
[CrossRef] [PubMed]
16. Ozder, A.; Eker, H.H. Investigation of mean platelet volume in patients with type 2 diabetes mellitus and in subjects with
impaired fasting glucose: A cost-effective tool in primary health care? Int. J. Clin. Exp. Med. 2014, 7, 2292–2297.
17. Zaccardi, F.; Rocca, B.; Rizzi, A.; Ciminello, A.; Teofili, L.; Ghirlanda, G.; De Stefano, V.; Pitocco, D. Platelet indices and
glucose control in type 1 and type 2 diabetes mellitus: A case-control study. Nutr. Metab. Cardiovasc. Dis. 2017, 27, 902–909.
[CrossRef] [PubMed]
18. Kaur, R.; Kaur, M.; Singh, J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: Molecular insights and
therapeutic strategies. Cardiovasc. Diabetol. 2018, 17, 121. [CrossRef]
J. Clin. Med. 2021, 10, 2419 10 of 14

19. Ghoshal, K.; Bhattacharyya, M. Overview of platelet physiology: Its hemostatic and nonhemostatic role in disease pathogenesis.
Sci. World J. 2014, 2014, 781857. [CrossRef]
20. Giannella, A.; Ceolotto, G.; Radu, C.M.; Cattelan, A.; Iori, E.; Benetti, A.; Fabris, F.; Simioni, P.; Avogaro, A.; Vigili de Kreutzen-
berg, S. PAR-4/Ca(2+)-calpain pathway activation stimulates platelet-derived microparticles in hyperglycemic type 2 diabetes.
Cardiovasc. Diabetol. 2021, 20, 77. [CrossRef] [PubMed]
21. Rusak, T.; Misztal, T.; Rusak, M.; Branska-Januszewska, J.; Tomasiak, M. Involvement of hyperglycemia in the development of
platelet procoagulant response: The role of aldose reductase and platelet swelling. Blood Coagul. Fibrinolysis 2017, 28, 443–451.
[CrossRef] [PubMed]
22. Kito, K.; Tanabe, K.; Sakata, K.; Fukuoka, N.; Nagase, K.; Iida, M.; Iida, H. Endothelium-dependent vasodilation in the cerebral
arterioles of rats deteriorates during acute hyperglycemia and then is restored by reducing the glucose level. J. Anesth. 2018, 32,
531–538. [CrossRef] [PubMed]
23. American Diabetes, A. Standards of medical care in diabetes-2015 abridged for primary care providers. Clin. Diabetes 2015, 33,
97–111. [CrossRef]
24. Baldane, S.; Ipekci, S.H.; Kebapcilar, A. Relationship Between Insulin Resistance and Mean Platelet Volume in Gestational
Diabetes Mellitus. J. Lab. Physicians 2015, 7, 112–115. [CrossRef]
25. Voigt, M.; Gebert, M.; Haug, U.; Hulko, M.; Storr, M.; Boschetti-de-Fierro, A.; Beck, W.; Krause, B. Retention of beneficial
molecules and coagulation factors during haemodialysis and haemodiafiltration. Sci. Rep. 2019, 9, 6370. [CrossRef]
26. Esteghamat, F.; Broughton, J.S.; Smith, E.; Cardone, R.; Tyagi, T.; Guerra, M.; Szabo, A.; Ugwu, N.; Mani, M.V.; Azari, B.; et al.
CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet
activation. Nat. Genet. 2019, 51, 1233–1243. [CrossRef] [PubMed]
27. Chan, P.C.; Liao, M.T.; Hsieh, P.S. The Dualistic Effect of COX-2-Mediated Signaling in Obesity and Insulin Resistance. Int. J. Mol.
Sci. 2019, 20, 3115. [CrossRef]
28. Wu, H.; Tremaroli, V.; Schmidt, C.; Lundqvist, A.; Olsson, L.M.; Kramer, M.; Gummesson, A.; Perkins, R.; Bergstrom, G.;
Backhed, F. The Gut Microbiota in Prediabetes and Diabetes: A Population-Based Cross-Sectional Study. Cell Metab. 2020, 32,
379–390e3. [CrossRef]
29. Witkowski, M.; Weeks, T.L.; Hazen, S.L. Gut Microbiota and Cardiovascular Disease. Circ. Res. 2020, 127, 553–570. [CrossRef]
30. Zhu, W.; Gregory, J.C.; Org, E.; Buffa, J.A.; Gupta, N.; Wang, Z.; Li, L.; Fu, X.; Wu, Y.; Mehrabian, M.; et al. Gut Microbial
Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 2016, 165, 111–124. [CrossRef]
31. Nemet, I.; Saha, P.P.; Gupta, N.; Zhu, W.; Romano, K.A.; Skye, S.M.; Cajka, T.; Mohan, M.L.; Li, L.; Wu, Y.; et al. A Cardiovascular
Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. Cell 2020, 180, 862–877e22. [CrossRef] [PubMed]
32. Wu, H.; Esteve, E.; Tremaroli, V.; Khan, M.T.; Caesar, R.; Manneras-Holm, L.; Stahlman, M.; Olsson, L.M.; Serino, M.; Planas-Felix,
M.; et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic
effects of the drug. Nat. Med. 2017, 23, 850–858. [CrossRef]
33. Favaloro, E.J.; Lippi, G. Understanding the extent of the diagnostic potential of coagulation factors. Expert Rev. Mol. Diagn 2020,
20, 273–276. [CrossRef] [PubMed]
34. Dayer, M.R.; Mard-Soltani, M.; Dayer, M.S.; Alavi, S.M. Causality relationships between coagulation factors in type 2 diabetes
mellitus: Path analysis approach. Med. J. Islam Repub. Iran 2014, 28, 59. [PubMed]
35. Kasthuri, R.S.; Glover, S.L.; Boles, J.; Mackman, N. Tissue factor and tissue factor pathway inhibitor as key regulators of global
hemostasis: Measurement of their levels in coagulation assays. Semin. Thromb. Hemost. 2010, 36, 764–771. [CrossRef]
36. Boden, G.; Rao, A.K. Effects of hyperglycemia and hyperinsulinemia on the tissue factor pathway of blood coagulation. Curr.
Diab. Rep. 2007, 7, 223–227. [CrossRef]
37. Soma, P.; Swanepoel, A.C.; Bester, J.; Pretorius, E. Tissue factor levels in type 2 diabetes mellitus. Inflamm. Res. 2017, 66,
365–368. [CrossRef]
38. Schwarz, S.; Mrosewski, I.; Silawal, S.; Schulze-Tanzil, G. The interrelation of osteoarthritis and diabetes mellitus: Considering
the potential role of interleukin-10 and in vitro models for further analysis. Inflamm. Res. 2018, 67, 285–300. [CrossRef] [PubMed]
39. Meerarani, P.; Moreno, P.R.; Cimmino, G.; Badimon, J.J. Atherothrombosis: Role of tissue factor; link between diabetes, obesity
and inflammation. Indian J. Exp. Biol. 2007, 45, 103–110. [PubMed]
40. Chaudhuri, J.; Bains, Y.; Guha, S.; Kahn, A.; Hall, D.; Bose, N.; Gugliucci, A.; Kapahi, P. The Role of Advanced Glycation End
Products in Aging and Metabolic Diseases: Bridging Association and Causality. Cell Metab. 2018, 28, 337–352. [CrossRef] [PubMed]
41. Calabro, P.; Cirillo, P.; Limongelli, G.; Maddaloni, V.; Riegler, L.; Palmieri, R.; Pacileo, G.; De Rosa, S.; Pacileo, M.; De Palma, R.;
et al. Tissue factor is induced by resistin in human coronary artery endothelial cells by the NF-kB-dependent pathway. J. Vasc.
Res. 2011, 48, 59–66. [CrossRef] [PubMed]
42. Witkowski, M.; Weithauser, A.; Tabaraie, T.; Steffens, D.; Krankel, N.; Witkowski, M.; Stratmann, B.; Tschoepe, D.; Landmesser, U.;
Rauch-Kroehnert, U. Micro-RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor.
Arterioscler. Thromb. Vasc. Biol. 2016, 36, 1263–1271. [CrossRef]
43. Witkowski, M.; Tabaraie, T.; Steffens, D.; Friebel, J.; Dorner, A.; Skurk, C.; Witkowski, M.; Stratmann, B.; Tschoepe, D.; Landmesser,
U.; et al. MicroRNA-19a contributes to the epigenetic regulation of tissue factor in diabetes. Cardiovasc. Diabetol. 2018, 17, 34.
[CrossRef] [PubMed]
J. Clin. Med. 2021, 10, 2419 11 of 14

44. Witkowski, M.; Witkowski, M.; Saffarzadeh, M.; Friebel, J.; Tabaraie, T.; Ta Bao, L.; Chakraborty, A.; Dorner, A.; Stratmann, B.;
Tschoepe, D.; et al. Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes.
Cardiovasc. Diabetol. 2020, 19, 20. [CrossRef]
45. Fu, G.; Yan, Y.; Chen, L.; Zhang, M.; Ming, L. Shortened Activated Partial Thromboplastin Time and Increased Superoxide
Dismutase Levels Are Associated with Type 2 Diabetes Mellitus. Ann. Clin. Lab. Sci 2018, 48, 469–477. [PubMed]
46. van der Toorn, F.A.; de Mutsert, R.; Lijfering, W.M.; Rosendaal, F.R.; van Hylckama Vlieg, A. Glucose metabolism affects
coagulation factors: The NEO study. J. Thromb. Haemost. 2019. [CrossRef]
47. Lallukka, S.; Luukkonen, P.K.; Zhou, Y.; Isokuortti, E.; Leivonen, M.; Juuti, A.; Hakkarainen, A.; Orho-Melander, M.; Lundbom,
N.; Olkkonen, V.M.; et al. Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in
humans. Thromb. Haemost. 2017, 117, 286–294. [CrossRef] [PubMed]
48. Neergaard-Petersen, S.; Hvas, A.M.; Kristensen, S.D.; Grove, E.L.; Larsen, S.B.; Phoenix, F.; Kurdee, Z.; Grant, P.J.; Ajjan, R.A.
The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease. Thromb. Haemost. 2014, 112,
1142–1150. [CrossRef] [PubMed]
49. Abdul Razak, M.K.; Sultan, A.A. The importance of measurement of plasma fibrinogen level among patients with type- 2 diabetes
mellitus. Diabetes Metab. Syndr. 2019, 13, 1151–1158. [CrossRef]
50. Yamaguchi, T.; Kimura, H.; Yokota, S.; Yamamoto, Y.; Hashimoto, T.; Nakagawa, M.; Ito, M.; Ogura, T. Effect of IL-6 elevation in
malignant pleural effusion on hyperfibrinogenemia in lung cancer patients. Jpn. J. Clin. Oncol. 2000, 30, 53–58. [CrossRef]
51. Pieters, M.; van Zyl, D.G.; Rheeder, P.; Jerling, J.C.; Loots du, T.; van der Westhuizen, F.H.; Gottsche, L.T.; Weisel, J.W. Glycation of
fibrinogen in uncontrolled diabetic patients and the effects of glycaemic control on fibrinogen glycation. Thromb. Res. 2007, 120,
439–446. [CrossRef]
52. White, N.J.; Wang, Y.; Fu, X.; Cardenas, J.C.; Martin, E.J.; Brophy, D.F.; Wade, C.E.; Wang, X.; St John, A.E.; Lim, E.B.; et al.
Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury. Free Radic. Biol.
Med. 2016, 96, 181–189. [CrossRef]
53. Park, H.S.; Gu, J.Y.; Yoo, H.J.; Han, S.E.; Park, C.H.; Kim, Y.I.; Nam-Goong, I.S.; Kim, E.S.; Kim, H.K. Thrombin Generation Assay
Detects Moderate-Intensity Statin-Induced Reduction of Hypercoagulability in Diabetes. Clin. Appl. Thromb. Hemost. 2018, 24,
1095–1101. [CrossRef] [PubMed]
54. Chitongo, P.B.; Roberts, L.N.; Yang, L.; Patel, R.K.; Lyall, R.; Luxton, R.; Aylwin, S.J.B.; Arya, R. Visceral Adiposity Is an
Independent Determinant of Hypercoagulability as Measured by Thrombin Generation in Morbid Obesity. TH Open 2017, 1,
e146–e154. [CrossRef]
55. Salvagno, G.L.; Favaloro, E.J.; Demonte, D.; Gelati, M.; Poli, G.; Targher, G.; Lippi, G. Influence of hypertriglyceridemia,
hyperbilirubinemia and hemolysis on thrombin generation in human plasma. Clin. Chem. Lab. Med. 2019. [CrossRef] [PubMed]
56. Kearney, K.; Tomlinson, D.; Smith, K.; Ajjan, R. Hypofibrinolysis in diabetes: A therapeutic target for the reduction of cardiovas-
cular risk. Cardiovasc. Diabetol. 2017, 16, 34. [CrossRef] [PubMed]
57. Draxler, D.F.; Medcalf, R.L. The fibrinolytic system-more than fibrinolysis? Transfus. Med. Rev. 2015, 29, 102–109. [CrossRef] [PubMed]
58. Ajjan, R.A.; Gamlen, T.; Standeven, K.F.; Mughal, S.; Hess, K.; Smith, K.A.; Dunn, E.J.; Anwar, M.M.; Rabbani, N.; Thornalley, P.J.;
et al. Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and
enzyme-specific activity. Blood 2013, 122, 134–142. [CrossRef]
59. Canecki-Varzic, S.; Prpic-Krizevac, I.; Bilic-Curcic, I. Plasminogen activator inhibitor-1 concentrations and bone mineral density
in postmenopausal women with type 2 diabetes mellitus. BMC Endocr. Disord. 2016, 16, 14. [CrossRef]
60. Bryk, A.H.; Prior, S.M.; Plens, K.; Konieczynska, M.; Hohendorff, J.; Malecki, M.T.; Butenas, S.; Undas, A. Predictors of neutrophil
extracellular traps markers in type 2 diabetes mellitus: Associations with a prothrombotic state and hypofibrinolysis. Cardiovasc.
Diabetol. 2019, 18, 49. [CrossRef]
61. Freeland, B. Hypoglycemia in Diabetes Mellitus. Home Healthc. Now 2017, 35, 414–419. [CrossRef] [PubMed]
62. Arora, S.; Damle, N.A.; Passah, A.; Sharma, R.; Goyal, H.; Arunraj, S.T.; Gupta, P.; Jana, M. Tracer Accumulation in Relation to
Venous Thrombus on (18)F-DOPA PET/CT in a Case of Persistent Hyperinsulinemic Hypoglycemia of Infancy. Nucl. Med. Mol.
Imaging 2019, 53, 148–151. [CrossRef]
63. King, R.; Ajjan, R. Hypoglycaemia, thrombosis and vascular events in diabetes. Expert Rev. Cardiovasc. Ther. 2016, 14, 1099–1101.
[CrossRef] [PubMed]
64. Yamamoto, K.; Ito, T.; Nagasato, T.; Shinnakasu, A.; Kurano, M.; Arimura, A.; Arimura, H.; Hashiguchi, H.; Deguchi, T.;
Maruyama, I.; et al. Effects of glycemic control and hypoglycemia on Thrombus formation assessed using automated microchip
flow chamber system: An exploratory observational study. Thromb. J. 2019, 17, 17. [CrossRef] [PubMed]
65. Joy, N.G.; Mikeladze, M.; Younk, L.M.; Tate, D.B.; Davis, S.N. Effects of equivalent sympathetic activation during hypoglycemia
on endothelial function and pro-atherothrombotic balance in healthy individuals and obese standard treated type 2 diabetes.
Metabolism 2016, 65, 1695–1705. [CrossRef]
66. Chow, E.; Iqbal, A.; Walkinshaw, E.; Phoenix, F.; Macdonald, I.A.; Storey, R.F.; Ajjan, R.; Heller, S.R. Prolonged Prothrombotic
Effects of Antecedent Hypoglycemia in Individuals with Type 2 Diabetes. Diabetes Care 2018, 41, 2625–2633. [CrossRef] [PubMed]
67. Iglay, K.; Hannachi, H.; Joseph Howie, P.; Xu, J.; Li, X.; Engel, S.S.; Moore, L.M.; Rajpathak, S. Prevalence and co-prevalence of
comorbidities among patients with type 2 diabetes mellitus. Curr. Med. Res. Opin. 2016, 32, 1243–1252. [CrossRef]
J. Clin. Med. 2021, 10, 2419 12 of 14

68. Klovaite, J.; Benn, M.; Nordestgaard, B.G. Obesity as a causal risk factor for deep venous thrombosis: A Mendelian randomization
study. J. Intern. Med. 2015, 277, 573–584. [CrossRef]
69. Christiansen, S.C.; Lijfering, W.M.; Naess, I.A.; Hammerstrom, J.; van Hylckama Vlieg, A.; Rosendaal, F.R.; Cannegieter, S.C. The
relationship between body mass index, activated protein C resistance and risk of venous thrombosis. J. Thromb. Haemost. 2012, 10,
1761–1767. [CrossRef] [PubMed]
70. Kopp, C.W.; Kopp, H.P.; Steiner, S.; Kriwanek, S.; Krzyzanowska, K.; Bartok, A.; Roka, R.; Minar, E.; Schernthaner, G. Weight loss
reduces tissue factor in morbidly obese patients. Obes. Res. 2003, 11, 950–956. [CrossRef] [PubMed]
71. Perego, F.; Davi, G. Beyond hyperglycemia in diabetes: Role of statin treatment on thrombogenesis triggered by inflammation:
Editorial to: “Impact of statins on the coagulation status of type 2 diabetes patients evaluated by a novel thrombin-generations
assay” by Ferroni, P. Cardiovasc. Drugs Ther. 2012, 26, 281–284. [CrossRef] [PubMed]
72. Kim, J.A.; Kim, J.E.; Song, S.H.; Kim, H.K. Influence of blood lipids on global coagulation test results. Ann. Lab. Med. 2015, 35,
15–21. [CrossRef] [PubMed]
73. Krysiak, R.; Handzlik, G.; Okopien, B. Hemostatic effects of fenofibrate in patients with mixed dyslipidemia and impaired fasting
glucose. Pharmacol. Rep. 2010, 62, 1099–1107. [CrossRef]
74. Verbree-Willemsen, L.; Zhang, Y.N.; Gijsberts, C.M.; Schoneveld, A.H.; Wang, J.W.; Lam, C.S.P.; Vernooij, F.; Bots, M.L.; Peelen,
L.M.; Grobbee, D.E.; et al. LDL extracellular vesicle coagulation protein levels change after initiation of statin therapy. Findings
from the METEOR trial. Int. J. Cardiol. 2018, 271, 247–253. [CrossRef] [PubMed]
75. Younossi, Z.M.; Golabi, P.; de Avila, L.; Paik, J.M.; Srishord, M.; Fukui, N.; Qiu, Y.; Burns, L.; Afendy, A.; Nader, F. The global
epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J. Hepatol. 2019, 71,
793–801. [CrossRef]
76. Kotronen, A.; Joutsi-Korhonen, L.; Sevastianova, K.; Bergholm, R.; Hakkarainen, A.; Pietilainen, K.H.; Lundbom, N.; Rissanen, A.;
Lassila, R.; Yki-Jarvinen, H. Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease. Liver Int.
2011, 31, 176–183. [CrossRef] [PubMed]
77. Verrijken, A.; Francque, S.; Mertens, I.; Prawitt, J.; Caron, S.; Hubens, G.; Van Marck, E.; Staels, B.; Michielsen, P.; Van Gaal, L.
Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2014,
59, 121–129. [CrossRef]
78. Mauri, L.; Kereiakes, D.J.; Yeh, R.W.; Driscoll-Shempp, P.; Cutlip, D.E.; Steg, P.G.; Normand, S.L.; Braunwald, E.; Wiviott,
S.D.; Cohen, D.J.; et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N. Engl. J. Med. 2014, 371,
2155–2166. [CrossRef]
79. ASCEND Study Collaborative Group; Bowman, L.; Mafham, M.; Wallendszus, K.; Stevens, W.; Buck, G.; Barton, J.; Murphy, K.;
Aung, T.; Haynes, R.; et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N. Engl. J. Med. 2018, 379,
1529–1539. [CrossRef]
80. Alzahrani, S.H.; Ajjan, R.A. Coagulation and fibrinolysis in diabetes. Diab. Vasc. Dis. Res. 2010, 7, 260–273. [CrossRef]
81. Ma, N.; Yang, Y.; Liu, X.; Li, S.; Qin, Z.; Li, J. Plasma metabonomics and proteomics studies on the anti-thrombosis mechanism of
aspirin eugenol ester in rat tail thrombosis model. J. Proteom. 2020, 215, 103631. [CrossRef] [PubMed]
82. American Diabetes, A. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2019. Diabetes
Care 2019, 42 (Suppl. S1), S103–S123. [CrossRef] [PubMed]
83. Antithrombotic Trialists, C.; Baigent, C.; Blackwell, L.; Collins, R.; Emberson, J.; Godwin, J.; Peto, R.; Buring, J.; Hennekens, C.;
Kearney, P.; et al. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual
participant data from randomised trials. Lancet 2009, 373, 1849–1860. [CrossRef]
84. Capodanno, A.D. Antithrombotic therapy for atherosclerotic cardiovascular disease risk mitigation in patients with coronary
artery disease and diabetes mellitus. Circulation 2020, 142, 17. [CrossRef]
85. Morel, O.; El Ghannudi, S.; Hess, S.; Reydel, A.; Crimizade, U.; Jesel, L.; Radulescu, B.; Wiesel, M.L.; Gachet, C.; Ohlmann, P. The
extent of P2Y12 inhibition by clopidogrel in diabetes mellitus patients with acute coronary syndrome is not related to glycaemic
control: Roles of white blood cell count and body weight. Thromb. Haemost. 2012, 108, 338–348. [CrossRef]
86. Lee, S.W.; Park, S.W.; Yun, S.C.; Kim, Y.H.; Park, D.W.; Kim, W.J.; Lee, J.Y.; Lee, C.W.; Hong, M.K.; Kim, J.J.; et al. Triple antiplatelet
therapy reduces ischemic events after drug-eluting stent implantation: Drug-Eluting stenting followed by Cilostazol treatment
REduces Adverse Serious cardiac Events (DECREASE registry). Am. Heart J. 2010, 159, 284–291e1. [CrossRef]
87. Gresele, P.; Migliacci, R. Picotamide versus aspirin in diabetic patients with peripheral arterial disease: Has David defeated
Goliath? Eur. Heart J. 2004, 25, 1769–1771. [CrossRef] [PubMed]
88. Hiatt, W.R.; Money, S.R.; Brass, E.P. Long-term safety of cilostazol in patients with peripheral artery disease: The CASTLE study
(Cilostazol: A Study in Long-term Effects). J. Vasc. Surg. 2008, 47, 330–336. [CrossRef] [PubMed]
89. Rishavy, M.A.; Hallgren, K.W.; Wilson, L.; Singh, S.; Runge, K.W.; Berkner, K.L. Warfarin alters vitamin K metabolism: A
surprising mechanism of VKORC1 uncoupling necessitates an additional reductase. Blood 2018, 131, 2826–2835. [CrossRef]
90. Makani, A.; Saba, S.; Jain, S.K.; Bhonsale, A.; Sharbaugh, M.S.; Thoma, F.; Wang, Y.; Marroquin, O.C.; Lee, J.S.; Estes, N.A.M.; et al.
Safety and Efficacy of Direct Oral Anticoagulants Versus Warfarin in Patients with Chronic Kidney Disease and Atrial Fibrillation.
Am. J. Cardiol. 2020, 125, 210–214. [CrossRef]
91. Bansilal, S.; Bloomgarden, Z.; Halperin, J.L.; Hellkamp, A.S.; Lokhnygina, Y.; Patel, M.R.; Becker, R.C.; Breithardt, G.; Hacke,
W.; Hankey, G.J.; et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: The
J. Clin. Med. 2021, 10, 2419 13 of 14

Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). Am. Heart J. 2015, 170, 675–682e8. [CrossRef]
92. Baker, W.L.; Beyer-Westendorf, J.; Bunz, T.J.; Eriksson, D.; Meinecke, A.K.; Sood, N.A.; Coleman, C.I. Effectiveness and safety of
rivaroxaban and warfarin for prevention of major adverse cardiovascular or limb events in patients with non-valvular atrial
fibrillation and type 2 diabetes. Diabetes Obes. Metab. 2019, 21, 2107–2114. [CrossRef] [PubMed]
93. Rocha, B.M.L.; da Cunha, G.J.L.; Aguiar, C.M.T. A narrative review of low-dose rivaroxaban in patients with atherothrombotic car-
diovascular disease: Vascular protection beyond anticoagulation. Cardiovasc. Diagn. Ther. 2021, 11, 130–141. [CrossRef] [PubMed]
94. Hylek, E.M.; Held, C.; Alexander, J.H.; Lopes, R.D.; De Caterina, R.; Wojdyla, D.M.; Huber, K.; Jansky, P.; Steg, P.G.; Hanna, M.;
et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for
Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes.
J. Am. Coll. Cardiol. 2014, 63, 2141–2147. [CrossRef]
95. Brambatti, M.; Darius, H.; Oldgren, J.; Clemens, A.; Noack, H.H.; Brueckmann, M.; Yusuf, S.; Wallentin, L.; Ezekowitz, M.D.;
Connolly, S.J.; et al. Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation: Results from the RE-LY
trial. Int. J. Cardiol. 2015, 196, 127–131. [CrossRef] [PubMed]
96. Markowicz-Piasecka, M.; Huttunen, K.M.; Broncel, M.; Sikora, J. Sulfenamide and Sulfonamide Derivatives of Metformin—A
New Option to Improve Endothelial Function and Plasma Haemostasis. Sci. Rep. 2019, 9, 6573. [CrossRef]
97. Witkowski, M.; Friebel, J.; Tabaraie, T.; Grabitz, S.; Dorner, A.; Taghipour, L.; Jakobs, K.; Stratmann, B.; Tschoepe, D.; Landmesser,
U.; et al. Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes.
Cardiovasc. Drugs Ther. 2020. [CrossRef] [PubMed]
98. Khanolkar, M.P.; Morris, R.H.; Thomas, A.W.; Bolusani, H.; Roberts, A.W.; Geen, J.; Jackson, S.K.; Evans, L.M. Rosiglitazone
produces a greater reduction in circulating platelet activity compared with gliclazide in patients with type 2 diabetes mellitus—An
effect probably mediated by direct platelet PPARgamma activation. Atherosclerosis 2008, 197, 718–724. [CrossRef] [PubMed]
99. Goldberg, R.B.; Temprosa, M.G.; Mather, K.J.; Orchard, T.J.; Kitabchi, A.E.; Watson, K.E.; Diabetes Prevention Program Research
Group. Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention
program except in those who develop diabetes. Diabetes Care 2014, 37, 2253–2260. [CrossRef]
100. Verdoia, M.; Pergolini, P.; Rolla, R.; Ceccon, C.; Caputo, M.; Aimaretti, G.; Suryapranata, H.; De Luca, G. Use of Metformin
and Platelet Reactivity in Diabetic Patients Treated with Dual Antiplatelet Therapy. Exp. Clin. Endocrinol. Diabetes 2018.
[CrossRef] [PubMed]
101. Pal, P.; Kanaujiya, J.K.; Lochab, S.; Tripathi, S.B.; Sanyal, S.; Behre, G.; Trivedi, A.K. Proteomic analysis of rosiglitazone and
guggulsterone treated 3T3-L1 preadipocytes. Mol. Cell Biochem. 2013, 376, 81–93. [CrossRef]
102. Henriksson, C.E.; Hellum, M.; Haug, K.B.; Aass, H.C.; Joo, G.B.; Ovstebo, R.; Troseid, A.M.; Klingenberg, O.; Kierulf, P.
Anticoagulant effects of an antidiabetic drug on monocytes in vitro. Thromb. Res. 2011, 128, e100–e106. [CrossRef] [PubMed]
103. Barazzoni, R.; Kiwanuka, E.; Zanetti, M.; Cristini, M.; Vettore, M.; Tessari, P. Insulin acutely increases fibrinogen production in
individuals with type 2 diabetes but not in individuals without diabetes. Diabetes 2003, 52, 1851–1856. [CrossRef]
104. Marso, S.P.; Daniels, G.H.; Brown-Frandsen, K.; Kristensen, P.; Mann, J.F.; Nauck, M.A.; Nissen, S.E.; Pocock, S.; Poulter,
N.R.; Ravn, L.S.; et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 311–322.
[CrossRef] [PubMed]
105. Barale, C.; Buracco, S.; Cavalot, F.; Frascaroli, C.; Guerrasio, A.; Russo, I. Glucagon-like peptide 1-related peptides increase nitric
oxide effects to reduce platelet activation. Thromb. Haemost. 2017, 117, 1115–1128. [CrossRef]
106. Simeone, P.; Liani, R.; Tripaldi, R.; Di Castelnuovo, A.; Guagnano, M.T.; Tartaro, A.; Bonadonna, R.C.; Federico, V.; Cipollone,
F.; Consoli, A.; et al. Thromboxane-Dependent Platelet Activation in Obese Subjects with Prediabetes or Early Type 2 Diabetes:
Effects of Liraglutide- or Lifestyle Changes-Induced Weight Loss. Nutrients 2018, 10, 1872. [CrossRef] [PubMed]
107. Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Pocock, S.J.; Carson, P.; Januzzi, J.; Verma, S.; Tsutsui, H.; Brueckmann, M.; et al.
Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N. Engl. J. Med. 2020, 383, 1413–1424. [CrossRef]
108. Tanaka, A.; Shimabukuro, M.; Machii, N.; Teragawa, H.; Okada, Y.; Shima, K.R.; Takamura, T.; Taguchi, I.; Hisauchi, I.;
Toyoda, S.; et al. Effect of Empagliflozin on Endothelial Function in Patients with Type 2 Diabetes and Cardiovascular Disease:
Results from the Multicenter, Randomized, Placebo-Controlled, Double-Blind EMBLEM Trial. Diabetes Care 2019, 42, e159–e161.
[CrossRef] [PubMed]
109. Uthman, L.; Homayr, A.; Juni, R.P.; Spin, E.L.; Kerindongo, R.; Boomsma, M.; Hollmann, M.W.; Preckel, B.; Koolwijk, P.; van
Hinsbergh, V.W.M.; et al. Empagliflozin and Dapagliflozin Reduce ROS Generation and Restore NO Bioavailability in Tumor
Necrosis Factor alpha-Stimulated Human Coronary Arterial Endothelial Cells. Cell Physiol. Biochem. 2019, 53, 865–886. [CrossRef]
110. Sakurai, S.; Jojima, T.; Iijima, T.; Tomaru, T.; Usui, I.; Aso, Y. Empagliflozin decreases the plasma concentration of plasminogen
activator inhibitor-1 (PAI-1) in patients with type 2 diabetes: Association with improvement of fibrinolysis. J. Diabetes Complicat.
2020, 34, 107703. [CrossRef]
111. Bray, G.A.; Fruhbeck, G.; Ryan, D.H.; Wilding, J.P. Management of obesity. Lancet 2016, 387, 1947–1956. [CrossRef]
112. Stolberg, C.R.; Mundbjerg, L.H.; Funch-Jensen, P.; Gram, B.; Juhl, C.B.; Bladbjerg, E.M. Effects of gastric bypass followed by a
randomized study of physical training on markers of coagulation activation, fibrin clot properties, and fibrinolysis. Surg. Obes.
Relat. Dis. 2018, 14, 918–926. [CrossRef]
J. Clin. Med. 2021, 10, 2419 14 of 14

113. Gram, A.S.; Petersen, M.B.; Quist, J.S.; Rosenkilde, M.; Stallknecht, B.; Bladbjerg, E.M. Effects of 6 Months of Active Commuting
and Leisure-Time Exercise on Fibrin Turnover in Sedentary Individuals with Overweight and Obesity: A Randomised Controlled
Trial. J. Obes. 2018, 2018, 7140754. [CrossRef]
114. Teng, K.T.; Chang, L.F.; Vethakkan, S.R.; Nesaretnam, K.; Sanders, T.A.B. Effects of exchanging carbohydrate or monounsaturated
fat with saturated fat on inflammatory and thrombogenic responses in subjects with abdominal obesity: A randomized controlled
trial. Clin. Nutr. 2017, 36, 1250–1258. [CrossRef]
115. Horber, S.; Lehmann, R.; Fritsche, L.; Machann, J.; Birkenfeld, A.L.; Haring, H.U.; Stefan, N.; Heni, M.; Fritsche, A.; Peter,
A. Lifestyle intervention improves prothrombotic coagulation profile in individuals at high-risk for type 2 diabetes. J. Clin.
Endocrinol. Metab. 2021. [CrossRef]
116. Toso, A.; De Servi, S.; Leoncini, M.; Angiolillo, D.J.; Calabro, P.; Piscione, F.; Cattaneo, M.; Maffeo, D.; Bartorelli, A.; Palmieri, C.;
et al. Effects of statin therapy on platelet reactivity after percutaneous coronary revascularization in patients with acute coronary
syndrome. J. Thromb. Thrombolysis 2017, 44, 355–361. [CrossRef] [PubMed]
117. Undas, A.; Celiniska-Lowenhoff, M. Antiplatelet effects of micronized fenofibrate in subjects with dyslipidemia. Pol. Arch. Med.
Wewn 2007, 117, 235–240. [CrossRef] [PubMed]
118. Mobarrez, F.; He, S.; Broijersen, A.; Wiklund, B.; Antovic, A.; Antovic, J.; Egberg, N.; Jorneskog, G.; Wallen, H. Atorvastatin
reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients
with peripheral arterial occlusive disease. Thromb. Haemost. 2011, 106, 344–352. [CrossRef] [PubMed]
119. Paciullo, F.; Momi, S.; Gresele, P. PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in
Cardiovascular Prevention. Thromb. Haemost. 2019, 119, 359–367. [CrossRef]