article 7.pdf about pneumonia nad vascualr

REVIEW ARTICLE
Pneumonia, thrombosis and vascular disease
F. VIOLI, R. CANGEMI and C. CALVIERI
Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
To cite this article: Violi F, Cangemi R, Calvieri C. Pneumonia, thrombosis and vascular disease. J Thromb Haemost 2014; 12: 1391–400.
Summary. An enhanced risk of cardiovascular mortality
has been observed after pneumonia. Epidemiological
studies have shown that respiratory tract infections are
associated with an increased risk of thrombotic-related
vascular disease such as myocardial infarction, ischemic
stroke and venous thrombosis. Myocardial infarction and
stroke have been detected essentially in the early phase of
the disease (i.e. within 48 h from hospital admission),
with an incidence ranging from as low as 1% to as high
as 11%. Age, previous cardiovascular events and high
pneumonia severity index were independent predictors of
myocardial infarction; clinical predictors of stroke were
not identified. Deep venous thrombosis and pulmonary
embolism may also occur after pneumonia but incidence
and clinical predictors must be defined. The biological
plausibility of such an association may be deduced by
experimental and clinical studies, showing that lung infec-
tion is complicated by platelet aggregation and clotting
system activation, as documented by up-regulation of tis-
sue factor and down-regulation of activated protein C.
The effect of antithrombotic drugs has been examined in
experimental and clinical studies but results are still
inconclusive.
Keywords: blood coagulation; cardiovascular diseases;
platelet activation; pneumonia; thrombosis.
Introduction
Community-acquired pneumonia (CAP) is the most com-
mon infection leading to hospitalization in intensive care
units and the most common cause of death associated
with infective diseases in developed countries [1]. At the
global level, lower respiratory tract infections, including
pneumonia, are the fourth most common cause of death
[2]. Age and co-morbidities greatly increase the risk of
death: in Europe approximately 90% of deaths due to
pneumonia occur in people aged > 65 years [1].
Epidemiological studies have shown that respiratory
tract infections are associated with an increased risk of
vascular disease, including artery and venous thrombosis.
Among artery thrombosis, the acute phase of pneumonia
is complicated by myocardial infarction [3] and ischemic
stroke [4–8]; there are also other cardiac complications
possibly not strictly related to vascular disease, such as
heart failure and atrial fibrillation [6]. This link is further
supported by studies indicating that influenza vaccination
is associated with a reduced risk of hospitalization for
pneumonia as well as heart disease, cerebrovascular
disease and the risk of death from all causes during the
influenza season in the elderly [9].
In addition to artery thrombosis, patients with pneumo-
nia may experience venous thrombosis and pulmonary
embolism, further reinforcing the concept that pneumonia
is associated with activation of the clotting system [10–13].
Systemic coagulation abnormalities, including clotting
activation and inhibition of anticoagulant factors, have
been observed not only in sepsis but also in pneumonia
[14–16]. Furthermore, sepsis is known to be associated
with thrombocytopenia. Functional studies demonstrated
that infections or bacteria-derived lipopolysaccharide may
mediate platelet activation and eventually favor throm-
botic events complicating the clinical course of pneumo-
nia [17,18].
Prospective and retrospective studies that estimated the
association between community-acquired pneumonia and
risk of vascular diseases, including major arterial and
venous thrombosis, were examined along with experimen-
tal and clinical studies, which investigated clotting
changes occurring after pneumonia and the effect of anti-
thrombotic drugs.
The aims of this review are to analyze the incidence of
thrombotic-related vascular disease, give insight into the
mechanism(s) potentially accounting for artery and
venous thrombosis in patients with pneumonia and dis-
cuss a potentially useful therapeutic approach to lower
pneumonia-related thrombotic complications.
Correspondence: Francesco Violi, I Clinica Medica, Sapienza
University of Rome, Viale del Policlinico 155, Roma 00161, Italy.
Tel.: +39 64461933; fax: +39 649970103.
E-mail: francesco.violi@uniroma1.it
Received 1 April 2014
Manuscript handled by: F. R. Rosendaal
Final decision: F. R. Rosendaal, 16 June 2014
© 2014 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis, 12: 1391–1400 DOI: 10.1111/jth.12646

Thrombosis and pneumonia
Search strategy
We searched the PubMed database without language
restriction for studies in human patients published before
March 2014, with a combination of text words and Medi-
cal Subject Headings, including ‘pneumonia’, ‘community-
acquired pneumonia’, ‘myocardial infarction’, ‘stroke’,
‘cardiovascular mortality’, ‘deep venous thrombosis’ and
‘pulmonary embolism’. Any disagreement was resolved by
additional review until a consensus was reached between
the authors.
We included all clinical studies that estimated the inci-
dence of vascular diseases, including major arterial and
venous thrombosis, as outcomes in patients who experi-
enced community-acquired pneumonia. In particular,
myocardial infarction, stroke and cardiovascular mortal-
ity were considered outcomes for arterial thrombosis
events; deep venous thrombosis and pulmonary embolism
were considered outcomes for venous thrombosis events.
We excluded studies in which pneumonia followed a
vascular disease OR studies without a clear time-relation-
ship between pneumonia and vascular events OR studies
that did not involve CAP patients by design (i.e. involv-
ing only chronic obstructive pulmonary disease or hospi-
tal-acquired pneumonia patients), OR case reports and
studies that included < 100 patients. The screening of
potentially eligible studies was carried out through three
sequential steps (Fig. 1).
Arterial thrombosis and pneumonia
Data connecting acute respiratory tract infections and
arterial thrombosis events mainly stem from case‒control
or retrospective cohort studies (Table 1).
Three large studies overall recruited 33 563 patients
with a first-time diagnosis of acute myocardial infarction
(AMI) and 28 271 patients with a first diagnosis of stroke
to analyze a possible link between these events and a pre-
vious infectious disease [4,5,19]. Meier et al. [19] com-
pared 1922 patients who experienced AMI with 7649
matched controls, finding a relative risk of 2.7 for AMI
in relation to an acute respiratory-tract infection in the
10 days before. Smeeth et al. [4] analyzed retrospectively
20 486 patients with AMI and 19 063 patients with stroke
who had an inflammatory exposure (i.e. acute infection
or vaccination) in the previous 91 days; they found that
the risk of both events was substantially higher after a
diagnosis of systemic respiratory-tract infection with an
incidence peak in the first 3 days. More recently, Clayton
et al. [5] performed a case–control study, finding strong
evidence of an increased risk of MI and stroke in the
7 days following an acute respiratory-tract infection.
Other studies examined patients with pneumonia to
explore the incidence of acute cardiac events during a
short-term follow-up. Most of them were retrospective
cohort studies; globally considered they showed an inci-
dence of myocardial infarction ranging between 1.5% and
10.7%, which occurred mostly during the hospital stay
[6,20–23]. Very few cohort studies prospectively analyzed
patients with pneumonia with the aim of evaluating the
incidence of cardiovascular events. Some of these ana-
lyzed the long-term mortality of patients with pneumonia
after discharge from hospital, reporting an increased risk
of cardiovascular mortality ranging from 1.2% at 90 days
to 8% after 7 years [24–26]. Only recently, prospective
studies examined the occurrence of fatal and non-fatal
cardiovascular events in the acute phase of pneumonia. A
multicenter cohort study [27] analyzed 2287 patients,
divided into 1343 inpatients and 944 outpatients, and
found an overall incidence of cardiac complications in
26.7% and 2.1%, respectively; on average, 3.1% of inpa-
tients with pneumonia suffered from myocardial infarc-
tion. These complications occurred more frequently
within the first 7 days after presentation, with > 50% on
the first day of hospitalization; patients with higher dis-
ease severity, as assessed by the Pneumonia Severity
Index score [28], and a history of cardiovascular diseases
were at higher risk of suffering from cardiac events.
Another large prospective cohort study [29] confirmed
these findings: of 3921 patients with CAP, 8% had one
or more acute cardiac events during hospitalization
(including new-onset or worsening cardiac arrhythmias,
new-onset or worsening congestive heart failure and myo-
cardial infarction). Factors associated with these events
were age > 65 years, chronic heart disease, chronic kidney
disease, tachycardia, septic shock, multilobar pneumonia,
hypoalbuminemia and pneumococcal pneumonia. Finally,
a very recent prospective study, [30] which examined high
sensitivity T troponins (hs-cTnT) every 12 h after hospi-
talization in 248 consecutive patients with community-
acquired pneumonia, reported more than 50% of patients
with pneumonia having hs-cTnT elevation, which was iso-
lated or associated with signs of myocardial infarction in
about 12% of cases. Of note, most of the patients who
experienced myocardial infarction did not have chest pain
[30]. Age, CAP severity and a history of cardiovascular
disease were consistently associated with an increased risk
of cardiovascular events [27,29,30].
A few cohort studies prospectively evaluated the associ-
ation between pneumonia and risk of ischemic stroke.
Using data from a nationwide database in Taiwan, the
National Health Insurance Research Database, 1094
patients with mycoplasma pneumonia were compared
with 5168 sex-, age- and comorbidity-matched subjects
without pneumonia. During an average follow-up period
of 2.13 years, the incidence of stroke among pneumonia
patients was higher than in controls (1.1% vs. 0.7%,
P = 0.01) and pneumonia was shown to be an indepen-
dent risk factor for stroke [7]. More recently, using the
same national database, 745 patients hospitalized for
1392 F. Violi et al
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pneumococcal pneumonia were compared with a random
sample of control individuals (n = 1490) and followed-up
for 2 years. The risk of stroke was 3.65 times higher
(P < 0.001) in patients with pneumococcal pneumonia
after adjusting for patient characteristics and co-morbidi-
ties, with an overall incidence of 10.7% (vs. 4.9% among
control subjects) [8].
Venous thrombosis and pneumonia
A few epidemiological population-based studies investi-
gated the association of infection with venous thrombo-
embolism (VTE) (Table 2). Most of the analyzed patients
experienced VTE in relation to the presence of pneumo-
nia in the previous weeks.
In 2006 Smeeth et al. [10] used data from the UK’s
Health Improvement Network database to study the risk
of deep vein thrombosis (DVT) and pulmonary embolism
(PE) after acute infections. A cohort of patients with a
first-time diagnosis of DVT (n = 7278) or PE (n = 3755)
was retrospectively analyzed. They found that the risk of
DVT, but not PE, was significantly raised up to 6 months
following a respiratory infection and was higher in the
first 2 weeks.
In a case–control study, comparing 11 557 patients
with a first-time diagnosis of DVT or PE with similar
numbers of matched controls, Clayton et al. [12] showed
evidence of an increased risk of DVT and PE in the
3 months following respiratory infections.
These results were recently confirmed by another popu-
lation-based case–control study (MEGA study) [13]
including patients with DVT and/or PE and age- and
sex-matched controls. In the year before the thrombotic
event, pneumonia was present in 7.2% of patients and in
1.5% of controls. Participants with prior pneumonia
were almost four times more likely to have venous
thrombosis (odds ratio, 3.8; 95% CI, 2.9–5.1) than those
without pneumonia, after adjusting for age, sex, classical
risk factors for venous thrombosis, lifestyle and immobi-
lization.
1761 PubMed articles
1055 articles screened for initial
evaluation
706 articles were excluded because
case reports OR review OR meta-analysis.
929 articles did not meet inclusion
criteria based on title and abstract
reveiw
105 studies in which pneumonia
followed a vascular disease OR studies
without a clear time-relationship
between pneumonia and vascular
events OR studies including less than
100 patients OR studies that did not
involve CAP patients by design
126 articles screened for more
detailed evaluation
21 studies finally included in the
reveiw.
17 clinical studies about “arterial
thrombosis and pneumonia”
4 clinical studies about “venous
thrombosis and pneumonia”
Fig. 1. Flow diagram for inclusion and exclusion of studies.
Pneumonia, thrombosis and vascular disease 1393
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Table 1 Arterial thrombosis and pneumonia: evidence from clinical studies
Clinical study Study design
Population
studied N
Sex
(male %) Follow-up Endpoints and results
Meier et al.
(1998) [19]
Case–control
study
AMI 1922 75 Respiratory tract infection
increased risk of AMI
during the first 10 days
(OR 2.7; 95% CI 1.6–4.7)
Controls 7649 75
Smeeth et al.
(2004) [4]
Retrospective
cohort study
AMI 20 486 59.1 Respiratory tract infection
increased risk of AMI
(OR, 4.95; 95% CI,
4.43–5.53) and stroke
(OR, 3.19; 95% CI,
2.81–3.62) during the
first 3 days
Stroke 19 063 68.1
Musher et al.
(2007) [20]
Retrospective
cohort study
Pneumococcal
CAP
170 – Intra-hospital
stay
AMI: 7.1%
Arrhythmias: 4.7%
HF: 7.6%
Becker et al.
(2007) [21]
Retrospective
cohort study
CAP 391 50 Intra-hospital
stay
AMI: 7.9%
Arrhythmias: 2.8%
HF: 12.3%
Ramirez et al.
(2008) [22]
Retrospective
cohort study
stay
AMI: 5.8%
Clayton et al.
(2008) [5]
Case–control
study
AMI 11 155 61 Increased risk of AMI
(OR, 2.10) and stroke
(OR, 1.92) in the 7 days
following CAP
Stroke 9208 45
Controls
(AMI)
11 155 61
Controls
(stroke)
9208 45
Corrales-Medina
et al. (2009)
[23]
Retrospective
cohort study
CAP 206 – 15 days AMI: 10.7%
Perry et al.
(2011) [71]
Retrospective
cohort study
CAP 50 119 98 90 days AMI: 1.5%
Arrhythmias: 9.5%
HF: 10.2%
Mandal et al.
(2011) [6]
Retrospective
cohort study
stay
AMI: 5%
Atrial fibrillation: 9.3%
Stroke: 2.2%
Mortensen et al.
(2002) [24]
Prospective
cohort study
CAP 2287 (1343 inpatients
944 outpatients)
50 90 days Cardiovascular mortality:
1.2%
Yende et al.
(2008) [25]
Prospective
cohort study
CAP 1799 51.8 1 year Cardiovascular mortality:
5%
Bruns et al.
(2011) [26]
Prospective
cohort study
CAP 356 37 7 years Cardiovascular mortality:
8%
Corrales-Medina
et al. (2012)
[27]
Prospective
cohort study
CAP 2287
(1343 inpatients
944 outpatients)
50 30 days Inpatients
AMI: 3.1%
Arrhythmias: 10.2%
HF 20.8%
Outpatients
AMI: 0.1%
Arrhythmias: 1.0%
HF: 1.4%
Viasus et al.
(2013) [29]
Prospective
cohort study
stay
Arrhythmias: 5%
HF: 3%
AMI: 0.8%
Cangemi et al.
(2013) [30]
Prospective
cohort study
stay
AMI 11.6%
Chiang et al.
(2011) [7]
Prospective
cohort study
Mycoplasma –
CAP
1094 42.5 2.13 years Stroke: 1.1% (CAP)
Controls 5168 42.5 Stroke: 0.7% (controls)
Chen et al.
(2012) [8]
Prospective
cohort study
Pneumococcal-
CAP
745 67 2 years
follow-up
Stroke: 10.7% (CAP)
Controls 1490 67 Stroke: 4.9% (controls)
AMI, acute myocardial infarction; CAP, community-acquired pneumonia; CI, confidence interval; HF, heart failure; OR, odds ratio.
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Finally, Gangireddy et al. [11] retrospectively analyzed
the data of 75 771 surgical patients presenting to the Veter-
ans Health Administration Hospitals in the USA between
1996 and 2001 to evaluate perioperative demographic and
clinical variables associated with occurrence of postopera-
tive symptomatic VTE. In this large cohort of surgical
patients, the overall incidence of symptomatic VTE was low
(0.68%), but it was associated with increased mortality at
30 days. Patients who had postoperative complications of
an infectious nature, and in particular pneumonia, showed
an increased risk of developing a VTE (OR, 2.7; 95% CI,
2.1–3.5).
Together these data pointed to an association between
pneumonia and venous thrombosis but the real estimation
of its incidence cannot be drawn at the moment because
prospective studies are still lacking. Furthermore, it is
unclear if pneumonia per se carries a risk of venous
thrombosis or, as in the case of artery thrombosis, some
peculiar clinical characteristics are associated with an
enhanced risk of venous thrombosis.
Mechanisms of disease
Coagulation activation in pneumonia
Several mechanisms may be hypothesized for explaining
the link between pneumonia and the higher risk of death,
particularly due to acute cardiovascular events. Activation
of the hemostatic system is one of the mechanisms poten-
tially responsible for a prothrombotic state during acute
infection and eventually thrombosis-related vascular dis-
ease [31]. Thus, in a large multicenter cohort of survivors
of CAP hospitalization, the increase of hemostatic mark-
ers, such as thrombin-antithrombin complexes (TAT) and
D-dimer, during pneumonia was associated with 1-year
cardiovascular mortality [31]. There is a growing body of
evidence to suggest that activation of tissuefFactor (TF),
a glycoprotein that coverts the factor X to Xa [32], is a
key step for the activation of the clotting system occur-
ring during infections. In particular, TF is secreted by
alveolar macrophages and alveolar epithelial cells after a
proinflammatory stimulus [33] and may be detected in the
bronco-alveolar lavage (BAL) of patients with pneumonia
[34]. Inhalation of nebulized lipopolysaccharides (LPS) or
bronchial instillation of LPS into lungs induced activation
of coagulation in the bronco-alveolar space [35,36] and,
in particular, an increase of TF-microparticles (MPs) [37].
These findings were corroborated by in vitro experi-
ments where, in response to a proinflammatory stimulus,
alveolar epithelial cells secreted TF-MPs, suggesting a
potential source of TF procoagulant activity in the air
space in acute respiratory distress syndrome [38]. In
accordance with this, inhibition of TF activity prevented
local clotting activation in models of pneumonia. In fact,
in the BAL of patients affected by pneumonia and in
mice with pneumonia induced by intranasal inoculation
of S. pneumoniae, inhibition of TF-FVIIa by subcutane-
ous injection of recombinant nematode anticoagulant pro-
tein (rNAPc2) attenuated the procoagulant response in
the lung [34]. Also, in LPS-injured rats treated with site-
inactivated FVIIa (FFR-FVIIa), a decreased intra-alveo-
lar inflammation and fibrin deposition, as compared with
untreated mice, was demonstrated [39].
Impairment in protein C (PC) system activation may
be another mechanism leading to thrombosis in pneumo-
nia and sepsis [40]. Activated protein C (aPC) exerts anti-
coagulant effects via inactivation of factors Va and VIIIa.
The rate of conversion of the zymogen PC into the active
end-product of the PC system, aPC, is regulated by the
endothelial protein C receptor (EPCR) [41].
Inhibition of endogenous aPC in endotoxemia and sep-
sis results in exacerbation of coagulation and
Table 2 Venous thrombosis and pneumonia. Evidence from clinical studies
Clinical study Study design Population N
Sex
(male %) Follow-up Endpoints and results
Smeeth et al. (2006) [10] Retrospective
cohort study
DVT 7278 41.6 10.2 years Increased risk of DVT in the 2
weeks following a respiratory
tract infection: OR, 1.91
(95% CI, 1.49–2.44)
Gangireddy et al. (2007) [11] Retrospective
cohort study
Postoperative
patients
75 771 96.6 5 years Pneumonia increased DVT risk:
OR, 2.7 (95% CI, 2.1–3.5)
Clayton et al. (2011) [12] Case–control
study
DVT
PE
DVT controls
PE controls
11 557 5162
11 557
5162
42.1
41.6
42.1
41.6
Increased risk of DVT in the month
following infection: OR, 2.64
(95% CI, 1.62–4.29).
Increased risk of PE in the 3
months following infection:
OR, 2.5 (95% CI, 1.33–4.72)
Ribeiro Ribeiro (2012) [13] Case–control
study
DVT PE DVT
Controls
2887
2069
6297
46
46
46
Pneumonia increased VTE risk:
OR, 3.8 (95% CI, 2.9–5.1)
CI, confidence interval; DVT, deep venous thrombosis, OR, odds ratio; PE, pulmonary embolism.
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inflammation, with consequent enhanced lethality [41].
Previous reports in humans showed low PC and aPC lev-
els in patients with sepsis, which were correlated with
severe organ dysfunction, early mortality and adverse
outcomes [42,43]. An experimental study in PC-deficient
mice demonstrated worse outcomes, severe disseminate
intravascular coagulation, increased fibrin deposition and
higher levels of proinflammatory cytokines after LPS
injection [44,45]. In a model of Gram-negative pneumo-
sepsis, caused by Burkholderia (B.) pseudomallei, inhibi-
tion of aPC enhanced coagulation activation [46]. Fur-
thermore, in a murine model of pneumococcal
pneumonia and sepsis, EPCR knock-out mice showed
enhanced activation of coagulation in the early phase of
disease compared with wild-type mice [47].
Platelet activation in pneumonia
A few data are reported on the interplay between platelet
number and activation in human infections. In a retro-
spective cohort study of 500 consecutive CAP patients,
Mirsaeidi et al. [48] demonstrated that an increase of
platelet count was more predictive of clinical outcomes
than abnormalities of leukocyte count in patients with
CAP. In particular, they showed an independent associa-
tion of thrombocytosis with an increased length of stay
and mortality in hospitalized CAP patients. In another
study, Kreutz et al. [49] found increased platelet reactivity
and activation in patients affected by viral upper respira-
tory tract infection compared with healthy control sub-
jects.
In a larger cohort, Modica et al. [50] analyzed platelet
aggregation and aspirin non-responsiveness in 328
patients with an acute coronary syndrome, of whom 66
had an infection during their hospital stay. Platelet aggre-
gation was more pronounced during an infection, mostly
in patients with severe infection, such as pneumonia;
moreover, non-responsiveness to aspirin was more fre-
quent in patients with pneumonia, suggesting that lung
infection could be a trigger for platelet activation. Inflam-
mation markers, such as CRP levels, were independently
associated with platelet aggregation and non-responsive-
ness to aspirin in this setting.
Several mechanisms have been suggested to explain the
interplay between acute infections and platelet activation
[51]. Platelets have been shown to interact with Gram-
negative and Gram-positive bacteria via bacteria binding
to platelets. This occurs either directly through a bacterial
surface protein or indirectly by a plasma-bridging mole-
cule linking bacterial and platelet surface receptors
[52,53]. Different bacteria isolated from patients with
Gram-positive bacteremia have been shown to induce
platelet activation and aggregation, and formation of
platelet-neutrophil complexes [54]. In addition to a direct
interaction between bacteria and platelets, LPS is another
mechanism through which bacteria may activate platelets
[55]. In response to LPS from Gram-negative bacteria,
platelets bind more avidly to fibrinogen under flow condi-
tions via Toll-like receptor-4 (TLR4); this was experimen-
tally evidenced in mice when platelet accumulation in the
lungs did not occur in the case of TLR4 deficiency [56].
However, it remains to be established if LPS is able to
activate platelets in vivo, because experimental studies
provided equivocal results as to whether LPS per se is
able to trigger platelet activation [57]. More recent data,
however, suggested that LPS per se is unable to activate
platelets but it amplifies platelet response to a common
agonist via interaction with TLR4 [18]. Mechanisms of
platelet and clotting activation elicited by bacteria in
pneumonia are summarized in Fig. 2.
Antithrombotic therapy in pneumonia
Anticoagulants
A small amount of data is available about new anticoagu-
lant therapies in pneumonia. The majority of clinical tri-
als were conducted with inhibitors of coagulation, such as
TFPI and recombinant human aPC, to improve the prog-
nosis of infection but the reports are equivocal.
In the PROWESS study [58], drotrecogin alfa, a recom-
binant form of human aPC, was associated with a signifi-
cant benefit for survival when administered to patients
with severe sepsis from CAP reporting also a rate of seri-
ous bleeding of 3.5%. However, a recent meta-analysis
including 25 studies showed a higher rate of serious
bleeding events (5.6%) after administration of drotrecogin
alfa, which were defined as life-threatening bleeding, cere-
bral hemorrhage, or requirement of more than three units
of packed red blood cells on two consecutive days [59].
Instead, the largest clinical trial (CAPTIVATE) on tifaco-
gin, a recombinant human tissue factor pathway inhibi-
tor, showed no benefit for mortality in patients with
severe CAP [60]. Studies using aPC administration
showed attenuation of pulmonary coagulopathy during
bacterial or viral pneumonia [58,61]. These findings were
corroborated by Schouten et al. [62], who reported inhibi-
tion of pulmonary and systemic activation of coagulation
as reflected by lower levels of thrombin-antithrombin
complexes and D-dimer by early treatment with recombi-
nant murine aPC (rm-aPC) in mice with pneumococcal
pneumonia.
The clinical impact of aPC administration has been
tested in humans with sepsis. Thus, infusion of recombi-
nant human aPC improved survival of patients with
severe sepsis due to pneumococcal pneumonia or with
severe sepsis and a high risk of death [58,63].
Antiplatelet treatment
Only a few clinical studies reported the effects of antiplat-
elet drugs, which were investigated to assess their effect
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on clinical outcomes in patients with pneumonia. In a
prospective observational study of 1007 patients admitted
to the hospital with CAP, Chalmers et al. [64] found a
non-significant reduction in 30-day mortality in patients
using low-dose aspirin. Conversely, a small retrospective
study in elderly patients hospitalized for CAP (n = 127)
showed a significant association between the use of anti-
platelet drugs (low-dose aspirin or thienopyridines) and
reduced need for intensive care and shorter hospital stays
[65]. In another retrospective cohort study, CAP patients
receiving clopidogrel prescription showed a trend towards
a reduction in CAP severity and mortality, compared
with patients not receiving clopidogrel [66].
Perspectives and conclusions
The findings herein reported are consistent with an associa-
tion between pneumonia and vascular disease occurring in
both artery and venous circulation. Acute coronary artery
disease such as MI may occur in about 1–11% of patients
in the early phase of acute infections. This wide range in
incidence may depend on several factors, including diag-
nostic approach and concomitant confounding clinical pic-
tures [30]. At the present, however, elderly patients with
severe disease, as assessed by Pneumonia Severity Index
score, and previous cardiovascular disease should be
regarded as at high risk of MI and carefully monitored in
terms of daily ECG and troponin measurements, particu-
larly in the first 48 h after hospitalization [3,30].
A similar wide variation in terms of incidence is
reported for stroke, which may be detected in 1–11% of
patients with pneumonia. However, in contrast to
myocardial infarction, clinical predictors of stroke were
not reported and should be investigated in the future.
As for strokes, the occurrence of deep venous thrombo-
sis is less clinically characterized. Thus, acute venous
thrombosis does not occur far from the acute lung infec-
tion but its occurrence rate, as well as predictors of venous
thrombosis, are still to be defined. This lack of informa-
tion depends essentially on the fact that all the analyses of
the relationship between pneumonia and venous thrombo-
sis stem essentially from retrospective studies, which did
not provide clinical clues to identify patients who are actu-
ally at higher risk of venous thrombosis.
Bacterium
Thrombin
Thrombin
endothelial cell
Mo
TF
TF
LPS
TLR4
PLT
Fxa
FVa
PC
EPCR
aPC
FVIIIa
FVa
Fxa
Thrombus
FVIIIa
Fig. 2. Schematic mechanism of platelet and clotting activation elicited by bacteria in pneumonia. The dotted lines indicate inhibition; the solid
lines indicate activation. TF, tissue factor; LPS, lipopolysaccharides; PC, protein C; aPC, activated protein C; EPCR, endothelial protein C
receptor; MO, monocyte-macrophage; TLR4, Toll-like receptor 4; PLT, platelet.
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The mechanism accounting for the association between
pneumonia and vascular disease cannot be fully eluci-
dated at the moment, but there is experimental and clini-
cal evidence to suggest that clotting and platelet
activation may occur during pneumonia and precipitate
thrombosis in artery and venous circulation. In support
of this, preliminary but still inconclusive experimental
data from animal and clinical studies suggest a potential
usefulness of anticoagulants for the treatment of pneumo-
nia and randomized clinical trials with antithrombotic
drugs are needed to explore their clinical value. In this
context, it is worth noting the potential usefulness of sta-
tins, which possess both anticoagulant and antiplatelet
activities [67], for the treatment of pneumonia. Thus, sta-
tins have been shown to inhibit clotting activation via tis-
sue factor down-regulation and to inhibit platelet
activation via lowering production of thromboxane A2
and isoprostanes [68]. In a recent meta-analysis, statin use
was associated with lower short-term mortality in patients
with CAP [69]. This finding was confirmed in a more
recent study, which included 21 985 patients with pneu-
monia and demonstrated a significant reduction in all-
cause mortality within 90 days from hospital admission
among statin users [70].
In conclusion, pneumonia is frequently complicated by
artery and venous thrombosis, which results in a poor
outcome of the disease. Pneumonia still has a high preva-
lence in the world and is complicated by a high mortality
rate. This may depend not only on lung function deterio-
ration but also on dysfunction of other vital organs,
which may be affected by pneumonia infection. In this
context, thrombotic-related vascular disease, such as acute
myocardial infarction, stroke and venous thrombosis,
should be regarded as a sign of poor prognosis and be
carefully monitored, particularly in the acute phase of the
disease. Prevention of such complications by appropriate
antithrombotic treatment may represent an important
objective for improving clinical outcomes in pneumonia.
Acknowledgements
We thank A. Borello for her valuable help in the graphic
design of the figure.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interests.
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