Mechanisms of atherothrombosis in chronic obstructive pulmonary disease

Figures & data

Figure 1 The COPD-atherothrombosis network.

Table 1 Mechanisms of systemic inflammation in COPD

References	Type of study	Main evidence
^CitationPasceri et al 2000	Basic research	CPR upregulates the production of pro-inflammatory cytokines and tissue factor by monocytes. It increases the uptake of LDL by macrophages with foam cells formation and directly induces expression of adhesion molecules by human endothelial cells.
Sin et al 2003	Population-based	CRP is increased in COPD.
^CitationMan et al 2006	Population-based	CRP is a prognostic factor in COPD.
^CitationJoppa et al 2006	Cross-sectional	Systemic inflammation might be pathogenetically related to pulmonary hypertension complicating COPD.
^CitationGan et al 2004	Meta-analysis	Serum levels of TNF-α, IL 6, IL 8, CRP, and fibrinogen are increased in COPD.

Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; LDL, low-density lipoprotein; TNF-α, tumor necrosis factor-alpha; IL 6, interleukin-6; IL 8, interleukin-8.

Table 2 Mechanisms explaining the procoagulant status which characterizes COPD (see also Table 3)

References	Type of study	Main evidence
^CitationOgawa et al 1990	Basic research	Hypoxia dynamically modulates endothelial function.The ensuing endothelial dysfunction might promote microvascular lesions.
^CitationAlessandri et al 1994, ^CitationAshitani et al 2002 and ^CitationXie et al 1998	Case-control Case-control Case-control	COPD patients have an ongoing prothrombotic state which might explain the high prevalence of thrombosis in pulmonary vessels.
^CitationWedzicha et al 2000	Prospective	Fibrinogen levels, which are basically higher than normal, further raise during COPD exacerbation.
^CitationDanesh et al 1998	Meta-analysis	High levels of serum fibrinogen reliably predicts cardiovascular events in the general population.

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 3 Epidemiological evidence and mechanisms of platelet hyperaggregability in COPD

References	Type of study	Main evidence
^CitationPonicke et al 1987	Basic research	Hypoxia induces metabolic changes on the platelet membrane, leading to increased activation of cyclooxygenase-1 with thromboxane formation.
^CitationDavì et al 1997	Case-control	Thromboxane excretion is increased in COPD, inversely correlates with oxygen tension and is significantly lowered by short-term oxygen supplementation.
^CitationCordova et al 1985; ^CitationWedzicha et al 1991	Case-control	Increased platelet aggregability in hypoxemic COPD patients.

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 4 Potential mechanisms of oxidative stress in COPD

References	Type of study	Main evidence
^CitationDevaraj et al 2001	Basic research	The assay of prostaglandin-like compounds in the urine is a reliable measure of in vivo oxidative stress and represents a marker of LDL oxidation.
^CitationPraticò et al 1998	Case-control	Independently of current smoking, the excretion of F2-isoprostane is increased in COPD and peaks during exacerbations.

Abbreviations: LDL, low-density lipoprotein; COPD, chronic obstructive pulmonary disease.

Table 5 Lipid status and metabolic risk in COPD

References	Type of study	Main evidence
^CitationBasili et al 1999	Case-control	COPD patients and healthy subjects have comparable lipid levels.
^CitationRana et al 2004	Prospective	COPD might be a risk factor for incident type 2 diabetes mellitus.
^CitationFord et al 2004	Prospective	Restrictive, but not obstructive, subjects are at increased risk of developing type 2 diabetes mellitus.
^CitationFimognari et al 2007	Population-based	Metabolic syndrome and insulin-resistance are highly prevalent in nondiabetic subjects with restrictive dysfunction, but not in COPD patients.

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 6 Potential therapies of systemic inflammation in COPD

References	Type of study	Main evidence
^CitationSin et al 2004	Randomized placebo-control	Inhaled corticosteroids reduce plasma CRP levels in stable COPD.
^CitationPinto-Plata et al 2006	Cross-sectional analysis	“Cooling” effect of inhaled corticosteroids on systemic inflammation.
^CitationHuiart et al 2005	Observational	COPD patients taking 50–200 μg/day of inhaled steroids have a 32% fall of the risk of myocardial infarction.
^CitationMacie et al 2006	Observational	Reduction in cardiovascular mortality by 38% accounts for the improved survival associated with chronic use of inhaled steroids.
Sin et al 2005	Pooled analysis from 7 RCT’s	27% mortality decrease in COPD patients taking inhaled corticosteroids.
^CitationLofdahl et al 2005	RCT	40% reduction in the rate of coronary artery disease events after therapy with inhaled budesonide compared with the placebo group.
Cochrane 2005	Meta-analysis	The only evidence-based treatment improving survival is long-term oxygen therapy in hypoxemic patients. To note: Oxygen has antioxidant and anti-inflammatory activity in hypoxemic COPD.

Abbreviations: CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease; RCT, randomized controlled trials.

PasceriVWillersonJTYehETDirect proinflammatory effect of C-reactive protein on human endothelial cellsCirculation20001022165811056086

 PubMed Web of Science ®Google Scholar

ManSFConnettJEAnthonisenNRC-reactive protein and mortality in mild to moderate chronic obstructive pulmonary diseaseThorax2006618495316738034

 PubMed Web of Science ®Google Scholar

JoppaPPetrasovaDStancakBSystemic inflammation in patients with COPD and pulmonary hypertensionChest20061303263316899829

 PubMed Web of Science ®Google Scholar

GanWQManSFSenthilselvanAAssociation between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysisThorax2004595748015223864

 PubMed Web of Science ®Google Scholar

OgawaSShreeniwasRBrettJThe effect of hypoxia on capillary endothelial cell function: modulation of barrier and coagulant functionBr J Haematol199075517242169857

 PubMed Web of Science ®Google Scholar

AlessandriCBasiliSVioliFHypercoagulability state in patients with chronic obstructive pulmonary disease Chronic Obstructive Bronchitis and Haemostasis GroupThromb Haemost19947234367855781

 PubMed Web of Science ®Google Scholar

AshitaniJMukaeHArimuraYElevated plasma procoagulant and fibrinolytic markers in patients with chronic obstructive pulmonary diseaseIntern Med200241181511929177

 PubMed Web of Science ®Google Scholar

XieMWangZPrethrombotic state in patients with chronic obstructive pulmonary disease and treatment with heparinHua Xi Yi Ke Da Xue Xue Bao1998294111410743240

 PubMedGoogle Scholar

WedzichaJASeemungalTAMacCallumPKAcute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levelsThromb Haemost2000842101510959691

 PubMed Web of Science ®Google Scholar

DaneshJCollinsRApplebyPAssociation of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studiesJAMA19982791477829600484

 PubMed Web of Science ®Google Scholar

PonickeKSternitzkyRMestHJStimulation of aggregation and thromboxane A2 formation of human platelets by hypoxiaProstaglandins Leukot Med19872949593478738

 PubMedGoogle Scholar

DavìGBasiliSVieriMEnhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis and Haemostasis Study GroupAm J Respir Crit Care Med1997156179499412557

 PubMed Web of Science ®Google Scholar

CordovaCMuscaAVioliFPlatelet hyperfunction in patients with chronic airways obstructionEur J Respir Dis1985669122579841

 PubMedGoogle Scholar

WedzichaJASyndercombe-CourtTanKCIncreased platelet aggregate formation in patients with chronic airflow obstruction and hypoxaemiaThorax19914650471877038

 PubMed Web of Science ®Google Scholar

DevarajSHiranySVBurkRFDivergence between LDL oxidative susceptibility and urinary F(2)-isoprostanes as measures of oxidative stress in type 2 diabetesClin Chem2001471974911673365

 PubMed Web of Science ®Google Scholar

PraticòDBasiliSVieriMChronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stressAm J Respir Crit Care Med19981581709149847257

 PubMed Web of Science ®Google Scholar

BasiliSFerroniPVieriMLipoprotein(a) serum levels in patients affected by chronic obstructive pulmonary diseaseAtherosclerosis19991472495210559510

 PubMed Web of Science ®Google Scholar

RanaJSMittlemanMASheikhJChronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in womenDiabetes Care20042724788415451919

 PubMed Web of Science ®Google Scholar

FordESManninoDMProspective association between lung function and the incidence of diabetes: findings from the National Health and Nutrition Examination Survey Epidemiologic Follow-up StudyDiabetes Care20042729667015562215

 PubMed Web of Science ®Google Scholar

FimognariFLPasqualettiPMoroLThe association between metabolic syndrome and restrictive ventilatory dysfunction in older personsJ Gerontol A Biol Sci Med2007627605

 PubMed Web of Science ®Google Scholar

SinDDLacyPYorkEEffects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2004170760515229100

 PubMed Web of Science ®Google Scholar

Pinto-PlataVMMullerovaHTosoJFC-reactive protein in patients with COPD, control smokers and non-smokersThorax20066123816143583

 PubMed Web of Science ®Google Scholar

HuiartLErnstPRanouilXLow-dose inhaled corticosteroids and the risk of acute myocardial infarction in COPDEur Respir J200525634915802336

 PubMed Web of Science ®Google Scholar

MacieCWooldrageKManfredaJInhaled corticosteroids and mortality in COPDChest2006130640616963657

 PubMed Web of Science ®Google Scholar

LofdahlCGPostmaDPrideNDoes inhaled budesonide protect against cardio-ischemic events in mild-moderate COPD: a post-hoc evaluation of the EUROSCOP Study [Abstract]European Respiratory Society Conference, Copenhagen 20052005

 Google Scholar