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REVIEW
Obstructive sleep apnea syndrome: coagulation anomalies
and treatment with continuous positive airway pressure
Domenico Maurizio Toraldo
1
&Michele De Benedetto
2
&
Egeria Scoditti
3
&Francesco De Nuccio
4
Received: 18 March 2015 /Revised: 22 June 2015 / Accepted: 29 June 2015 / Published online: 14 July 2015
#Springer-Verlag Berlin Heidelberg 2015
Abstract
Introduction Obstructive sleep apnea syndrome (OSAS) is a
highly prevalent sleep disorder associated with severe cardio-
vascular events, morbidity and mortality. Recent evidence has
highlighted OSAS as an independent risk factor for an exces-
sive platelet activation and arterial thrombosis, but the under-
lying mechanisms have not yet been determined. Studies in
cell culture and animal models have significantly increased
our understanding of the mechanisms of inflammation in
OSAS. Hypoxia is a critical pathophysiological element that
leads to an intense sympathetic activity, in association with
systemic inflammation, oxidative stress and procoagulant ac-
tivity. While platelet dysfunction and/or hypercoagulability
play an important role in the pathogenesis of vascular disease,
there are limited studies on the potential role of blood viscos-
ity in the development of vascular disease in OSAS.
Conclusion Further studies are required to determine the pre-
cise role of hypercoagulability in the cardiovascular pathogen-
esis of OSAS, particularly its interaction with oxidative stress,
thrombotic tendency and endothelial dysfunction. Nasal con-
tinuous positive airway pressure (nCPAP), the gold standard
treatment for OSAS, not only significantly reduced apnea-
hypopnoea indices but also markers of hypercoagulability,
thus representing a potential mechanisms by which CPAP
reduces the rate of cardiovascular morbidity and mortality in
OSAS patients.
Keywords Obstructive sleep apnea syndrome .
Coagulability .Thromboelastography .Continuous positive
airway pressure .Inflammation
Introduction
Obstructive sleep apnea syndrome (OSAS) is a highly preva-
lent sleep disorder characterized by repeated upper airway
obstruction during sleep, resulting in episodes of reduced
(hypopnoea) or absent (apnea) air flow and consequent
hypoxaemia followed by reoxygenation. OSAS is becoming
an increasingly important public health issue and the most
common form of sleep-disordered breathing worldwide over
the next few years. Given the rapid rise in the incidence of
obesity, one of the most important risk factors for OSAS, the
prevalence of OSAS is expected to increase in the near future.
Common adverse sequelae of OSAS are sleep fragmentation,
excessive daytime sleepiness and impairment of cognitive per-
formance and quality of life [1]. However, the major health
problem in OSAS patients is the increased risk for all-cause
mortality and in particular cardiovascular mortality, and its
independent association with cardiovascular complications,
including hypertension, coronary artery disease, myocardial
infarction, congestive heart failure and stroke [2]. The associ-
ation between atherosclerotic vascular diseases and OSAS
persists after controlling for known cardiovascular risk factors
such as diabetes, hypertension, smoking and dyslipidaemia [3,
4]. Evidence linking OSAS to cardiovascular disorders are
*Francesco De Nuccio
francesco.denuccio@unisalento.it
1
“VFazzi”Hospital Rehabilitation Department, Respiratory Care
Unit, ASL Lecce, Lecce, Italy
2
“V. Fazzi”Hospital, ENT Unit, ASL Lecce, Lecce, Italy
3
National Research Council (CNR), Institute of Clinical Physiology,
Lecce, Italy
4
Laboratory of Human Anatomy and Neuroscience, Department of
Biological and Environmental Sciences and Technologies,
University of Salento, Via Prov. le Lecce-Monteroni (Centro
Ecotekne), 73100 Lecce, Italy
Sleep Breath (2016) 20:457–465
DOI 10.1007/s11325-015-1227-6
provided by a recent cohort study [5] in which an independent
association between apnea-hypopnoea index (AHI) used to
estimate OSAS severity and cardiovascular diseases (heart
attack, stroke, congestive heart failure and all-cause mortality)
has been found, but this association became non-significant
after controlling for potential confounding factors. The re-
searchers have identified other OSAS-related predictors, such
as sleep time spent with SatO
2
less than 90 % (CT
90
), the
number of awakenings and sleep fragmentation or sleep dep-
rivation (arousal), mean heart rate or presence of excessive
diurnal somnolence. All these factors have been significantly
and independently associated with a 5 to 50 % increased risk
of development of composite cardiovascular outcomes. Nasal
continuous positive airway pressure (nCPAP) therapy is the
most effective treatment of OSAS and is also associated with a
significant reduction in cardiovascular events and mortality
after long-term treatment [6]. The pathophysiological mecha-
nisms underlying cardiovascular complications in OSAS are
incompletely understood but seem to be multifactorial and
include sympathetic activation, inflammation and oxidative
stress, leading to endothelial dysfunction and atherosclerosis
development [7–9]. Recently, it has been increasingly clear
from several clinical studies that hypercoagulability may be
a mechanism substantially contributing to the increased car-
diovascular risk in OSAS, especially stroke and myocardial
infarction [10,11]. Increase in blood clotting is determined by
changes in the rheological properties of blood, which is an
important factor associated with cardiovascular events in
OSAS [12]. Data suggest that chronic intermittent hypoxia
(IH) experienced by patients during apnea may be responsible
for a greater sympathetic nervous system activity in associa-
tion with elevation of inflammatory and oxidative stress
markers as well as an increased blood coagulability (e.g. plate-
let activation and decreased fibrinolytic activity), which pre-
disposes patients to thrombotic episodes [13].
The goals of this critical review are (1) providing an anal-
ysis of the updated evidence of an association between OSAS
and haemostatic alterations, and (2) evaluating the effects of
CPAP therapy on coagulation disorders in OSAS.
Mechanisms linking OSAS to coagulopathies: role
of IH-induced inflammation
The recognition that OSAS is associated with the develop-
ment of systemic inflammation [14], oxidative stress [15],
endothelial dysfunction, coagulation disorders [16] and meta-
bolic syndrome [17] has led to a better understanding of car-
diovascular diseases in OSAS. The role of hypercoagulability
in OSAS-related adverse sequelae is a recently emerged open
issue that contributes to the complexity of OSAS in terms of
pathophysiology and treatment strategies (Fig. 1). A major
problem in assessing the association of OSAS with a state of
hypercoagulability is the coexistence of many confounding
factors in OSAS patients, such as obesity, hypertension, dia-
betes mellitus, dyslipidemia and smoking, which are per se
able of altering the haemostatic system. Obesity is associated
with a state of chronic low-grade systemic and tissue inflam-
mation and oxidative stress, which are intimately linked to the
development of insulin resistance, metabolic syndrome and
cardiovascular diseases. In obesity, dysfunctional adipose tis-
sue increases the production of inflammatory adipokines in-
cluding cytokines, chemokines as well as prothrombotic fac-
tors such as plasminogen activator inhibitor (PAI)-1, while
reduces the levels of vasculoprotective adipokines such as
adiponectin. In concert, these alterations predispose to the
development of atherosclerosis and impaired haemostasis
[18]. Similarly, increased levels of PAI-1 and platelet hyper-
reactivity have been reported in hypertension, diabetes
mellitus, hypercholesterolemia and chronic smoking [19].
The mechanisms for increased coagulability in OSAS have
not yet fully elucidated, but the peculiar form of hypoxia oc-
curring in OSAS, i.e. intermittent hypoxia, is likely to play a
role in inducing an inflammatory milieu that causes endothe-
lial dysfunction, vascular derangement and therefore alters the
coagulation system. While sustained hypoxia leads to the ac-
tivation of the transcription factor hypoxia-inducible factor-1
(HIF-1), resulting in adaptive and protective responses, in cell
culture models of IH as well as in OSAS patients, a preferen-
tial activation of inflammatory pathways regulated by the tran-
scription factor nuclear factor-κB(NF-κB) has been clearly
demonstrated [20]. NF-κB mediates the expression of genes
encoding for inflammatory cytokines, such as interleukin(IL)-
1, IL-6, tumour necrosis factor (TNF)-α, chemokines, includ-
ing IL-8, adhesion molecules, as well as procoagulant factors,
Fig. 1 Schematic illustration suggestive of the central role played by
nocturnal chronic intermittent hypoxia, systemic inflammation and
oxidative stress in OSA, and the development of associated condition of
systemic inflammation and hypercoagulability
458 Sleep Breath (2016) 20:457–465
including PAI-1 and tissue factor pathway inhibitor (TFPI)
[21]. Humoral factors including cytokines may be one of the
factors causing platelet hyperaggregability [22]. Furthermore,
hypoxia has been demonstrated to directly affect platelet func-
tion by increasing platelet reactivity and inducing the expres-
sion of proteins involved in coagulation [23]. In hypoxic en-
dothelial cells, the production of TF is increased while that of
thrombomodulin, a cofactor in the thrombin-induced activa-
tion of protein C in the anticoagulant pathway, is suppressed,
thus unbalancing the haemostatic system [24]. Interestingly,
human adipocytes exposed to IH have been shown to specif-
ically upregulate NF-κB-dependent expression and produc-
tion of inflammatory adipokines, to a greater extent compared
with endothelial cells, thus underscoring the important contri-
bution of adipose tissue in the inflammatory and related
procoagulant milieu observed in OSAS [25]. The sympathetic
hyperreactivity associated with OSAS and the resulting ele-
vated circulating catecholamines may also cause platelet ag-
gregation [26], thus aggravating the propensity of an athero-
sclerotic plaque to rupture precipitating thrombotic events.
Analysis of hypercoagulability in OSAS
and influence of CPAP therapy on coagulability
and vascular damage
The nature of hypercoagulability observed in OSAS is
complex and multifactorial. The system of blood clotting
is one of the pathophysiological mechanisms of athero-
thrombosis and cardiovascular damage [27]. Fibrinogen
and factor VII clotting activity (FVIIc) are independent risk
factors for cardiovascular disorder [10]. These factors are
predictors of fatal cardiovascular events and are correlated
with serum cholesterol, triglyceride concentration and body
mass index [28]. Increased levels of circulating activated
clotting factors are reported in untreated OSAS patients
[29], and CPAP treatment, the gold standard treatment for
OSAS, has resulted in an improvement of coagulation pa-
rameters (Table 1). Two studies have shown an increase in
blood level of D-dimer in untreated OSAS patients [40,41]
that is correlated with the severity of nocturnal hypoxemia,
suggesting that this is potentially involved in cardiovascu-
lar risk in patients with OSAS.
Other researches have shown (a) an increase in blood vis-
cosity in adults with untreated OSAS [42], (b) an increase in
the level of fibrinogen in both adults and children with sleep-
disordered breathing [43]and(c)anincreaseinmeanplatelet
volume, an indicator of platelet activation and aggregation,
which was reduced after treatment with CPAP therapy [30,
44]. Most studies have shown elevated individual components
of the haemostatic system in patients with OSAS, including
enhanced platelet activation and increased plasma levels of
TFPI, von Willebrand factor (vWF) and PAI-1 [31,45].
Whole blood coagulability
Unlike other standard clotting tests, measuring individual as-
pect of haemostasis such as prothrombin time (PT), partial
thromboplastin time (APTT), platelet aggregation or fibrinogen
level, the thromboelastography (TEG) is a method providing
detailed information of the entire haemostatic process, starting
from the initial stages of the fibrin formation, platelet count and
function, to clot lysis (fibrinolysis). Two recent human studies
have used TEG to assess coagulability in patients with OSAS
[35,46]. Guardiola et al. [46] evaluated only the latency of clot
formation (R time, time to initiate clotting) and found a signif-
icant association between OSAS and hypercoagulability (short-
ened R time). However, healthy subjects were included as con-
trols, thus not controlling for comorbidities of OSAS, such as
obesity, arterial hypertension and metabolic syndrome, as po-
tential confounding factors that may affect haemostasis.
A more recent prospective crossover study [35]usedall
TEG parameters in assessing hypercoagulability in patients
with severe OSAS. Twelve patients were randomized to either
CPAP or no-CPAP for 2 weeks, a 1-week washout period, and
then the other testing period for 2 weeks. The study demon-
strated that severe OSAS was associated with global hyperco-
agulability, and CPAP significantly reduced AHI index, clot
strength and clotting index.
Haematocrit
Some studies have demonstrated that patients with OSAS de-
velop an increased erythropoietin level and that the
haematocrit level is positively correlated with the severity of
OSAS [47–49]. An increase in haematocrit may predispose
patients to an increased tendency to thrombus formation, but
the mechanisms are still unclear. The reduction in haematocrit
is related to an improvement in cardiovascular outcomes of
OSAS. Treatment with CPAP therapy in the short term (one
night to 3 months) and long term(1 year) improves the level of
haematocrit and polyglobulia [36,50,51].
Blood viscosity
Blood viscosity is defined as the internal resistance of the blood
to shear forces. Blood viscosity is determined by plasma viscos-
ity, haematocrit (volume fraction of erythrocytes, which consti-
tute 99.9 % of the cellular elements) and the mechanical behav-
iour of erythrocytes [52]. OSAS patients, not treated with CPAP,
demonstrate an increase in blood viscosity, which could result in
a slowdown of the blood flow, stasis, clot formation and vessel
occlusion [53,54]. Some authors [55] demonstrated that noctur-
nal desaturation is correlated with the increased diurnal blood
viscosity in untreated OSAS patients. The cause of this increase
Sleep Breath (2016) 20:457–465 459
can be explained by chronic IH that increases the activity of
fibrinogen with increased plasma viscosity and also by the de-
formation and aggregation of erythrocytes and platelet activation.
A short study [38] analysed rheological measurements (e.g.
blood viscosity, plasma viscosity, erythrocyte elongation and
erythrocyte deformability) in patients with OSAS, before and
after five nights of CPAP therapy, as compared with a well-
matched control group. The study showed that five consecu-
tive nights of CPAP therapy improved blood rheological prop-
erties. Increased blood clotting, caused by modifications in the
rheological characteristics of blood and plasma, seems to be
an important factor linking OSAS and cardiovascular disorder
[42]. Many studies on OSAS and cardiovascular risk factors
have been published, but few studies have assessed the role of
blood and the influence of OSAS onthe rheological properties
on the blood coagulation [56], and hyper-viscosity is a poten-
tial mechanism for increased coagulability [57,58].
Fibrinolysis
PAI-1, a member of the serine protease inhibitor family, is an
important component of the coagulation system that
downregulates fibrinolysis. It has been demonstrated that
low level of oxygen desaturation was associated with a higher
concentration of circulating PAI-1 in a group of OSAS pa-
tients [29]. Increased concentrations of PAI-1 predict the oc-
currence of acute myocardial infarction in men and women
with a high prevalence of coronary heart disease [59].
Recently, one study [60] has demonstrated increased pulmo-
nary artery hypertension (PAH) in OSAS patients, which
could be correlated with a genotypic heterogeneity with PAI-
1 5G/5G polymorphism, possibly in relation to the severity of
nocturnal hypoxaemia and apnea index. This study showed
that vascular remodelling of the pulmonary artery may be
related to a genotypic alteration of the PAI 1.
von Willebrand factor
vWF is a glycoprotein that plays an important role in stopping
the escape of blood from vessels (haemostasis) following vas-
cular injury. vWF works by mediating the adherence of plate-
lets to one another and to sites of endothelial damage, and it
prevents factor-VIII degradation. Scientific evidence
Tabl e 1 Summary table
describing effects of
CPAP therapy on
coagulabilityinpatients
with OSAS
Factor Reference
Platelet activity:
•Platelet aggregation: controlled study; 3 months CPAP, improvement of parameters Hui et al. [30]
•Platelet activation: (sCD40L) and (sP-selectin); nonrandomized controlled trial;
8 weeks CPAP
Akinnusi et al. [31]
•Platelet aggregability: nonrandomized controlled trial; one night; reduced
platelet aggregation
Bokinsky et al. [32]
Clotting factors:
•Fibrinogen and FVIIc: randomized controlled trials; 1 month CPAP; improvement
of parameters
Robinson et al. [29]
•VWF, FVIII and FV: randomized crossover trial; CPAP reduced the early morning
level of vWF, and nocturnal levels of FVIII and FV; 2 months CPAP
Phillips et al. [33]
•VWF: double-blind randomized to 2 weeks CPAP; decreased level von Kanel et al. [34]
Tissue factor
•TF: double-blind randomized to 2 weeks CPAP; no result Von Kanel et al. [34]
•TF: nonrandomized nonequivalence controlled trial; 8 weeks CPAP; decrease level El Solh et al. [61]
Fibrin degradation fragment
•D-Dimer: double-blind randomized to 2 weeks; not significant von Kanel et al. [34]
Thromboelastography
•TEG: crossover study; 2 weeks CPAP; reduced clotting index Toukh et al. [35]
Plasminogen activator inhibitor-1
•PAI-1: randomized controlled study; 2 weeks; decreased level von Kanel et al. [34]
Haematocrit
•Hct: uncontrolled intervention study; 3 months; decreased level Saarelainen et al. [36]
•Hct and blood viscosity: case–control study; no effects. Reinhart et al. [37]
•Blood viscosity: short stud; improved blood rheological properties Tazbirek et al. [38]
•Vascular function: randomized, double-blind, placebo-controlled, crossover
trial; 6 weeks CPAP; improved vascular function
Cross et al. [39]
460 Sleep Breath (2016) 20:457–465
regarding the relationship between OSAS and vWF highlights
an increase in vWF levels in OSAS patients [61].
Coagulation factors
Coagulation factors including XIIa (FXIIa) and VIIa (FVIIa)
and thrombin play a key role in the cascade coagulation. Rises
in the FXIIa, FVIIa, thrombin and antithrombin (TAT) have
been shown in patients with OSAS [62]. TAT is a marker of
thrombin turnover and indicates a tendency to blood clotting
disorders [63]. Moreover, TAT is increased in patients with
severe nocturnal desaturation and FVIIa has been found to
decrease in 30 % of patients who practiced CPAP therapy
[64]. Both FVIIa and FXIIa have been associated with in-
creased mortality from cardiovascular disorders [65,66], thus
suggesting another potential mechanisms predisposing OSAS
patients to cardiovascular events.
Platelet function
Elevated levels of soluble CD40 ligand (sCD40L) and soluble
P-selectin (sP-selectin), two markers of platelet activation,
have been shown in OSAS patients, in correlation with noc-
turnal oxygen desaturation, and were reduced by CPAP ther-
apy [31]. CD40L and sP-selectin appear in plasma during the
early stage of blood coagulation and are well-known indica-
tors of thrombogenic conditions, such as disseminated intra-
vascular coagulation (DIC) [67]. Furthermore, levels of both
sCD40L and sP-selectin are increased in patients with hyper-
tension, hyperlipidemia and diabetes mellitus. In acute myo-
cardial infarction (AMI), platelets play a key role in thrombot-
ic processes that limit the patency of the recanalized, infarct-
related coronary artery.
Although not consistently [37,68], some studies have doc-
umented platelet function abnormalities in OSAS patients
where a close association between platelet activation and se-
verity of OSAS has been shown [32,69]. Furthermore, plate-
let aggregation is correlated with the severity of vascular dam-
age [11,70]. One study [30] demonstrated that platelet aggre-
gation is reduced after 3 months’treatment with CPAP com-
pared with a control group. Another study [71] has shown that
positive effects of CPAP therapy on platelet aggregation were
seen only after 3 months of treatment, but not after 1 month.
Tissue factor pathway inhibitor
TFPI is a protein that initiates the extrinsic coagulation path-
way [72], exerting a direct thrombotic action in close relation
to cardiovascular disorder. Although TFPI serum levels have
been reported to be increased in patients with OSAS [73],
TFPI elevation does not correlate with the severity of OSAS
and no definitive evidence on the effect of CPAP treatment on
TFPI has been produced [34]. The chronic intermittent hyp-
oxia induces the production of TFPI via the activation of tran-
scription factor early growth factor 1 [74–76], but available
data do not support TFPI as a pathophysiological mechanism
linking OSAS and cardiovascular disorder. Recently, a role for
TFPI in signal transduction, tumour metastasis, growth,
wound-healing and angiogenesis has been reported [77].
Circadian rhythm of coagulation factors and effect
of CPAP
Long-term treatment of severe OSAS has been correlated with
a decrease of cardiovascular morbidity and mortality. The
mechanisms responsible for the reduction of cardiovascular
risk with CPAP treatment are thought to include direct im-
provements in endothelial function, and vascular inflammato-
ry markers, that also contribute to improved outcomes [16,
39]. However, some studies have documented a temporal
alignment between increased coagulability and frequency of
cardiac events in OSAS, further supporting that CPAP-
mediated reduction of cardiovascular risk may also occur
through an improvement in the coagulation system.
Haus et al. [78] have studied coagulation markers over 24 h
and have found a diurnal biorhythm that shows an increase in
coagulability in the early morning, when a peak in the tempo-
ral occurrence of cardiovascular events such as myocardial
infarction, stroke and sudden cardiac death has been reported
in the general population [79]. Of note, in OSAS patients, the
frequency of cardiac events is higher during sleep.
Accordingly, platelet aggregation and increased activation
overnight have been reported in patients with OSAS com-
pared to the period before the sleep, with significant decreases
after CPAP therapy [32].
A randomized, placebo-controlled crossover trial has dem-
onstrated that treatment of OSAS with 2-month CPAP therapy
reduced the early morning level of vWF and the nocturnal
levels of FVIII and FV [33]. These data suggest that CPAP
may reduce cardiovascular events in OSAS, partly through
reducing risk of nocturnal thrombosis. Treatment with CPAP
acts during night hours when procoagulant factors are activat-
ed. In addition, the study revealed diurnal variations in many
coagulation markers.
In contrast, another study included 51 OSAS patients and
24 non-OSAS controls, and investigated day/night rhythm of
several prothrombotic markers and their potential changes
with therapeutic CPAP [80]. The authors have demonstrated
a day/night biorhythm for some prothrombotic factors in
OSAS patients compared with controls, but treatment with
CPAP therapy for 3 weeks did not influence day/night rhythm
Sleep Breath (2016) 20:457–465 461
of prothrombotic markers in patients with OSAS compared to
the placebo-CPAP.
Association between obesity, OSAS
and hypercoagulability
The obesity epidemic is an alarming worldwide public health
problem [81]. Obesity predicts various health outcomes such
as diabetes, cardiovascular and metabolic diseases, and mor-
tality [82]. In obese patients, the white adipose tissue becomes
hypoxic and dysfunctional leading to a chronic inflammatory
state and to dysregulation of the endocrine and paracrine ac-
tions of adipocyte-derived factors. In particular, it may play a
role in the obesity-associated prothrombotic and
hypofibrinolytic state as it increases the production of pro-
inflammatory and procoagulant factors, and can induce plate-
let activation and coagulation cascade, that could lead to in-
creased formation of thrombus and insoluble fibrin deposition.
Several mechanisms, such as systemic inflammation and ox-
idative stress, endothelial dysfunction, disturbances of lipid
metabolism and insulin resistance, also contribute to the hy-
percoagulable state in obesity [83]. Obesity has been reported
as a risk factor for OSA [84], with between 60 and 90 % of
OSAS patients being obese [85]. Gaining in weight worsens
the severity of OSA, while a drastic weight reduction through
diet or surgical interventions improves it [86]. It has been
recently demonstrated that obesity may contribute to the path-
ogenesis of OSA through to pharyngeal collapse in patients
without responsiveness of upper airway dilator muscle [87].
On the other hand, OSAS may contribute to obesity through
increased sympathetic activation, sleep deprivation, nocturnal
intermittent hypoxia and disrupted metabolism [88].
Furthermore, OSA may be related to changes in leptin, ghrelin
and orexin levels, and thus may increase individuals’appetite
and caloric intake, which exacerbate obesity [89].
Two small longitudinal studies found a no statistically sig-
nificant correlation between change in OSA and changes in
BMI [90,91], whereas several more recent epidemiologic
studies have demonstrated significant correlations between
OSA and general and abdominal obesity [84,92,93]
As discussed above, both obesity and OSA are accompa-
nied by important changes in the haemostatic system and by
endothelial dysfunction, inflammation and oxidative stress
that may mutually and synergistically favour the development
of thrombosis [94]. This has led to the recognition of obesity
as a major confounding factor in the relationship between
OSAS and hypercoagulability. Results from clinical studies
are mixed with regard to the impact of adiposity, with some
studies demonstrating an independent association between
OSA and hypercoagulability [68], and others showing that
the relationship between OSA and hypercoagulability was
attenuated after controlling for BMI [95]. It can be
hypothesized that adiposity represents a major contributing
factor in specific derangements of the haemostatic system,
but the influence of OSA-dependent mechanism(s) cannot
be ruled out and deserves further evaluation. Well-designed
longitudinal and interventional studies that take confounding
variables, mostly obesity, into account are therefore needed to
demonstrate an independent causal link between OSA and
coagulation anomalies, to investigate underlying mechanisms
and to address whether they may be improved by CPAP
therapy.
Conclusion and future directions
Epidemiological studies have demonstrated that OSAS is as-
sociated with coagulation anomalies that may contribute to
increased cardiovascular risk in patients with OSAS. Several
pathophysiological mechanisms are involved in the hyperco-
agulable state associated with OSAS, with important contri-
butions of IH-driven inflammation and obesity. Although
CPAP therapy has been demonstrated to play a beneficial role
in the coagulation disorders as well as in the vascular derange-
ments in OSAS, the available data suggest that future longi-
tudinal studies are needed to determine the relationship be-
tween OSAS severity and hypercoagulability, and the role of
anti-coagulants in patients with poor adherence to CPAP. In
addition, future trials are warranted to explore the mechanisms
that control diurnal/night variation in haemostatic balance and
if these variation is improved by long-term CPAP treatment.
Definitive evidence that reducing hypercoagulability in OSAS
may translate into reduced cardiovascular events is lacking,
and therefore would require conformation in prospective ran-
domized longitudinal studies
Conflict of interest All authors certify that they have no affiliations
with or involvement in any organization or entity with any financial
interest or non-financial interest in the subject matter or materials
discussed in this manuscript.
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