Vol.

9 (2024) 37
Cardiovascular Innovations and Applications ISSN 2009-8618
DOI 10.15212/CVIA.2024.0013

REVIEW

Precision Monitoring of Antithrombotic Therapy

in Cardiovascular Disease
Meng Yuan1, Haichu Wen2, Yuan Wang2 and Jie Du2
1
Cardiovascular Biology Laboratory, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
2
Cardiovascular Biology Laboratory, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen ­Hospital,
Capital Medical University, Key Laboratory of Remodeling-related Cardiovascular Disease, Ministry of Education &
­Collaborative Innovation Center for Cardiovascular Disorder, Beijing 100029, China
Received: 16 November 2023; Revised: 20 January 2024; Accepted: 22 January 2024

Abstract
Thrombosis, the process of blood clot formation in blood vessels, is an important protective mechanism for avoiding
excessive blood spillage when an individual is exposed to trauma. The body has both a thrombosis inhibition and a
thrombus removal system, which interact in a balanced manner. If these mechanisms become unbalanced, and too
many clots form and block the lumen, thrombosis occurs. Thrombosis is currently the leading cause of death from
disease in humans and is one of the most common events leading to many cardiovascular diseases. Antithrombotic
drugs are an integral part of the pharmacological treatment regimens, and interventional strategies are currently recom-
mended for thrombotic complications in patients with thrombosis. Despite major advances in these therapies, the high
risk associated with thrombosis and bleeding remains, because of the complex interplay among patient comorbidities,
drug combinations, multifaceted dose adjustments, and care settings. Detailed assessment of the effects of bleeding
and thrombosis is necessary to establish optimal treatment plans for patients with thrombosis. This study retrospec-
tively evaluated methods for assessing the risk of bleeding/ischemia in thrombosis and the individualized use of these
methods.

Keywords: cardiovascular disease; antithrombotic therapy; individualized monitoring

Introduction movement of a thrombus within the bloodstream,

Thrombosis is a common condition that severely
endangers human health [1]. This pathological con-
dition occurs when a blood clot (embolus) forms
and obstructs blood vessels, thereby impairing cir-
culation. Thromboembolism, the detachment and
Correspondence: Yuan Wang and Jie Du, Beijing
Anzhen Hospital, No. 2 Anzhen Rd, Chaoyang District,
Beijing 100029, China, E-mail: wangyuan980510@163.com;
jiedu@ccmu.edu.cn
may potentially cause vessel blockage and result in
tissue hypoxia, necrosis, or edema. This collective
process, termed thrombosis, is categorized into arte-
rial or venous thrombosis, according to the affected
vessel type [2, 3]. Arterial thrombosis can lead to
life-threatening diseases, such as myocardial infarc-
tion and cerebral infarction, and venous thrombosis
can lead to complications such as pulmonary embo-
lism and deep vein thrombosis. Standard anticoagu-
lant therapy for formed thrombi is an important tool
to decrease morbidity and mortality [4]. However,
because of interindividual differences in metabolic

© 2024 Cardiovascular Innovations and Applications. Creative Commons Attribution-NonCommercial 4.0 International License
2 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
processes and pharmacodynamic responsiveness
to anticoagulants, even with standard treatment in
accordance with guidelines, some patients experi-
ence secondary complications, such as severe gas-
trointestinal bleeding or ischemic events. Therefore,
precise individualized anticoagulation therapy is
essential.
Anticoagulation effects can be monitored through
the detection of indicators such as prothrombin time
(PT), activated partial thromboplastin time (APTT),
and international normalized ratio (INR) [5], and
treatment plans can be adjusted to some extent.
However, these indicators cannot adequately reflect
interindividual differences in the status of the coag-
ulation system. In recent years, new technologies
such as thromboelastography have brought hope for
individualized treatment; these methods can detect
multiple dimensions, such as thrombin generation
and platelet aggregation force, thus aiding in the
assessment of individual coagulation function [6]
and providing a basis for formulating precise anti-
coagulation treatment intensity. In addition, new
tools such as genetic testing have shown promise
[7] by enabling the identification of individual dif-
ferences in patients’ prothrombin activity, platelet
adhesion capability, and other relevant functions.
Some studies have also sought to establish new
scoring ­systems that include clinical factors to guide
individualized medication.
However, truly accurate and individualized antico-
agulation treatment protocols and guidelines remain
lacking, because of the following reasons: the tests
reflect only a portion of coagulation function, thus
making the assessment incomplete; no operational
scoring system incorporating clinical characteristics
is available; and consideration of age, renal function,
and other differences in the development of individ-
ualized monitoring and medication regimens is lack-
ing. Therefore, new comprehensive and accurate
testing technology must be developed and used in
combination with clinical characteristics to establish
personalized treatment and ­monitoring strategies as
illustrated by Figure 1. Only in this way can anti-
coagulation therapy be transformed from traditional
group monitoring to truly individualized monitor-
ing, to benefit more patients with thrombosis.
In this article, we review dilemmas in the field
of anticoagulation therapy for thromboembolic
disease, existing progress in achieving treatment
Vein
Artery
Thrombosis
K - MA
R
Amplitude
LY30
angle
Clot Formation Fibrinolysis
Time
Figure 1 Timeline for the Evaluation of Hemorrhage and
Ischemia Detection Techniques.
R: reaction time, K: setting time, αAngle: blood clot forma-
tion rate, MA: maximum clot intensity, LY30: dissolution
degree of blood clot.
individualization, and the future outlook, to promote
the development of this field, and the improvement of
the effectiveness and safety of anticoagulation therapy.
Classification, Epidemiology, and
Status of Thrombosis Treatments
According to the site of thrombus formation, throm-
bosis can be classified into two main categories:
arterial thrombosis and venous thrombosis. Arterial
thrombosis occurs primarily in the cardiovascular
system, and common forms of arterial thrombosis
include coronary artery thrombosis and cerebral
artery thrombosis [8]. Arterial thrombosis directly
blocks blood vessels and causes tissue necrosis,
thereby leading to myocardial infarction, cerebral
infarction, and other life-threatening diseases in
severe cases [9]. Venous thrombosis, which occurs
primarily in the deep veins of the lower limbs and
leads to varicose veins and skin color changes, can
also cause dangerous pulmonary embolism if the
thrombus dislodges in the pulmonary artery [10].
According to epidemiological data, the morbidity
and mortality of thrombotic diseases are high. More
than 3 million venous thrombosis events occur per
year in China, and more than 200,000 patients die
from pulmonary embolism [11]. Arterial thrombosis
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
is also extremely common, and is one of the leading
causes of stroke and myocardial infarction [12]. The
incidence of thrombosis is also high in developed
countries: each year, approximately 600,000 peo-
ple in the United States experience venous throm-
bosis, and more than 100,000 die from pulmonary
embolism [13]. Hence, thrombosis has become a
major threat to human health, and in-depth research
on the mechanism of thrombus formation must be
strengthened, to develop effective methods for pre-
dicting thrombus formation, and design appropriate
preventive measures.
Arterial thrombus formation is an extremely com-
plex process that involves several key aspects, such
as damage to vascular endothelial cells, platelet
activation and aggregation, thrombin generation
and activation, and coagulation protein synthesis
and deposition [9]. When vascular endothelial cells
are damaged by various factors, the tissue factor
under the vascular endothelium is exposed and acti-
vates plasminogen, which in turn is converted into
thrombin. Thrombin cleaves fibrinogen and cata-
lyzes its polymerization, thereby producing fibrin,
and promoting platelet adhesion and aggregation.
Activated platelets also release large amounts of
procoagulant substances, which further activate
thromboplastin and accelerate thrombin production
[14]. The large amount of generated thrombin can
cleave more fibrinogen and activate procoagulant
factors, such as coagulation factor V and coagula-
tion factor VIII, which amplify the entire coagula-
tion reaction and ultimately lead to large amounts of
fibrin deposition, platelet aggregation, and throm-
bus formation [15]. Therefore, arterial thrombosis
occurs through interactions among the coagulation
system, platelets, and vascular endothelium.
The mechanism of venous thrombosis is simi-
lar to that of arterial thrombosis, and involves a
hypercoagulable state of the blood, platelet activa-
tion, and endothelial damage. As the venous blood
flow slows, blood tends to aggregate and activate
the coagulation system. When the production of
thrombin and fibrinogen increases, platelet aggre-
gation is promoted, and a white thrombus is formed.
Simultaneously, activated platelets release procoag-
ulant substances that continue to activate t­hrombin
production and promote red blood cell thrombus
formation. The poor elasticity of the venous wall
makes vascular endothelial cells susceptible to
3
damage when blood flow is stagnant, and exacer-
bates the coagulation response [16]. In addition,
coagulation products such as D-dimers directly
stimulate endothelial cells and impair endothelial
anticoagulation [17]. Therefore, venous thrombosis
equally involves activation of the coagulation sys-
tem, platelet aggregation, and vascular endothelial
damage [18].
Current clinical guidelines recommend initiat-
ing antithrombotic therapy as soon as possible after
the confirmation of thrombosis. Commonly used
anticoagulant or antithrombotic drugs include low-
molecular-weight heparin, warfarin, aspirin, and
P2Y12 inhibitors. The main mechanism of action
of anticoagulant drugs involves inhibition of the
generation and activation of thrombin, and decreas-
ing the amount of fibrin generated by thrombin
cleavage of fibrinogen, to inhibit de novo thrombus
formation and dissolve the existing thrombus [19].
The main mechanism of action of antiplatelet drugs
involves inhibition of platelet aggregation, thereby
preventing adenosine diphosphate–induced plate-
let aggregation and increasing cyclic adenosine
monophosphate levels, and consequently inhibiting
platelet activation and aggregation [20].
Numerous clinical studies have demonstrated
that standard anticoagulation therapy significantly
decreases patient mortality rates after thrombosis
and the incidence of serious thrombosis-related
complications, such as pulmonary embolism and
cerebral infarction [21, 22]. Therefore, anticoagu-
lation has become the standard of care for throm-
botic disorders, and guidelines recommend initiat-
ing anticoagulation therapy immediately after the
diagnosis of thrombosis. Although anticoagula-
tion therapy is recommended by the guidelines, a
small number of patients with thrombosis experi-
ence severe secondary bleeding or ischemic events
[23–32]. These adverse outcomes may be associ-
ated with the f­ollowing factors: interindividual
differences in thrombin generation and platelet
­
adhesion and aggregation, which prevent stand-
ard-dose anticoagulation from achieving effective
anticoagulation; inability of some large thrombi
to be completely dissolved, and risk of dislodg-
ing residual thrombi; and insufficient monitoring
of coagulation recovery during anticoagulation
therapy, thus precluding timely adjustment of the
therapeutic regimen (Table 1).
 4

Table 1 Randomized Clinical Trials on Antiplatelet Therapy in Patients with Thrombotic Diseases.

Study Size Follow up Treatment Primary endpoint Outcome

ARAMIS [23] 163,038 36 hours NOAC Intracranial hemorrhage 3.7% vs 3.2%;
RR −0.51 (−1.36 to 0.34)
NCDR LAAO [24] 31,994 45 days and Aspirin vs warfarin vs Incidence of major adverse events, any 36.9% vs 20.8% vs
6 months DOAC vs DAPT stroke or transient ischemic attack, and 13.5% vs 12.3%;
readmission events HR 0.692 (0.569–0.841)
ACTIV-4B [25] 657 45 days Aspirin vs apixaban All causes of death, symptomatic venous, 2.0% vs 4.5%;
arterial thromboembolism, stroke, or MI RR 0.2 (−0.27 to 0.68)
INSPIRATION [26] 562 30 days Intermediate-dose Composite of venous or arterial 45.7% vs 44.1%;
enoxaparin vs standard thrombosis, treatment with OR 1.0 (0.76–1.48)
enoxaparin extracorporeal membrane oxygenation,
or mortality within 30 days
Voyager PAD [27] 6564 3 years Aspirin vs levofloxacin First occurrence of acute lower limb HR 0.86 (0.75–0.98)
+ aspirin ischemia, vascular major amputation, MI,
ischemic stroke, or cardiovascular death
MARINER [28] 4909 45 days Rivaroxaban vs Symptomatic VTE, non-hemorrhagic 1.28% vs 1.77%;
placebo stroke, cardiovascular death, or MI RR 0.8 (0.04–0.91)
TO-ACT [29] 67 1 year Heparin Ratio of mRS 0–1 points RR 0.99 (0.71–1.38)
Rivaroxaban with or without aspirin 7470 21 months Oral rivaroxaban + Cardiovascular death, MI, or stroke 5% vs 7%;
in patients with stable peripheral or aspirin vs aspirin HR 0.72 (0.57–0.90)
carotid artery disease [30]
ISAR-TRIPLE [31] 614 9 months 6 weeks clopidogrel vs Composite of death, MI, definite stent 9.8% vs 8.8%;
6 months clopidogrel thrombosis, stroke, or TIMI major bleeding HR 1.14 (0.68–1.91)
PLATO [32] 18,624 1 year Ticagrelor + aspirin vs Composite of vascular death, MI, or 9.8% vs 11.7%
Clopidogrel + aspirin stroke HR (0.77–0.92)
M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease

CV, cardiovascular; DAPT, dual antiplatelet therapy; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction; OR, odds ratio; RR, rela-
tive risk; ST, stent thrombosis; TIMI, thrombolysis in myocardial infarction.
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
Mechanisms Underlying Bleeding/
Ischemic Events
Genetic factors are important risk factors for throm-
bosis. Several inherited coagulation factor defects or
anticoagulation factor defects, such as defects in anti-
coagulant proteins C and S, the presence of antico-
agulant protein antibodies, and mutations at the fac-
tor V locus [33, 34], increase thrombosis risk. These
genetic defects lead to dysfunction of the coagulation
system and promote excessive coagulation.
Infections, another common thrombotic trigger,
can cause inflammatory responses, cytokine release,
activation of the coagulation system and platelets,
and damage to the vascular endothelium. Severe
infections can also cause dehydration and impaired
venous reflux, and further increase thrombosis risk
[27]. Moreover, certain pathogens directly affect
the coagulation system and induce thrombosis [35].
Novel coronaviruses directly invade the vascular
endothelium and activate platelets and coagulation
factors, thereby leading to virus-associated thrombo-
sis. In addition, viral infections can initiate the body’s
immune-mediated coagulation response and even the
development of antibodies against anticoagulant pro-
teins, thus resulting in immune-associated thrombosis
[36]. These findings provide new perspectives regard-
ing the mechanism of viral infection–associated
thrombosis. In recent years, new mechanisms through
which viral infections regulate the balance of the
coagulation system have received extensive research
attention. In infections caused by novel coronaviruses,
viral proteins activate platelets and endothelial cells,
and lead to abnormal release of cytokines, which in
turn activate thrombin generation [37]. In addition,
novel coronaviruses can directly induce local throm-
bosis by destroying the endothelial cells of pulmonary
microvessels [38]. Potential mechanisms underlying
the occurrence of hemorrhagic events include exces-
sive inhibition of the coagulation system by antico-
agulant drugs, which disrupt the normal connection
between the thrombus and the vessel wall, and con-
sequently lead to dislodgement of the thrombus and
hemorrhage. Ischemic events are associated with
mechanisms such as dislodgement of residual throm-
bus and vessel embolization, as well as insufficient
recovery of platelet function after discontinuation of
anticoagulant drugs, thus leading to re-aggregation
of emboli [39]. Therefore, monitoring the recovery
5
of embolic lesions and coagulation function while
performing anticoagulation therapy is important to
guide the adjustment of anticoagulation therapy and
decrease the risk of secondary adverse events.
For different types of thrombosis, individualized
monitoring strategies are required, depending on
the characteristics of the condition, to prevent sec-
ondary bleeding and ischemic events to the greatest
extent possible. Moreover, for myocardial i­ nfarction
or cerebral infarction caused by acute arterial throm-
bosis, given the rapid thrombus formation and the
high risk of bleeding transformation, the intensity of
anticoagulation must be monitored to avoid exces-
sive anticoagulation, and prevent thrombus rupture
and bleeding. Simultaneously, cardiac enzymes,
electroencephalograms, and other indicators should
be monitored, and timely adjustment of treatment
plans is necessary if ischemia worsens. For deep
vein thrombosis of the lower extremities, residual
thrombus size changes and D-dimer levels should
be monitored to determine the effects of throm-
bolysis, to avoid large residual thrombus dislodge-
ment and subsequent pulmonary artery embolism.
Simultaneously, recovery of coagulation function
should be monitored, and the intensity of anticoagu-
lation should be individualized accordingly.
For postoperative venous thrombosis, in ­addition
to standard anticoagulation therapy, monitoring
of the mobility of the affected limbs, promoting
­physical activity, and avoiding prolonged bed rest
are ­necessary. For patients with underlying hyper-
coagulable states, long-term monitoring is needed
to prevent new thrombus formation after anticoagu-
lation is discontinued. Personalized monitoring of
different types of thrombotic lesions can effectively
predict and prevent secondary serious adverse
events, and guide the adjustment of anticoagulant
therapy, to ensure therapeutic efficacy.
Updated Approaches for Predicting
Thrombosis/Bleeding-Related
Events in Venous Thromboembolism
Definition of the Disease, Epidemiology,
and Guideline-Recommended Treatment
Deep venous thrombosis is a venous return disorder
characterized by the formation of abnormal blood
6 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
clots in the deep veins, typically in the lower extrem-
ities. Dislodgement of these thrombi can lead to
pulmonary embolism (PE). Together, deep venous
thrombosis and pulmonary embolism are referred
to as venous thromboembolism (VTE) [40]. VTE
manifests at a rate of 1–2 incidents per 1000 per-
son-years, and has a higher prevalence in men than
women. Notably, its incidence escalates to 1 event
per 100 person-years in individuals over 55 years
of age [41]. The prevalence of VTE is lower in Asia
than in Europe and the United States. Alarmingly,
approximately 20% of patients with VTE die within
1 year of diagnosis. Current guidelines advocate
the use of novel anticoagulants, such as direct oral
anticoagulants (DOACs), which inhibit thrombin
generation and activation, thereby decreasing fibrin
formation [42].
Subsequent Bleeding/Ischemic Events
after Antithrombotic Therapy and Risk
Stratification Tools for Patients with VTE
Olaf and colleagues have demonstrated that the inci-
dence of pulmonary embolism can be significantly
decreased, from 20% with no treatment to 3% with
standard anticoagulation therapy. Hisada et al. [43]
have reported post-anticoagulation complications,
such as severe gastrointestinal bleeding, in 1.5%
of patients. Despite standard anticoagulation treat-
ment, a small proportion of patients experience
secondary adverse events [44], such as ischemic
incidents or gastrointestinal bleeding. Therefore,
personalized risk assessment and tailored anticoag-
ulation strategies are needed to minimize the likeli-
hood of such adverse events.
The risk of adverse events after venous throm-
bosis is influenced by patient-specific risk factors,
such as age over 70 years, hepatic and renal insuf-
ficiency, hypoproteinemia, and a history of acid-
suppressing drug use. Older patients and those with
renal insufficiency face a particularly elevated risk
of gastrointestinal bleeding, because of diminished
clearance of anticoagulants [45, 46]. Concurrent
conditions such as ulcerative colitis further increase
this risk. Therefore, anticoagulation therapy must
be individualized according to a comprehen-
sive risk assessment in high-risk patients, such as
older people, or those with hepatic or renal insuf-
ficiency. Using decreased doses of anticoagulants
and closely monitoring coagulation parameters are
critical to avoid excessive anticoagulation and sub-
sequent bleeding. For patients with lower bleeding
risk, standard dosing can be applied, with continu-
ous monitoring to balance the risk of ischemia and
serious bleeding [47]. This approach ensures a more
personalized, safer anticoagulation strategy.
Limitations of Existing Methods and the
Dilemma of Detection
Traditional prothrombin time assays indicate
thrombin generation, and the APTT evaluates both
endogenous and exogenous thrombin activation.
However, neither assay directly measures changes
in fibrin levels. In contrast, iProspect technology
directly quantifies fibrin D-dimer levels, thus ena-
bling more dynamic assessment of fibrin ­production
and lysis [48]. Accurately determining anticoagula-
tion intensity and overall coagulation status requires
more than a single index; instead, multiple test
results must be integrated with the clinical picture.
Current models, such as the Padua prediction in
ACCP guidelines, use primarily prothrombin time
and D-dimer, but fall short in incorporating crucial
individual factors such as age and liver or renal
function, which are essential for assessing bleeding
risk [49].
Recommendations for normal values of existing
monitoring indicators are too general, and signifi-
cant differences exist among types and stages of
venous thrombosis; however, refined and clearly
defined guideline thresholds are lacking [33]. The
current limitations in the clinical applicability of
monitoring results are evident, particularly because
most indicators detect primarily overt hemorrhage
without predicting concealed chronic blood loss.
Enhancing clinical utility requires establishing
clearer and more stringent risk value intervals tai-
lored to different disease types and stages. This
approach would enable the conversion of monitor-
ing results into clinically actionable recommenda-
tions for adjusting treatment protocols – a crucial
step toward achieving personalized anticoagula-
tion therapy. In patients with high-risk venous
thrombosis with multiple comorbidities, such as
heart failure or malignant tumors, the coagula-
tion status is notably complex and variable. The
evident dysfunction in the blood circulation and
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
coagulation systems significantly affects the effi-
cacy and outcomes of anticoagulation therapy
[50]. However, the current monitoring system
does not consider these key influencing factors in
developing targeted testing protocols and medi-
cation strategy recommendations. Therefore, the
establishment of a new comprehensive assessment
model and the development of novel testing indi-
cators, to optimize individualized monitoring and
treatment regimen selection for patients with such
complex venous thrombosis, will be an important
direction of development for increasing the preci-
sion of anticoagulation therapy.
Current monitoring models have notable limita-
tions in facilitating individualized anticoagulation
therapy, and often cannot support precise assess-
ment and interpretation of the coagulation status
and anticoagulation response in specific patient
groups. A clear need exists for a more scientific
and rational scoring system incorporating patients’
individual characteristics alongside existing test-
ing indices. Moreover, therapeutic objectives and
risk criteria tailored to different types of venous
thrombosis and stages of disease progression must
crucially be defined. This approach would enable
the development of truly personalized anticoagu-
lation treatment plans, thus enhancing the effec-
tiveness and safety of medications for patients
with venous thrombosis. Achieving this goal will
necessitate close collaboration between clinicians
and laboratory personnel, and fostering a patient-
centered approach in the treatment of venous
thrombosis.
Updated Approaches for Predicting
Thrombosis/Bleeding-Related
Events in Acute Coronary Syndrome
and Chronic Coronary Syndrome
Definition of the Disease, Epidemiology,
and Guideline-Recommended Treatment
Acute coronary syndrome (ACS) is a group of
clinical syndromes in which myocardial ischemia
and hypoxia are caused by decreased or inter-
rupted coronary blood flow due to coronary
thrombosis. Its main manifestations include
acute angina pectoris, ST-segment changes, and
7
elevated cardiac enzymes [51]. Chronic coronary
syndrome (CCS) refers to chronic stenotic lesions
of the coronary arteries that result in myocardial
ischemia and hypoxia, which manifest as stable
angina [52]. The incidence rates of ACS and CCS
are high; notably, the incidence of CCS is two
times higher than that of myocardial infarction,
and CCS is projected to affect 18% of the adult
population by the year 2030 [53]. Percutaneous
coronary intervention (PCI) is recommended for
ACS to restore perfusion; PCI or coronary artery
bypass graft surgery is recommended for CCS, to
increase blood flow according to the severity of
the lesion; and antithrombotic therapy with anti-
platelet and anticoagulant drugs is recommended
to prevent de novo thrombosis [54].
Bleeding/Ischemic Events after
Antithrombotic Therapy and Risk
Stratification Tools for Patients with ACS
and CCS
According to the expert consensus report published
by the American Heart Association, approximately
5% of patients with ACS who have undergone
dual antithrombotic therapy with anticoagulation
and antiplatelets experience various degrees of
hemorrhagic adverse events, including severe
­
­gastro­intestinal bleeding and cerebral hemorrhage;
moreover, approximately 2% of these patients expe-
rience new ischemic cardiovascular events, such as
myocardial infarction extension and angina aggra-
vation [55]. In contrast, patients with CCS who
have received the same treatment have a 3% inci-
dence of bleeding events and a 7% incidence of new
ischemic events [55]. The difference in the inci-
dence of secondary adverse events after treatment is
associated with the pathophysiological characteris-
tics of both ACS and CCS [56]. In addition to the
traditional CRUSADE, Syntax, and GRACE scores
[57], the PRECISE DAPT score and the PRAISE
score are useful in the assessment of adverse clini-
cal events after hemodialysis in patients with ACS
[58]. The efficacy of anticoagulants can also be
determined by measuring plasma concentrations of
anticoagulant drugs; e.g., the efficacy of ticagrelor
can be assessed by measuring the plasma concentra-
tion of its main active metabolite (AR-C124910XX)
[59]. Traditional platelet function assays, such as
8 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
VerifyNow, light transmission aggregometry, multi-
electrode platelet aggregometry (MEA), and vaso-
dilator-stimulated phosphoprotein (VASP), have
been used to assess adverse ­ clinical events in
patients with ACS [60]. Introduced in 2005,
VerifyNow is a mass s­pectrometry-based system
that measures platelet aggregation. A blood sample
is mixed with a carrier containing a specific activa-
tor to stimulate platelet activation. The system eval-
uates the efficacy of antiplatelet drugs by monitor-
ing changes in optical signals after platelet
aggregation, thereby providing a precise method for
assessing the effects of antiplatelet therapy [61].
This method is used in clinical applications to help
assess patients’ responses to medications, guide
treatment adjustments, prevent the risk of bleeding
during surgery, and assess patients’ risk of thrombo-
sis, thus providing rapid and accurate results.
Although the VerifyNow assay has emerged as a
novel test of platelet function assessing platelet
aggregation capability, its relevance to ischemic
events in patients with cardiovascular disease has
not been validated in several clinical trials con-
ducted in recent years [62–64]. First introduced in
the early 1970s, light transmission aggregometry
remains a frequently used method for assessing
platelet function. On the basis of the Lorentz-
Boltzmann law, optical turbidimetry is used to eval-
uate platelet function by measuring the extent of
platelet aggregation in a solution. This method acti-
vates platelets and quantifies aggregation by meas-
uring changes in light transmission through the
sample before and after activation. Optical turbi-
dimetry is widely used in various clinical domains
and is instrumental in hematology, monitoring of
anticoagulant therapy, and assessing cardiovascular
diseases; it also plays a major role in drug develop-
ment and clinical trials. This enduring method
exemplifies the integration of classic principles with
modern medical practices [65], and serves as an
important tool for assessing platelet function, diag-
nosing blood clots and platelet dysfunction, and
monitoring antiplatelet therapy. However, the
requirement for large samples, poor reproducibility,
and long assay times can lead to a decrease in plate-
let activity [64, 65]. VASP research began around
1994, and initially focused on its role in cell signal-
ing, but VASP gained widespread attention in the
early 2000s for its utility in monitoring platelet
function. VASP assessment involves measuring its
phosphorylation levels in activated platelets, which
indicates platelet inhibition and is particularly valu-
able in evaluating the effects of antiplatelet drugs,
such as P2Y12 antagonists. VASP has become a
critical tool in clinical practice for assessing the
efficacy of antiplatelet drugs and platelet function.
This method aids in crafting personalized therapeu-
tic strategies and in risk assessment for thrombosis-
related disorders, thus advancing patient-specific
medical care [66, 67]. The limitations of VASP,
such as differences in technical standardization,
complexity, and uncertainty in the interpretation of
the results, have limited its widespread use as an
indicator of platelet function [68, 69]. Developed
between the late 2000s and 2010, MEA is a key
method for assessing platelet function and the
effects of antiplatelet therapy. MEA replicates the
platelet aggregation process after vascular injury
and uses multiple electrodes to monitor platelet
aggregation dynamics simultaneously. This tech-
nique is crucial in evaluating the effectiveness of
antiplatelet drugs, predicting surgical risk, diagnos-
ing platelet dysfunction, and preventing cardiovas-
cular and cerebrovascular diseases in clinical
­settings. MEA’s comprehensive approach enhances
the understanding of platelet behavior; therefore,
this method is integral to modern thrombosis-­
associated medical practice [70–72]. Thromboe­
lastography (TEG), an advanced technology for
dynamically monitoring coagulation function, sim-
ulates the in vivo clotting process and records
changes in blood samples placed in a specially
designed cup. TEG measures various parameters,
including clotting time, thrombus formation rate,
clot strength, stability, and thrombolysis rate. These
parameters collectively offer insights into coagula-
tion and fibrinolytic functions, and provide a more
comprehensive assessment than traditional coagu-
lation tests. The results are depicted graphically or
in chart form, thus enhancing the interpretability
and utility of the data in clinical settings. Therefore,
TEG is a valuable tool in the detailed evaluation of
hemostatic processes [73], and can be used to com-
prehensively and continuously assess the overall
effects of anticoagulants and antiplatelet agents on
the coagulation system, dynamically predict bleed-
ing and ischemic risk, provide a basis for individu-
alized drug adjustment, help physicians assess
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease 9

patient coagulation status and function, and guide
blood management during treatment or surgery
[74]. In one clinical trial, triple antiplatelet therapy
(clopidogrel + aspirin + cilostazol) for patients in
the clopidogrel low-responder group, identified on
the basis of TEG metrics, has been found to improve
the clinical prognosis of high-risk patients undergo-
ing elective PCI [75]. Overall, TEG can detect
changes in coagulation function holistically and
dynamically, and may predict the risk of complica-
tions of antithrombotic therapy; therefore, its
­application prospects are promising. Promoting the
clinical application of TEG in patients with ACS
and CCS may help achieve precision and individu-
alization of antithrombotic therapy, minimize the
occurrence of bleeding and ischemic events, and
improve the efficacy of medication. In addition,
new individualized assessment methods based on
genetic and metabolomic technologies have broad
application prospects. The above methods for
assessing ischaemic imbalance are summarized in
Figure 2. The detection of genes associated with the
metabolism of antithrombotic drugs, such as
CYP2C19 and VKORC1, can be used to identify
drug metabolism function in patients and guide the
selection of individualized drug regimens, and can
also detect changes in vasoactive substances, such
as NO and cGMP, and assess the effects of antithrom-
botic therapy on vascular endothelial function [76].
The use of metabolomic technology to detect
changes in metabolite composition in patients can
determine the effects of the target actions of antico-
agulation and antiplatelet therapy, predict bleeding
or ischemia risk, and provide a basis for treatment
[77]. The application of these new technological
tools may help achieve truly precise antithrombotic
therapy based on the individual characteristics of
patients with ACS and CCS, and has substantial
clinical dissemination value.
For the same type of thrombosis, individual dif-
ferences exist in the responsiveness to anticoagu-
lant and antiplatelet drugs [78]. Patients who exhibit
high platelet reactivity and anticoagulant resist-
ance can be assessed with several specific tests to
guide individualized dosing regimens. Detection
of genotypes associated with drug metabolism,
such as CYP2C19, can be applied to predict the
effect of clopidogrel on antiplatelet aggregation
[79]. Detection of polymorphisms of coagulation
factor genes, such as F5, can be used to assess the
anticoagulant responsiveness of warfarin [80]. In
addition, the pharmacokinetics of antithrombotic
drugs varies among individuals. Patients with,
rather than without, single-nucleotide polymor-
phisms in the coding region of CYP3A4/5 have
a 30%–40% lower ability to metabolize warfarin,
and require adjustment of the anticoagulant dose
[4]. In patients with combined hepatic and renal
insufficiency, which directly affects metabolic
processes and the excretion rates of anticoagulant
and antiplatelet drugs, blood levels of plasma-drug
concentration must be monitored and individual-
ized to mitigate the risk of excessive accumula-
tion, thereby preventing potential side effect such
as bleeding disorders or toxicity [81]. Patient age
is another factor influencing the sensitivity to
antithrombotic drugs. Only 50% of patients older
than 75 years achieve the desired INR value with
standard doses of warfarin, as compared with 80%
of younger patients [82].
Therefore, anticoagulation lower doses are
necessary in older patients to avoid bleeding. In

TEG VASP Verifynow

Thromboelastography (TEG) is a blood clotting The VASP (platelet activation status protein) assay is VerifyNow is a rapid, point-of-care blood test for
test used to assess and monitor the entire blood a laboratory test to assess the responsiveness of assessing the efficacy and platelet function of
clotting process. platelet inhibitory therapies, particularly clopidogrel. antiplatelet drugs such as aspirin and clopidogrel.

1948 1970 1994 2000 2005

LTA
Light transmission aggregometry (LTA) is a laboratory
test that assesses platelet function by measuring the time it
takes for a blood sample to form a clot in response to a
specific stimulus.
MEA
Multi-Electrode Platelet Aggregometry (MEPA) is
an advanced blood test for assessing platelet
aggregation function and drug effects.

Figure 2 Thromboelastography Predicts the Thrombus Formation-Dissolution Process.

10 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
Table 2 Monitoring Indicators for Anticoagulant Therapy in Patients with Acute Coronary Syndrome.
Monitoring indicators Normal range Change direction
Prothrombin time (s) [83] 11–13 Extend
APTT (s) [83] 25–40 Extend
Fibrinogen (g/L) [85] 2–4 Decrease
D-dimer (mg/L) [85] < 0.5 Increase
Platelet count (109/L) [85] 100–300 Decrease
a­ ddition, thrombin generation and platelet aggre-
gation in pediatric and adolescent patients also
differ significantly from those in adults, and
require the establishment of a specific antithrom-
botic regimen [83]. Finally, female patients also
have specific individual characteristics. In preg-
nant women and those who use hormonal contra-
ceptives, the blood is in a hypercoagulable state,
which may affect antithrombotic therapy [84].
Therefore, individualized antithrombotic medica-
tion and monitoring should be directed to differ-
ent patients through assessment of their individual
characteristics and clinical background informa-
tion. Consequently, physicians must develop a
specific treatment strategy for each patient to
achieve truly individualized and precise medica-
tion. Various monitoring indicators for anticoagu-
lant therapy in patients with ACS are compiled in
Table 2.
Limitations of Existing Methods and the
Dilemma of Detection
Current coagulation function testing and antithrom-
botic therapy monitoring systems have several
shortcomings. First, inconsistencies exist among
testing methods, and the interpretation of the results
must be comprehensive. Among platelet aggrega-
tion function tests, the VerifyNow test and VASP
test reflect only the inhibition effect of the adenosine
diphosphate pathway and P2Y12 receptor, whereas
TEG can detect the alteration of platelet aggrega-
tion function in multiple pathways. The results of
these assays are not completely consistent and must
be interpreted comprehensively [86]. For each test
indicator, the critical value should be set at dif-
ferent thresholds for different types of thrombotic
diseases. However, the current risk intervals of the
Clinical significance
Indication of increased anticoagulation strength
Indication of inhibition of endogenous and
exogenous thrombin production
Indication of decreased fibrinogen formation
Indication of old thrombolysis
Indication of antiplatelet drugs to take effect
monitoring indicators have not been fully integrated
with specific disease types, thereby decreasing the
clinical operability of the monitoring results [87].
No specific guidelines have been established for
patients with multiple risk factors and those under-
going complex surgical treatments. The changes in
coagulation function in these patients are complex,
and the use of standard monitoring protocols does
not fully reflect the effectiveness of their antithrom-
botic therapy; however, no monitoring strategy
has been developed specifically for this group of
high-risk patients, thus further limiting the devel-
opment of individualized therapy [88]. Monitoring
protocols must also be optimized for older patients,
patients with systemic disease comorbidities, and
patients with other comorbidities, because of dif-
ferences in drug metabolism. Owing to differences
in the pharmacokinetic and pharmacodynamic pro-
cesses in these patients, the monitoring protocol
must be adjusted to guide individualized medica-
tion. However, the applicability of the existing mon-
itoring indexes to this patient group must be further
verified [89]. The DAPT score and the PRECISE-
DAPT score rely excessively on clinical character-
istics and do not sufficiently consider coagulation
indexes; consequently, their value in guiding of
individualized medication administration is lim-
ited. The DAPT score includes clinical factors such
as age, smoking, and diabetes, and the PRECISE-
DAPT score includes laboratory indexes such as
hemoglobin and white blood cell count, but nei-
ther includes coagulation function indicators such
as thrombin generation and platelet aggregation
force in the assessment. Thus, these scores are not
comprehensive or sufficiently accurate in reflecting
patient coagulation status. The design of individu-
alized monitoring protocols, including coagulation
kinetics, platelet aggregation function, and drug
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
metabolism indexes of antithrombotic drugs, and
the development of actionable monitoring values
in different clinical scenarios, remains topics wor-
thy of in-depth study. A combination of basic and
clinical research will be required to establish a truly
reliable and applicable new antithrombotic therapy
monitoring system to achieve precise individual-
ized medication and management, and comparison
among various methods and evaluations.
In anticoagulation and antiplatelet therapy for
thrombotic diseases, such as coronary artery dis-
ease, determining how to achieve accurate pre-
diction of bleeding and ischemia risks based on
individual patient characteristics and conditions
is key to improving the safety and effectiveness
of medication. First, tools such as genetic testing
can be used to identify biological features such
as high thrombin generation and platelet aggre-
gation hyperfunction in some individuals; the
findings can suggest poor antithrombotic drug
sensitivity, and enable targeting of the dosages of
anticoagulant or antiplatelet drugs. In addition,
the establishment of new operable coagulation
kinetic monitoring protocols, such as TEG test-
ing, and the determination of critical values for
TEG parameters at different disease stages, can
enable dynamic assessment of patient coagulation
and fibrinolytic function, and guide adjustment of
the intensity of antithrombotic therapy. Second,
individual patients’ clinical background, such as
ACS and CCS disease types, surgical modali-
ties, and comorbidities, should be fully integrated
into the assessment of monitoring indicator find-
ings and the optimization of the antithrombotic
treatment protocols in various clinical scenarios.
Large-sample clinical studies are also necessary
to establish reliable bleeding and ischemia risk
assessment models to guide the selection and use
of antithrombotic drugs.
In summary, only by organically combining
advanced testing technologies with extensive clini-
cal experience, and developing personalized treat-
ment and monitoring strategies for different patients,
can the safety and efficacy of antithrombotic therapy
be improved while maximizing the prevention of
bleeding and ischemic events. Cooperation among
all medical specialties will be necessary to achieve
precise individualized medication.
11
Updated Approaches for
Thrombosis/Bleeding-Related
Events in Atrial Fibrillation
Definition of the Disease, Epidemiology,
and Guideline-Recommended Treatment
Atrial fibrillation (AF) is a cardiac arrhythmia char-
acterized by rapid irregular beating of the atria [90].
According to epidemiological studies, in 2019,
approximately 59.7 million cases of AF (including
atrial flutter) occurred worldwide, and the preva-
lence of AF in China was 2.3%. The prevalence
and incidence of AF increase gradually with age,
and are higher in men than women across all age
groups. Most AF cases (80–90%) are nonvalvular
AF (NVAF), which is also the most common form
of AF in China. NVAF guidelines recommend med-
ications, electrophysiological therapy, and DOACs
to decrease the risk of stroke [85, 91].
Subsequent Bleeding/Ischemic Events
after Antithrombotic Therapy and Risk
Stratification Tools for Patients with AF
Clinical guidelines advise maintaining an INR
between 2.0 and 3.0 for patients with AF who lack
additional risk factors. Tailoring anticoagulation
or antiplatelet therapy is crucial for these patients,
given their stroke risk. Particularly for individu-
als with multiple stroke risk factors, such as heart
failure, a history of hypertension, and age over 75
years, guidelines strongly advocate for the use of
oral vitamin K antagonists. These anticoagulants,
aimed at achieving an INR of 2.5 to 3.0 or higher,
have potent anticoagulant properties and high effi-
cacy in decreasing thrombosis risk. This targeted
approach underscores the importance of individual-
ized therapy in optimizing patient outcomes in AF
management [91].
Among patients with AF with low stroke risk,
antiplatelet drugs such as aspirin – which do not
act directly on the coagulation system – may
be considered, and their relatively low antico-
agulant effects can decrease the risk of bleeding
[92]. The CHA2DS2-VASc score is a guideline-­
recommended tool for assessing the risk of stroke
in patients with AF. The score considers a range of
12 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
risk factors such as age, sex, hypertension, diabe-
tes mellitus, heart failure, stroke/transient ischemic
attack, and vascular disease. On the basis of the
total score, patients can be classified into stroke
risk groups, which indicate the need for anticoagu-
lant therapy [93]. The CHA2DS2 score is similar
to the CHA2DS2-VASc score and has also been
shown to be useful for assessing the risk of stroke
in patients with AF in clinical trials [94]. The HAS-
BLED score is used to assess the risk of bleeding in
patients with AF during anticoagulant therapy, and
considers factors such as hypertension, abnormal
liver function, stroke, history of bleeding, coagula-
tion abnormalities, age, and drug or alcohol use.
This score is used to determine whether patients are
suitable for anticoagulant therapy and how best to
manage the bleeding risk [95]. Routine tests such as
cardiac ultrasound (echocardiography) can deter-
mine the presence of blood clots within the heart
in patients with AF, to help assess the risk of stroke
and guide anticoagulant therapy [96]. Blood tests,
such as INR and PT, can test coagulation function,
to assess the effectiveness of anticoagulant therapy
and the risk of bleeding [97]. Continuous cardiac
monitoring, such as Holter monitoring or event
recording, can help identify changes in the heart
rhythm in patients with AF and assess their risk of
bleeding/ischemia [98].
Because of individual differences in drug
metabolism rates and sensitivity, patients with
NVAF have varying degrees of risk of thrombosis
and gastrointestinal bleeding after treatment with
DOACs [99]. Special attention should be paid to
patients with AF with moderate-to-severe renal
insufficiency. These patients are susceptible to
drug accumulation due to diminished glomerular
filtration rate, and excretion and clearance of anti-
coagulants, which may lead to severe gastrointes-
tinal hemorrhage and other adverse effects. Thus,
anticoagulation therapy in this group of patients is
highly challenging, and individualized dosing and
monitoring measures are necessary to decrease
the risk of severe hemorrhage [100]. Many cohort
studies have reported the incidence of gastrointes-
tinal bleeding and ischemic stroke after anticoagu-
lation in patients with NVAF. Lip et al. analyzed
17,633 patients with NVAF and showed that 4.9%
developed gastrointestinal hemorrhage, and 1.8%
developed ischemic stroke [99]. Pokorney et al.
examined 1820 patients with AF combined with
moderate-to-severe renal insufficiency and found
that the risk of gastrointestinal hemorrhage during
standard anticoagulation therapy was 1.7 times
higher than that in patients without renal impair-
ment [101].
The main indicators routinely used to moni-
tor the effectiveness of anticoagulation therapy
and the risk of bleeding in patients with NVAF
include PT, APTT, and INR. These indicators can
be used to assess the level of thrombosis and the
efficacy of anticoagulation therapy. In addition to
the CHA2DS2-VASc score and the HAS-BLED
score, the R2CHADS2 score [102] adds renal
impairment and an age range of 65–74 years to
the CHA2DS2-VASc score. The scoring system
categorizes patients with NVAF into four levels
(low, moderate, high, and very high risk), thereby
contributing to a more nuanced assessment of the
stroke risk.
Assessing levels of thrombosis and the efficacy of
anticoagulation therapy in patients with AF by mon-
itoring coagulation pathology indexes such as PT,
D-dimer, and APTT to guide the subsequent adjust-
ment of anticoagulation intensity can be applied to
predict the occurrence of adverse events such as
ischemic stroke. However, in patients with renal
impairment leading to anticoagulant accumulation,
the changes in the routine coagulation indexes do
not fully reflect the precise effects of anticoagulants
and therefore cannot provide reliable personalized
medication guidance for this high-risk group; this
aspect is one limitation of the current monitoring
system. For individuals with renal impairment, the
interpretation of all coagulation indexes is diffi-
cult, and actionable recommendations that can be
directly translated into medication and monitoring
protocols are lacking. These issues constrain safe
and effective personalized anticoagulation in this
group of patients with complex AF with high stroke
risk and renal impairment.
To achieve personalized and precise anticoagu-
lation for patients with NVAF with renal impair-
ment, while decreasing the risk of stroke and
controlling the risk of gastrointestinal bleeding,
the optimal range of anticoagulant concentrations
must be defined on the basis of advanced testing
techniques. Moreover, establishing personalized
medication and monitoring protocols for these
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
patients through prospective cohort studies, and
translating them into specific clinical protocols,
will be important. The optimal range of anticoagu-
lant concentrations for this group of patients can
be clearly defined on the basis of advanced test-
ing technology. Only by combining monitoring
technology with the individual clinical character-
istics of patients and formulating individualized
therapeutic strategies can the efficacy and safety
of anticoagulation be improved in patients with
NVAF combined with renal insufficiency. Close
collaboration among medical specialties will be
necessary to continually optimize patient antico-
agulation and monitoring.
Updated Approaches for Bleeding/
Ischemic Events in Valvular Disease
Definition, Prevalence, and ­Guideline-
Recommended Treatment of Valvular
Disease
Valvular disease is a heart disease involving a
structural or functional abnormality of the heart
valves. According to the EURO II Survey results,
the prevalence of valve disease is 2.5% in the over-
all population and increases significantly with age;
in the population over 75 years of age, the inci-
dence rate for all valves combined reaches nearly
14% [103]. The most common valve diseases are
mitral valve closure insufficiency and aortic steno-
sis [104], and the treatment options include phar-
macological management, surgical repair, or valve
replacement.
Subsequent Bleeding/Ischemic Events
after Antithrombotic Therapy and Risk
Stratification Tools for Patients with Valve
Disease
Patients undergoing heart valve replacement
surgery require long-term oral anticoagulation
­ tion fraction [110].
therapy. Current clinical guidelines generally rec-
ommend that patients undergoing mechanical
valve replacement surgery start taking vitamin K
antagonist anticoagulants such as warfarin orally in
the immediate postoperative period, to maintain a
high anticoagulation intensity with an INR value of
13
2.5–3.5, and minimize the probability of perivalvu-
lar thrombosis to the greatest extent possible [105].
In contrast, a lower anticoagulation intensity regi-
men (INR 2.0–3.0) may be chosen for patients at
low stroke risk with tissue or biologic valves [106].
Numerous cohort studies have reported the inci-
dence of gastrointestinal bleeding and thrombotic
events due to anticoagulation therapy after heart
valve replacement.
Oral anticoagulants have shown excellent anti-
coagulant efficacy and a relatively favorable safety
profile in clinical trials and practical clinical appli-
cations. However, serious bleeding events occur in
approximately 2–3.5% of patients receiving oral
anticoagulation each year [107]. These patients
may be at risk of thrombosis if anticoagulation is
discontinued. Sulman et al. have reported thrombo-
embolic events in 16% of patients undergoing bio-
prosthetic valve implantation and coronary artery
bypass grafting [107]. In patients with bioprosthetic
valves, the risk of gastrointestinal bleeding due to
overaccumulation of anticoagulants should not be
ignored, and a dynamic balance between bleeding
risk and thrombosis risk must be ensured through
regular monitoring.
Currently, for the monitoring of anticoagulation
therapy in patients after heart valve replacement,
conventional indicators such as PT and INR are
primarily used [108]. The cardiac renal hepatic
(CRH) score, a new score combining multiple
biomarkers of cardiac, renal, and hepatic func-
tion (NT-proBNP, creatinine, and albumin, respec-
tively), based on data from the CHINA-VHD study,
has been identified as the key predictor of mortal-
ity in patients with valvular heart disease [109].
Cardiac ultrasound, which indicates valve activity,
ventricular function, chamber size, and possible
complications, can be used to assess cardiac func-
tion and valve function after valve replacement.
The overall pumping function of the heart can also
be assessed by measuring cardiac function indexes
such as the cardiac index and left ventricular ejec-
Among mitral valve diseases, mitral valve clo-
sure insufficiency is the most common condition,
and TMVR is a common interventional treatment
for mitral valve closure insufficiency. However,
complications such as thrombosis and hemorrhage
persist in the postoperative period. The incidence
14 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
of stroke within 30 days of surgery ranges from
0.7% to 2.6%, and hemorrhagic complications
occur in approximately 13% of cases [110].
Among aortic valve diseases, aortic stenosis is
the most common. In a Danish study, ischemic
stroke has been found in 8% of 873,373 patients
[111]. Patients with mitral valve insufficiency and
aortic stenosis often have a combination of bleed-
ing risk factors, such as congestive heart failure,
hypertension, advanced age, renal insufficiency,
and diabetes mellitus. The ESC/EACTS 2017
and the ACC/American Heart Association 2020
guidelines do not provide a clear antithrombotic
protocol, and current policies are largely depend-
ent on clinician experience. Therefore, an urgent
need exists for effective protocols to individu-
alize patient treatment. In a study published by
the JACC, a simple and practical risk score was
developed through the COAPT research database,
which consisted of four clinical variables (New
York Heart Association functional class, chronic
obstructive pulmonary disease, AF or atrial flut-
ter, and chronic kidney disease) and four echo-
cardiographic variables (left ventricular ejection
fraction, left ventricular end-systolic internal
diameter, right ventricular systolic pressure, and
tricuspid regurgitation). The COAPT risk score
is useful in predicting the risk of death or hospi-
talization for heart failure in patients with severe
mitral regurgitation [112]. Elevated NT-proBNP
has been associated with elevated mortality in
patients with moderate aortic stenosis, but no stud-
ies have demonstrated whether early intervention
affects prognosis. In a population of patients with
moderate or severe aortic stenosis, high-sensitiv-
ity troponin I has been associated with increased
left ventricular mass and fibrosis on CMR imag-
ing, and with aortic valve replacement and death
[112]. Echocardiography can be used to assess the
extent of valvular disease in patients with mitral
valve closure insufficiency or aortic stenosis, to
assess prognosis [113].
Although interventional and antithrombotic
therapy in patients with valvular disease can effec-
tively improve prognosis, it cannot quantitatively
guide individualized medication use, because of
the lack of a clear definition of the optimal range
of anticoagulant intensity or blood concentra-
tion targets for different populations. In addition,
specifically formulated monitoring strategies and
medication recommendations are lacking for high-
risk groups, such as individuals with impaired
liver and kidney function or older individuals.
These issues limit the precision of anticoagulation
in specific patients.
Long-term anticoagulation is essential for
patients undergoing heart valve surgery but must
be balanced against thrombosis and bleeding risk,
to ensure the maximum efficacy and safety of the
therapy. Therefore, advanced testing techniques
and clinical experience must be combined to clearly
define the optimal range of anticoagulant strengths
for different patient groups, particularly those at
high risk. Individualized treatment and monitoring
plans must be developed to ensure that each patient
attains maximum therapeutic benefit. To achieve
this goal, all relevant areas of medicine must work
closely together to provide precise and individual-
ized anticoagulation for patients with heart valve
disease.
Conclusion and Outlook
This review summarized current dilemmas in
antithrombotic therapy, as well as strategies for
individualizing antithrombotic therapy by compar-
ing risk stratification tools for various thrombotic
diseases.
The primary challenge in current antithrom-
botic therapy is balancing the risks of bleeding
and ischemia. Individual variability and uncertain
drug response hinder the ability to achieve con-
sistent and balanced therapeutic effects. Recently,
TEG has emerged as a promising solution offer-
ing insights into thrombin generation and platelet
aggregation force. This method enables accurate
assessment of anticoagulation intensity and paves
the way to precision anticoagulation therapy. In
the future, TEG, particularly when integrated
with individual patient characteristics, is poised to
become an essential tool in monitoring anticoagu-
lation therapy.
In the future, with the development and in-depth
application of high-throughput detection tech-
nology and information technology, antithrom-
botic therapy monitoring systems could lead to
a shift from traditional group monitoring to truly
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease 15

individualized monitoring. The high throughput Sources of Funding

and high precision of various testing technologies
may provide the best and safest precise antithrom-
botic treatment plans tailored to different patients.
Hence, all relevant medical specialties must unite
in joint efforts to further improve the diagnosis
and treatment of thromboembolic diseases, as
well as the efficacy and safety of antithrombotic
therapy.
This work was supported by the Beijing Municipal
Medical Research Institutes Pilot Reform Project
(grant number 2021-07).
Conflict of interest
The authors declare no conflicts of interest.

References

1. Raskob GE, Angchaisuksiri P,
Blanco AN, Büller H, Gallus A,
Hunt BJ, et al. Thrombosis: a
major contributor to global disease
burden. Semin Thromb Hemost
2014;40(7):724–35.
2. Alkarithi G, Duval C, Shi Y, Macrae
FL, Ariëns RAS. Thrombus struc-
tural composition in Cardiovascular
Disease. Arterioscler Thromb Vasc
Biol 2021;41(9):2370–83.
3. Joundi RA, Menon BK. Thrombus
composition, imaging, and outcome
prediction in acute ischemic stroke.
Neurology 2021;97(20, Suppl 2):
S68–78.
4. Mackman N, Bergmeier W, Stouffer
GA, Weitz JI. Therapeutic strate-
gies for thrombosis: new targets and
approaches. Nat Rev Drug Discov
2020;19(5):333–52.
5. Dunois C. Laboratory monitoring of
direct oral anticoagulants (DOACs).
Biomedicines 2021;9(5):445.
6. Willis J, Carroll C, Planz V,
Galgano SJ. Thromboelastography:
a review for radiologists and impli-
cations on periprocedural bleed-
ing risk. Abdom Radiol (NY)
2022;47(8):2697–703.
7. McGuire AL, Gabriel S, Tishkoff
SA, Wonkam A, Chakravarti A,
Furlong EEM, et al. The road ahead
in genetics and genomics. Nat Rev
Genet 2020;21(10):581–96.
8. Chang JC. Novel classification
of thrombotic disorders based on
molecular hemostasis and thrombo-
genesis producing primary and sec-
ondary phenotypes of thrombosis.
Biomedicines 2022;10(11):2706.
9. Lippi G, Franchini M, Targher G.
Arterial thrombus formation in
cardiovascular disease. Nat Rev
Cardiol 2011;8(9):502–12.
10. Weitz JI, Fredenburgh JC,
Eikelboom JW. A test in ­ context:
D-dimer. J Am Coll Cardiol
2017;70(19):2411–20.
11. Andreoli L, Bertsias GK, Agmon-
Levin N, Brown S, Cervera R,
Costedoat-Chalumeau N, et al.
EULAR recommendations for wom-
en’s health and the management of
family planning, assisted reproduc-
tion, pregnancy and menopause in
patients with systemic lupus ery-
thematosus and/or antiphospho-
lipid syndrome. Ann Rheum Dis
2017;76(3):476–85.
12. Farge D, Frere C, Connors JM,
Khorana AA, Kakkar A, Ay C,
et al. International Initiative on
Thrombosis and Cancer (ITAC)
Advisory Panel. 2022 international
clinical practice guidelines for the
treatment and prophylaxis of venous
thromboembolism in patients
with cancer, including patients
with COVID-19. Lancet Oncol
2022;23(7):e334–47.
13. O’Leary JG, Greenberg CS, Patton
HM, Caldwell SH. AGA clini-
cal practice update: coagulation
in cirrhosis. Gastroenterology
2019;157(1):34–43.e1.
14. Bikdeli B, Madhavan MV, Jimenez
D, Chuich T, Dreyfus I, Driggin
E, et al.; Global COVID-19
Thrombosis Collaborative Group,
Endorsed by the ISTH, NATF,
ESVM, and the IUA, Supported
by the ESC Working Group on
Pulmonary Circulation and Right
Ventricular Function. COVID-19
and thrombotic or thromboem-
bolic disease: implications for pre-
vention, antithrombotic therapy,
and follow-up: JACC state-of-
the-art review. J Am Coll Cardiol
2020;75(23):2950–73.
15. Pieters M, Wolberg AS. Fibrinogen
and fibrin: an illustrated review.
Res Pract Thromb Haemost
2019;3(2):161–72.
16. Previtali E, Bucciarelli P, Passamonti
SM, Martinelli I. Risk factors for
venous and arterial thrombosis.
Blood Transfus 2011;9(2):120–38.
17. Dare S, Mackay DF, Pell JP.
Relationship between smoking and
obesity: a cross-sectional study of
499,504 middle-aged adults in the
UK general population. PLoS One
2015;10(4):e0123579.
18. Page MJ, Pretorius E. A cham-
pion of host defense: a generic
large-scale cause for platelet dys-
function and depletion in infec-
tion. Semin Thromb Hemost
2020;46(3):302–19.
19. Sun HJ, Wu ZY, Nie XW, Bian
JS. Role of endothelial dysfunc-
tion in cardiovascular diseases:
the link between inflammation and
hydrogen sulfide. Front Pharmacol
2020;10:1568.
20. Schofield Z, Baksamawi HA,
Campos J, Alexiadis A, Nash GB,
Brill A, et al. The role of valve
stiffness in the insurgence of deep
vein thrombosis. Commun Mater
2020;1(1):65.
16 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
21. Xue L, Tao L, Li X, Wang Y, Wang
B, Zhang Y, et al. Plasma fibrino-
gen, D-dimer, and fibrin degradation
product as biomarkers of rheumatoid
arthritis. Sci Rep 2021;11(1):16903.
22. Stark K, Massberg S. Interplay
between inflammation and thrombo-
sis in cardiovascular pathology. Nat
Rev Cardiol 2021;18(9):666–82.
23. Kam W, Holmes DN, Hernandez
AF, Saver JL, Fonarow GC, Smith
EE, et al. Association of recent
use of non-vitamin K antagonist
oral anticoagulants with intracra-
nial hemorrhage among patients
with acute ischemic stroke treated
with alteplase. J Am Med Assoc
2022;327(8):760–71.
24. Freeman JV, Higgins AY, Wang Y,
Du C, Friedman DJ, Daimee UA,
et al. Antithrombotic therapy after
left atrial appendage occlusion in
patients with atrial fibrillation. J Am
Coll Cardiol 2022;79(18):1785–98.
25. Connors JM, Brooks MM, Sciurba
FC, Krishnan JA, Bledsoe JR,
Kindzelski A, et al. ACTIV-4B
Investigators. Effect of antithrombotic
therapy on clinical outcomes in out-
patients with clinically stable symp-
tomatic COVID-19: the ACTIV-4B
randomized clinical trial. J Am Med
Assoc 2021;326(17):1703–12.
26. Sadeghipour P, Talasaz AH,
Rashidi F, Sharif-Kashani B,
Beigmohammadi MT, Farrokhpour
M, et al. Effect of intermediate-
dose vs standard-dose prophylac-
tic anticoagulation on thrombotic
events, extracorporeal membrane
oxygenation treatment, or mortal-
ity among patients with COVID-19
admitted to the intensive care unit:
the INSPIRATION randomized
clinical trial. J Am Med Assoc
2021;325(16):1620–30.
27. Bauersachs RM, Szarek M,
Brodmann M, Gudz I, Debus ES,
Nehler MR, et al. VOYAGER PAD
Committees and Investigators.
Total ischemic event reduction with
rivaroxaban after peripheral arterial
revascularization in the VOYAGER
PAD trial. J Am Coll Cardiol
2021;78(4):317–26.
28. Barkoudah E, Piazza G, Hecht TEH,
Grant P, Deitelzweig S, Fang MC,
et al. Extended venous thrombo-
embolism prophylaxis in medically
Ill patients: an NATF anticoagula-
tion action initiative. Am J Med
2020;133 Suppl 1:1–27.
29. Coutinho JM, Zuurbier SM,
Bousser MG, Ji X, Canhão P, Roos
YB, et al.; TO-ACT Investigators.
Effect of endovascular treatment
with medical management vs stand-
ard care on severe cerebral venous
thrombosis: the TO-ACT rand-
omized clinical trial. JAMA Neurol
2020;77(8):966–73.
30. Anand SS, Bosch J, Eikelboom JW,
Connolly SJ, Diaz R, Widimsky
P, et al.; COMPASS Investigators.
Rivaroxaban with or without aspirin
in patients with stable peripheral or
carotid artery disease: an interna-
tional, randomised, double-blind,
placebo-controlled trial. Lancet
2018;391(10117):219–29.
31. Fiedler KA, Maeng M, Mehilli J,
Schulz-Schüpke S, Byrne RA, Sibbing
D, et al. Duration of triple therapy in
patients requiring oral anticoagulation
after drug-eluting stent implantation:
the ISAR-TRIPLE trial. J Am Coll
Cardiol 2015;65(16):1619–29.
32. Wallentin L, Becker RC, Budaj A,
Cannon CP, Emanuelsson H, Held
C, et al. Ticagrelor versus clopi-
dogrel in patients with acute coro-
nary syndromes. N Engl J Med
2009;361(11):1045–57.
33. Valerio L, Mavromanoli AC, Barco
S, Abele C, Becker D, Bruch L,
et al. Chronic thromboembolic pul-
monary hypertension and impair-
ment after pulmonary embolism:
the FOCUS study. Eur Heart J
2022;43(36):3387–98.
34. Jovin TG, Nogueira RG, Lansberg
MG, Demchuk AM, Martins SO,
Mocco J, et al. Thrombectomy for
anterior circulation stroke beyond
6 h from time last known well
(AURORA): a systematic review and
individual patient data meta-analysis.
Lancet 2022;399(10321):249–58.
35. Büller HR, Prins MH, Lensin AW,
Decousus H, Jacobson BF, Minar
E, et al. Oral rivaroxaban for the
treatment of symptomatic pul-
monary embolism. N Engl J Med
2012;366(14):1287–97.
36. Shufelt C, LeVee A. Hormonal
contraception in women with
hypertension. J Am Med Assoc
2020;324(14):1451–52.
37. Vano YA, Elaidi R, Bennamoun M,
Chevreau C, Borchiellini D, Pannier
D, et al. Nivolumab, nivolumab-
ipilimumab, and VEGFR-tyrosine
kinase inhibitors as first-line treat-
ment for metastatic clear-cell renal
cell carcinoma (BIONIKK): a
biomarker-driven, open-label, non-
comparative, randomised, phase
2 trial. Lancet Oncol 2022;23(5):
612–24.
38. Capodanno D, Mehran R,
Krucoff MW, Baber U, Bhatt DL,
Capranzano P, et al. Defining
strategies of modulation of anti-
platelet therapy in patients with
coronary artery disease: a consen-
sus document from the Academic
Research Consortium. Circulation
2023;147(25):1933–44.
39. Molander V, Bower H, Frisell
T, Delcoigne B, Di Giuseppe D,
Askling J; ARTIS study group.
Venous thromboembolism with
JAK inhibitors and other immune-­
modulatory drugs: a Swedish com-
parative safety study among patients
with rheumatoid arthritis. Ann
Rheum Dis 2023;82(2):189–97.
40. Bertsias GK, Ioannidis JP, Aringer
M, Bollen E, Bombardieri S, Bruce
IN, et al. EULAR recommendations
for the management of systemic
lupus erythematosus with neuropsy-
chiatric manifestations: report of a
task force of the EULAR standing
committee for clinical affairs. Ann
Rheum Dis 2010;69(12):2074–82.
41. Naess IA, Christiansen SC,
Romundstad P, Cannegieter SC,
Rosendaal FR, Hammerstrøm J.
Incidence and mortality of venous
thrombosis: a population-based study.
J Thromb Haemost 2007;5(4):692–9.
42. Wolberg AS, Rosendaal FR, Weitz
JI, Jaffer IH, Agnelli G, Baglin T,
et al. Venous thrombosis. Nat Rev
Dis Primers 2015;1:15006.
43. Olaf M, Cooney R. Deep venous
thrombosis. Emerg Med Clin North
Am 2017;35(4):743–70.
44. Hisada Y, Mackman N. Cancer-
associated pathways and biomarkers
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
of venous thrombosis. Blood
2017;130(13):1499–506.
45. Watson HG, Baglin TP. Guidelines
on travel-related venous thrombosis.
Br J Haematol 2011;152(1):31–4.
46. Timp JF, Braekkan SK, Versteeg HH,
Cannegieter SC. Epidemiology of
cancer-associated venous thrombo-
sis. Blood 2013;122(10):1712–23.
47. Kakkos SK, Gohel M, Baekgaard N,
Bauersachs R, Bellmunt-Montoya
S, Black SA, et al. Editor’s Choice -
European Society for Vascular Surgery
(ESVS) 2021 Clinical Practice
Guidelines on the Management of
Venous Thrombosis. Eur J Vasc
Endovasc Surg 2021;61(1):9–82.
48. Tan R, Daneshmand A, Parys
S, Watanabe Y, Sieunarine K.
Splanchnic venous thrombosis: aeti-
ologies and a review of the literature.
ANZ J Surg 2022;92(9):2224–8.
49. van der Steen W, van de Graaf
RA, Chalos V, Lingsma HF, van
Doormaal PJ, Coutinho JM, et al. MR
CLEAN-MED Investigators. Safety
and efficacy of aspirin, unfraction-
ated heparin, both, or neither dur-
ing endovascular stroke treatment
(MR CLEAN-MED): an open-label,
multicentre, randomised controlled
trial. Lancet 2022;399(10329):
1059–69.
50. Pastori D, Cormaci VM, Marucci S,
Franchino G, Del Sole F, Capozza
A, et al. A comprehensive review
of risk factors for venous throm-
boembolism: from epidemiology
to pathophysiology. Int J Mol Sci
2023;24(4):3169.
51. Kumar A, Cannon CP. Acute coro-
nary syndromes: diagnosis and
management, part I. Mayo Clin Proc
2009;84(10):917–38.
52. Knuuti J, Wijns W, Saraste A,
Capodanno D, Barbato E, Funck-
Brentano C, et al. 2019 ESC Guidelines
for the diagnosis and management of
chronic coronary syndromes. Eur
Heart J 2020;41(3):407–77.
53. Timmis A, Kazakiewicz D,
Townsend N, Huculeci R, Aboyans
V, Vardas P. Global epidemiology of
acute coronary syndromes. Nat Rev
Cardiol 2023;20(11):778–88.
54. Lawton JS, Tamis-Holland JE,
Bangalore S, Bates ER, Beckie
TM, Bischoff JM, et al. 2021 ACC/
AHA/SCAI guideline for coronary
artery revascularization: executive
summary: a report of the American
College of Cardiology/American
Heart Association Joint Committee
on Clinical Practice Guidelines.
Circulation 2022;145(3):e4–17.
55. Heidenreich PA, Bozkurt B, Aguilar
D, Allen LA, Byun JJ, Colvin
MM, et al. 2022 AHA/ACC/HFSA
guideline for the management
of heart failure: executive sum-
mary: a report of the American
College of Cardiology/American
Heart Association Joint Committee
on clinical practice guidelines.
Circulation 2022;145(18):e876–94.
56. Lopes RD, Heizer G, Aronson R,
Vora AN, Massaro T, Mehran R,
et al. Antithrombotic therapy after
acute coronary syndrome or PCI
in atrial fibrillation. N Engl J Med
2019;380(16):1509–24.
57. Cordero A, Rodriguez-Manero M,
García-Acuña JM, López-Palop R,
Cid B, Carrillo P, et al. Additive
value of the CRUSADE score to
the GRACE score for mortality risk
prediction in patients with acute
coronary syndromes. Int J Cardiol
2017;245:1–5.
58. Costa F, van Klaveren D, James
S, Heg D, Räber L, Feres F, et al.
Derivation and validation of the
predicting bleeding complications
in patients undergoing stent implan-
tation and subsequent dual anti-
platelet therapy (PRECISE-DAPT)
score: a pooled analysis of individ-
ual-patient datasets from clinical
trials. Lancet 2017;389(10073):
1025–34.
59. Holm M, Tornvall P, Henareh L,
Jensen U, Golster N, Alström P,
et al. The MOVEMENT trial. J Am
Heart Assoc 2019;8(2):e010152.
60. Paniccia R, Priora R, Liotta AA,
Abbate R. Platelet function tests:
a comparative review. Vasc Health
Risk Manag 2015;11:133–48.
61. Price MJ, Berger PB, Teirstein PS,
Tanguay JF, Angiolillo DJ, Spriggs
D, et al. Standard- vs high-dose
clopidogrel based on platelet func-
tion testing after percutaneous coro-
nary intervention: the GRAVITAS
17
randomized trial. J Am Med Assoc
2011;305(11):1097–105.
62. Aradi D, Gross L, Trenk D, Geisler
T, Merkely B, Kiss RG, et al.
Platelet reactivity and clinical out-
comes in acute coronary syndrome
patients treated with ­ prasugrel
and clopidogrel: a pre-specified
exploratory analysis from the
TROPICAL-ACS trial. Eur Heart J
2019;40(24):1942–51.
63. Cayla G, Cuisset T, Silvain J,
Leclercq F, Manzo-Silberman S,
Saint-Etienne C, et al. Platelet
function monitoring to adjust anti-
platelet therapy in elderly patients
stented for an acute coronary syn-
drome (ANTARCTIC): an open-
label, blinded-endpoint, randomised
controlled superiority trial. Lancet
2016;388(10055):2015–22.
64. Moreo A, Ambrosio G, De Chiara B,
Pu M, Tran T, Mauri F, et al. Influence
of myocardial fibrosis on left ven-
tricular diastolic function: noninva-
sive assessment by cardiac magnetic
resonance and echo. Circ Cardiovasc
Imaging 2009;2(6):437–43.
65. Khandhar AP, Ferguson RM, Simon
JA, Krishnan KM. Tailored magnetic
nanoparticles for optimizing mag-
netic fluid hyperthermia. J Biomed
Mater Res A 2012;100(3):728–37.
66. Schlegel N, Waschke J. Vasodilator-
stimulated phosphoprotein: crucial
for activation of Rac1 in endothe-
lial barrier maintenance. Cardiovasc
Res 2010;87(1):1–3.
67. Tu K, Li J, Verma VK, Liu C,
Billadeau DD, Lamprecht G, et al.
Vasodilator-stimulated phosphopro-
tein promotes activation of hepatic
stellate cells by regulating Rab11-
dependent plasma membrane tar-
geting of transforming growth
factor beta receptors. Hepatology
2015;61(1):361–74.
68. Bonello L, Paganelli F, Arpin-
Bornet M, Auquier P, Sampol J,
Dignat-George F, et al. Vasodilator-
stimulated phosphoprotein phos-
phorylation analysis prior to per-
cutaneous coronary ­ intervention
for exclusion of postprocedural
major adverse cardiovascu-
lar events. J Thromb Haemost
2007;5(8):1630–6.
18 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
69. Oelze M, Mollnau H, Hoffmann
N, Warnholtz A, Bodenschatz M,
Smolenski A, et al. Vasodilator-
stimulated phosphoprotein serine 239
phosphorylation as a sensitive moni-
tor of defective nitric oxide/cGMP
signaling and endothelial dysfunc-
tion. Circ Res 2000;87(11):999–1005.
70. Morel-Kopp MC, Mullier F, Gkalea
V, Bakchoul T, Minet V, Elalamy
I, et al. Heparin-induced multi-
electrode aggregometry method for
­heparin-induced thrombocytope-
nia testing: communication from
the SSC of the ISTH. J Thromb
Haemost 2016;14(12):2548–52.
71. Tóth O, Calatzis A, Penz S,
Losonczy H, Siess W. Multiple elec-
trode aggregometry: a new device
to measure platelet aggregation
in whole blood. Thromb Haemost
2006;96(6):781–8.
72. Nwankwo JO, Gremmel T, Gerrits
AJ, Mithila FJ, Warburton RR, Hill
NS, et al. Calpain-1 regulates plate-
let function in a humanized mouse
model of sickle cell disease. Thromb
Res 2017;160:58–65.
73. Subramanian M, Kaplan LJ, Cannon
JW. Thromboelastography-guided
resuscitation of the Trauma patient.
JAMA Surg 2019;154(12):1152–3.
74. Da Luz LT, Nascimento B,
Shankarakutty AK, Rizoli S,
Adhikari NK. Effect of thromboe-
lastography (TEG®) and rotational
thromboelastometry (ROTEM®)
on diagnosis of coagulopathy,
transfusion guidance and mortality
in trauma: descriptive systematic
review. Crit Care 2014;18(5):518.
75. Tang YD, Wang W, Yang M,
Zhang K, Chen J, Qiao S, et al.
Randomized comparisons of dou-
ble-dose clopidogrel or adjunctive
cilostazol versus standard dual anti-
platelet in patients with high post-
treatment platelet reactivity: results
of the CREATIVE trial. Circulation
2018;137(21):2231–45.
76. Alseekh S, Aharoni A, Brotman Y,
Contrepois K, D’Auria J, Ewald
J, et al. Mass spectrometry-based
metabolomics: a guide for anno-
tation, quantification and best
reporting practices. Nat Methods
2021;18(7):747–56.
77. Qiu S, Cai Y, Yao H, Lin C, Xie Y,
Tang S, et al. Small molecule metab-
olites: discovery of biomarkers and
therapeutic targets. Signal Transduct
Target Ther 2023;8(1):132.
78. van Vlijmen EF, Wiewel-Verschueren
S, Monster TB, Meijer K. Combined
oral contraceptives, thrombophilia
and the risk of venous thromboem-
bolism: a systematic review and
meta-analysis. J Thromb Haemost
2016;14(7):1393–403.
79. Hassouna HI. Thrombophilia and
hypercoagulability. Med Princ Pract
2009;18(6):429–40.
80. Coen Herak D, Lenicek Krleza
J, Radic Antolic M, Horvat I,
Djuranovic V, Zrinski Topic R,
et al. Association of polymorphisms
in coagulation factor genes and
enzymes of homocysteine metabo-
lism with arterial ischemic stroke in
children. Clin Appl Thromb Hemost
2017;23(8):1042–51.
81. Musso G, Gambino R, Tabibian
JH, Ekstedt M, Kechagias S,
Hamaguchi M, et al. Association
of non-alcoholic fatty liver disease
with chronic kidney disease: a sys-
tematic review and meta-analysis.
PLoS Med 2014;11(7):e1001680.
82. Guo J, Huang X, Dou L, Yan M,
Shen T, Tang W, et al. Aging and
aging-related diseases: from molec-
ular mechanisms to interventions
and treatments. Signal Transduct
Target Ther 2022;7(1):391.
83. Capranzano P, Angiolillo DJ.
Antithrombotic management of
elderly patients with coronary artery
disease. JACC Cardiovasc Interv
2021;14(7):723–38.
84. Yang H, Guo R, Li S, Liang F, Tian
C, Zhao X, et al. Systematic analysis
of gut microbiota in pregnant women
and its correlations with individ-
ual heterogeneity. NPJ Biofilms
Microbiomes 2020;6(1):32.
85. Wu J, Zhang Y, Liao X, Lei Y.
Anticoagulation therapy for non-
valvular atrial fibrillation: a mini-
review. Front Med (Lausanne)
2020;7:350.
86. Luna DJ, Pandian NKR, Mathur T,
Bui J, Gadangi P, Kostousov VV,
et al. Tortuosity-powered micro-
fluidic device for assessment of
thrombosis and antithrombotic
therapy in whole blood. Sci Rep
2020;10(1):5742.
87. McRae HL, Militello L, Refaai
MA. Updates in anticoagulation
therapy monitoring. Biomedicines
2021;9(3):262.
88. Kleindorfer DO, Towfighi A,
Chaturvedi S, Cockroft KM,
Gutierrez J, Lombardi-Hill D, et al.
2021 guideline for the prevention
of stroke in patients with stroke and
transient ischemic attack: a guideline
from the American Heart Association/
American Stroke Association. Stroke
2021;52(7):e364–467.
89. Peyroteo M, Ferreira IA, Elvas
LB, Ferreira JC, Lapão LV.
Remote monitoring systems for
patients with chronic diseases in
primary health care: systematic
review. JMIR Mhealth Uhealth
2021;9(12):e28285.
90. Pellman J, Sheikh F. Atrial fibrilla-
tion: mechanisms, therapeutics, and
future directions. Compr Physiol
2015;5(2):649–65.
91. Huang YC, Huang YC, Cheng YC,
Chen M. Choice of antithrombotic
therapy for patients with atrial fibril-
lation undergoing carotid angio-
plasty and stenting: a nationwide
population-based study. Sci Rep
2022;12(1):1417.
92. Komen JJ, Pottegård A, Mantel-
Teeuwisse AK, Forslund T,
Hjemdahl P, Wettermark B, et al.
Oral anticoagulants in patients with
atrial fibrillation at low stroke risk: a
multicentre observational study. Eur
Heart J 2022;43(37):3528–38.
93. Chao TF, Liu CJ, Wang KL, Lin
YJ, Chang SL, Lo LW, et al. Using
the CHA2DS2-VASc score for
refining stroke risk stratification
in ‘low-risk’ Asian patients with
atrial fibrillation. J Am Coll Cardiol
2014;64(16):1658–65.
94. Chen JY, Zhang AD, Lu HY, Guo J,
Wang FF, Li ZC. CHADS2 versus
CHA2DS2-VASc score in assess-
ing the stroke and thromboembo-
lism risk stratification in patients
with atrial fibrillation: a system-
atic review and meta-­ analysis.
J Geriatr Cardiol 2013;10(3):
258–66.
 M. Yuan et al., Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease
95. Lane DA, Lip GY. Use of the
CHA(2)DS(2)-VASc and HAS-
BLED scores to aid decision making
for thromboprophylaxis in nonval-
vular atrial fibrillation. Circulation
2012;126(7):860–5.
96. Cameli M, Mandoli GE, Loiacono
F, Sparla S, Iardino E, Mondillo
S. Left atrial strain: a useful index
in atrial fibrillation. Int J Cardiol
2016;220:208–13.
97. Tripathi MM, Egawa S, Wirth
AG, Tshikudi DM, Van Cott EM,
Nadkarni SK. Clinical evalua-
tion of whole blood prothrombin
time (PT) and international nor-
malized ratio (INR) using a Laser
Speckle Rheology sensor. Sci Rep
2017;7(1):9169.
98. Wimmer NJ, Scirica BM, Stone
PH. The clinical significance of
continuous ECG (ambulatory
ECG or Holter) monitoring of the
ST-segment to evaluate ischemia:
a review. Prog Cardiovasc Dis
2013;56(2):195–202.
99. Lip GYH, Keshishian AV, Zhang
Y, Kang A, Dhamane AD, Luo
X, et al. Oral anticoagulants for
nonvalvular atrial fibrillation in
patients with high risk of gastro-
intestinal bleeding. JAMA Netw
Open 2021;4(8):e2120064.
100. Boriani G, Laroche C, Diemberger
I, Popescu MI, Rasmussen LH,
Petrescu L, et al. Glomerular fil-
tration rate in patients with atrial
fibrillation and 1-year outcomes.
Sci Rep 2016;6:30271.
101. Pokorney SD, Chertow GM,
Al-Khalidi HR, Gallup D, Dignacco
P, Mussina K, et al. Apixaban for
patients with atrial fibrillation on
hemodialysis: a multicenter rand-
omized controlled trial. Circulation
2022;146(23):1735–45.
102. Chao TF, Lin YJ, Chang SL,
Lo LW, Hu YF, Tuan TC, et al.
R2CHADS2 score and thromboem-
bolic events after catheter ablation
of atrial fibrillation in comparison
with the CHA2DS2-VASc score.
Can J Cardiol 2014;30(4):405–12.
103. Yang Y, Wang Z, Chen Z, Wang X,
Zhang L, Li S, et al. Current status
and etiology of valvular heart dis-
ease in China: a population-based
survey. BMC Cardiovasc Disord
2021;21(1):339.
104. Harky A, Botezatu B, Kakar S, Ren
M, Shirke MM, Pullan M. Mitral
valve diseases: Pathophysiology
and interventions. Prog Cardiovasc
Dis 2021;67:98–104.
105. Otto CM, Nishimura RA, Bonow
RO, Carabello BA, Erwin JP 3rd,
Gentile F, et al. 2020 ACC/AHA
guideline for the management
of patients with valvular heart
disease: executive summary: a
report of the American College
of Cardiology/American Heart
Association Joint Committee
on Clinical Practice Guidelines.
Circulation 2021;143(5):e35–71.
106. Singer DE, Chang Y, Fang MC,
Borowsky LH, Pomernacki NK,
Udaltsova N. Should patient charac-
teristics influence target anticoagu-
lation intensity for stroke prevention
in nonvalvular atrial fibrillation?:
the ATRIA study. Circ Cardiovasc
Qual Outcomes 2009;2(4):
297–304.
107. Natorska J, Mazur P, Undas A.
Increased bleeding risk in patients
19
with aortic valvular stenosis: from
new mechanisms to new therapies.
Thromb Res 2016;139:85–9.
108. Cheng A, Malkin C, Briffa NP.
Antithrombotic therapy after heart
valve intervention: review of
mechanisms, evidence and current
guidance. Heart 2023;110:87–93.
109. Lv J, Zhang B, Ye Y, Li Z, Wang
W, Zhao Q, et al. Assessment of
cardio-renal-hepatic function in
patients with valvular heart dis-
ease: a multi-biomarker approach-
the cardio-renal-hepatic score.
BMC Med 2023;21(1):257.
110. Potter E, Marwick TH. Assessment
of left ventricular function by echo-
cardiography: the case for rou-
tinely adding global longitudinal
strain to ejection fraction. JACC
Cardiovasc Imaging 2018;11(2 Pt
1):260–74.
111. Vinding NE, Butt JH, Lauridsen
MD, Kristensen SL, Johnsen SP,
Krøll J, et al. Long-term incidence
of ischemic stroke after transient
ischemic attack: a nationwide study
from 2014 to 2020. Circulation
2023;148(13):1000–10.
112. Shah N, Madhavan MV, Gray WA,
Brener SJ, Ahmad Y, Lindenfeld
J, et al. Prediction of death or HF
hospitalization in patients with
severe FMR: the COAPT risk
score. JACC Cardiovasc Interv
2022;15(19):1893–905.
113. Cavalcante JL, Lalude OO,
Schoenhagen P, Lerakis S.
Cardiovascular magnetic reso-
nance imaging for structural and
valvular heart disease interven-
tions. JACC Cardiovasc Interv
2016;9(5):399–425.